NZ751725B2 - Pyrazolopyridine derivative having glp-1 receptor agonist effect - Google Patents
Pyrazolopyridine derivative having glp-1 receptor agonist effect Download PDFInfo
- Publication number
- NZ751725B2 NZ751725B2 NZ751725A NZ75172517A NZ751725B2 NZ 751725 B2 NZ751725 B2 NZ 751725B2 NZ 751725 A NZ751725 A NZ 751725A NZ 75172517 A NZ75172517 A NZ 75172517A NZ 751725 B2 NZ751725 B2 NZ 751725B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- alkyl
- salt
- independently selected
- optionally substituted
- Prior art date
Links
- 230000000694 effects Effects 0.000 title description 13
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 title description 8
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 title description 8
- 150000005229 pyrazolopyridines Chemical class 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 796
- 150000003839 salts Chemical class 0.000 claims abstract description 120
- 125000001424 substituent group Chemical group 0.000 claims abstract description 73
- 239000012453 solvate Substances 0.000 claims abstract description 57
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 31
- 239000003814 drug Substances 0.000 claims abstract description 21
- 208000008589 Obesity Diseases 0.000 claims abstract description 15
- 235000020824 obesity Nutrition 0.000 claims abstract description 15
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 12
- 239000004480 active ingredient Substances 0.000 claims abstract description 10
- AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical group C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 claims abstract 3
- 125000000217 alkyl group Chemical group 0.000 claims description 221
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 101
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 85
- 125000005843 halogen group Chemical group 0.000 claims description 66
- 125000000623 heterocyclic group Chemical group 0.000 claims description 62
- 125000003545 alkoxy group Chemical group 0.000 claims description 54
- 125000003118 aryl group Chemical group 0.000 claims description 37
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 37
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 33
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 125000004076 pyridyl group Chemical group 0.000 claims description 13
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000004429 atom Chemical group 0.000 claims description 10
- 206010012289 Dementia Diseases 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 201000001421 hyperglycemia Diseases 0.000 claims description 7
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 7
- 208000002249 Diabetes Complications Diseases 0.000 claims description 6
- 206010012655 Diabetic complications Diseases 0.000 claims description 6
- 125000002837 carbocyclic group Chemical group 0.000 claims description 6
- 208000029078 coronary artery disease Diseases 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 claims description 6
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 5
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 5
- 206010020772 Hypertension Diseases 0.000 claims description 5
- 208000018737 Parkinson disease Diseases 0.000 claims description 5
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 5
- 201000008247 brain infarction Diseases 0.000 claims description 5
- 206010008118 cerebral infarction Diseases 0.000 claims description 5
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 5
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 5
- 230000003449 preventive effect Effects 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 11
- ARLZGEXVMUDUQZ-UHFFFAOYSA-N O.O.[Ca] Chemical compound O.O.[Ca] ARLZGEXVMUDUQZ-UHFFFAOYSA-N 0.000 claims 1
- 125000001041 indolyl group Chemical group 0.000 abstract description 112
- 239000000126 substance Substances 0.000 abstract description 87
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 8
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical group C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 abstract 1
- 230000000069 prophylactic effect Effects 0.000 abstract 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 308
- -1 3,3,3- trifluoropropyl Chemical group 0.000 description 307
- 230000014759 maintenance of location Effects 0.000 description 163
- 238000004458 analytical method Methods 0.000 description 160
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 153
- 238000004949 mass spectrometry Methods 0.000 description 144
- 239000003153 chemical reaction reagent Substances 0.000 description 132
- 239000000243 solution Substances 0.000 description 121
- 125000006431 methyl cyclopropyl group Chemical group 0.000 description 118
- 239000000203 mixture Substances 0.000 description 111
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 95
- 239000002904 solvent Substances 0.000 description 93
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 92
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 88
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 81
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 80
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 72
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 67
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- 238000006243 chemical reaction Methods 0.000 description 66
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 64
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 57
- 238000003786 synthesis reaction Methods 0.000 description 56
- 238000000034 method Methods 0.000 description 55
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- 230000015572 biosynthetic process Effects 0.000 description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 46
- 239000002585 base Substances 0.000 description 42
- 230000008569 process Effects 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 37
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 37
- 239000011541 reaction mixture Substances 0.000 description 34
- 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 33
- 235000019253 formic acid Nutrition 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- 239000012044 organic layer Substances 0.000 description 32
- WCXFPLXZZSWROM-UHFFFAOYSA-N 1h-pyrazolo[4,3-c]pyridine Chemical compound C1=NC=C2C=NNC2=C1 WCXFPLXZZSWROM-UHFFFAOYSA-N 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 29
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 29
- 238000000605 extraction Methods 0.000 description 28
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 27
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 26
- 239000007787 solid Substances 0.000 description 26
- 239000007864 aqueous solution Substances 0.000 description 25
- 230000035484 reaction time Effects 0.000 description 25
- 238000010898 silica gel chromatography Methods 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- 229940113088 dimethylacetamide Drugs 0.000 description 24
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 24
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 23
- 229910052757 nitrogen Inorganic materials 0.000 description 22
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 22
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 238000001914 filtration Methods 0.000 description 20
- 238000004519 manufacturing process Methods 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- 239000000725 suspension Substances 0.000 description 20
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 19
- 239000002253 acid Substances 0.000 description 19
- 150000001408 amides Chemical class 0.000 description 19
- 239000004210 ether based solvent Substances 0.000 description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 18
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- 238000001704 evaporation Methods 0.000 description 18
- 230000008020 evaporation Effects 0.000 description 18
- 102100027280 Fanconi anemia group A protein Human genes 0.000 description 17
- 101000914673 Homo sapiens Fanconi anemia group A protein Proteins 0.000 description 17
- 150000002366 halogen compounds Chemical class 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 229960004132 diethyl ether Drugs 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 14
- WZELXJBMMZFDDU-UHFFFAOYSA-N Imidazol-2-one Chemical compound O=C1N=CC=N1 WZELXJBMMZFDDU-UHFFFAOYSA-N 0.000 description 13
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 13
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 13
- 239000012299 nitrogen atmosphere Substances 0.000 description 13
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 13
- 125000006239 protecting group Chemical group 0.000 description 13
- 229940086542 triethylamine Drugs 0.000 description 13
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 12
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 12
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 12
- CCIZZSCISFKVOI-UHFFFAOYSA-N 5-bromo-1-fluoroindazole Chemical compound BrC1=CC=C2N(F)N=CC2=C1 CCIZZSCISFKVOI-UHFFFAOYSA-N 0.000 description 11
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 239000012267 brine Substances 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 description 11
- 229910052751 metal Inorganic materials 0.000 description 11
- 239000002184 metal Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 10
- 239000008103 glucose Substances 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- 235000011181 potassium carbonates Nutrition 0.000 description 10
- 239000012312 sodium hydride Substances 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 10
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 9
- PCJFEVUKVKQSSL-UHFFFAOYSA-N 2h-1,2,4-oxadiazol-5-one Chemical compound O=C1N=CNO1 PCJFEVUKVKQSSL-UHFFFAOYSA-N 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- ZWWNQLZODRDGJJ-UXHICEINSA-N C[C@@](CC1=C2C(C=O)=NN1)(C(C=C1C)=CC(C)=C1F)N[C@@]2(C)N(C=CN1)C1=O Chemical compound C[C@@](CC1=C2C(C=O)=NN1)(C(C=C1C)=CC(C)=C1F)N[C@@]2(C)N(C=CN1)C1=O ZWWNQLZODRDGJJ-UXHICEINSA-N 0.000 description 9
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- 150000004703 alkoxides Chemical class 0.000 description 9
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 9
- WRSXUNSJGJUKHE-UHFFFAOYSA-N indazole Chemical compound C1=CC=C[C]2C=NN=C21 WRSXUNSJGJUKHE-UHFFFAOYSA-N 0.000 description 9
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 9
- 150000003512 tertiary amines Chemical class 0.000 description 9
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 8
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 8
- 235000011054 acetic acid Nutrition 0.000 description 8
- PMZXXNPJQYDFJX-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid Chemical compound CC#N.OC(=O)C(F)(F)F PMZXXNPJQYDFJX-UHFFFAOYSA-N 0.000 description 8
- 239000005456 alcohol based solvent Substances 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 229910052987 metal hydride Inorganic materials 0.000 description 8
- 150000004681 metal hydrides Chemical class 0.000 description 8
- 229940098779 methanesulfonic acid Drugs 0.000 description 8
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 8
- 229910000105 potassium hydride Inorganic materials 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 8
- FRJJJAKBRKABFA-TYFAACHXSA-N (4r,6s)-6-[(e)-2-[6-chloro-4-(4-fluorophenyl)-2-propan-2-ylquinolin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=C(F)C=C1 FRJJJAKBRKABFA-TYFAACHXSA-N 0.000 description 7
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 7
- MMIWVFHURWULQG-UHFFFAOYSA-N CC1=CC(COC(C2=NNC3=C2CNCC3)=O)=CC(C)=C1F Chemical compound CC1=CC(COC(C2=NNC3=C2CNCC3)=O)=CC(C)=C1F MMIWVFHURWULQG-UHFFFAOYSA-N 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 125000004430 oxygen atom Chemical group O* 0.000 description 7
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 6
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- 150000003857 carboxamides Chemical class 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- 239000012973 diazabicyclooctane Substances 0.000 description 6
- 238000002050 diffraction method Methods 0.000 description 6
- 125000001153 fluoro group Chemical group F* 0.000 description 6
- 229930195733 hydrocarbon Natural products 0.000 description 6
- 150000002430 hydrocarbons Chemical class 0.000 description 6
- 125000002883 imidazolyl group Chemical group 0.000 description 6
- 229910017053 inorganic salt Inorganic materials 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- QPDJILZPDAMLFH-UHFFFAOYSA-N lithium;2-methylbutan-2-olate Chemical compound [Li]OC(C)(C)CC QPDJILZPDAMLFH-UHFFFAOYSA-N 0.000 description 6
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 6
- 229910052700 potassium Inorganic materials 0.000 description 6
- 239000011591 potassium Substances 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 235000017550 sodium carbonate Nutrition 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 238000004808 supercritical fluid chromatography Methods 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 5
- HCUARRIEZVDMPT-UHFFFAOYSA-M 1h-indole-2-carboxylate Chemical compound C1=CC=C2NC(C(=O)[O-])=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-M 0.000 description 5
- MWVKLRSIDOXBSE-UHFFFAOYSA-N 5-(1-piperidin-4-ylpyrazol-4-yl)-3-(6-pyrrolidin-1-yl-1,3-benzoxazol-2-yl)pyridin-2-amine Chemical compound NC1=NC=C(C2=CN(N=C2)C2CCNCC2)C=C1C(OC1=C2)=NC1=CC=C2N1CCCC1 MWVKLRSIDOXBSE-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 5
- SKOYLSSLFZLMOP-UHFFFAOYSA-N CC(C)(C)OC(C1=C(C(NCC2)N(C=CN3)C3=O)C2=NN1C(C=C1C)=CC(C)=C1F)=O Chemical compound CC(C)(C)OC(C1=C(C(NCC2)N(C=CN3)C3=O)C2=NN1C(C=C1C)=CC(C)=C1F)=O SKOYLSSLFZLMOP-UHFFFAOYSA-N 0.000 description 5
- NDFRUEZUQHFTBE-FQEVSTJZSA-N CC(C)(C)OC(C1=NNC2=C1[C@@](CC(C=C1C)=CC(C)=C1F)(N)NCC2)=O Chemical compound CC(C)(C)OC(C1=NNC2=C1[C@@](CC(C=C1C)=CC(C)=C1F)(N)NCC2)=O NDFRUEZUQHFTBE-FQEVSTJZSA-N 0.000 description 5
- CALGKFKOGNIWGX-UHFFFAOYSA-N CC(CO)COC(C=C1)=CC=C1OCBr Chemical compound CC(CO)COC(C=C1)=CC=C1OCBr CALGKFKOGNIWGX-UHFFFAOYSA-N 0.000 description 5
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 5
- MEKGTAJHXADGFZ-UHFFFAOYSA-M [Zn+]C1OCCCC1.[I-] Chemical compound [Zn+]C1OCCCC1.[I-] MEKGTAJHXADGFZ-UHFFFAOYSA-M 0.000 description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 5
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 5
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 5
- YBFBENHWPRGUMU-UHFFFAOYSA-N chembl398496 Chemical compound OC(=O)C1=CC=CC=C1NC(=O)N1CCN(C=2N=C3C=CC(O)=CC3=NC=2)CC1 YBFBENHWPRGUMU-UHFFFAOYSA-N 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 229910052698 phosphorus Inorganic materials 0.000 description 5
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 159000000000 sodium salts Chemical class 0.000 description 5
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 4
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 4
- COXVPYKZDDKVRF-ULQDDVLXSA-N (4,4-difluorocyclohexyl)methyl N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C[C@@H]1CCNC1=O)C=O)NC(=O)OCC2CCC(CC2)(F)F COXVPYKZDDKVRF-ULQDDVLXSA-N 0.000 description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 4
- QRDAPCMJAOQZSU-KQQUZDAGSA-N (e)-3-[4-[(e)-3-(3-fluorophenyl)-3-oxoprop-1-enyl]-1-methylpyrrol-2-yl]-n-hydroxyprop-2-enamide Chemical compound C1=C(\C=C\C(=O)NO)N(C)C=C1\C=C\C(=O)C1=CC=CC(F)=C1 QRDAPCMJAOQZSU-KQQUZDAGSA-N 0.000 description 4
- NNBUKAPOVBEMNI-UHFFFAOYSA-N 1,2-dichloro-1-ethoxyethane Chemical compound CCOC(Cl)CCl NNBUKAPOVBEMNI-UHFFFAOYSA-N 0.000 description 4
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 4
- GELKGHVAFRCJNA-UHFFFAOYSA-N 2,2-Dimethyloxirane Chemical compound CC1(C)CO1 GELKGHVAFRCJNA-UHFFFAOYSA-N 0.000 description 4
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 4
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- ZAJBYTSUTBCMRM-UHFFFAOYSA-N 5-(2-methylpyrazol-3-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylic acid Chemical compound CN1N=CC=C1C1CC(C(C(O)=O)=NN2)=C2C1 ZAJBYTSUTBCMRM-UHFFFAOYSA-N 0.000 description 4
- STVHMYNPQCLUNJ-UHFFFAOYSA-N 5-bromo-1h-indazole Chemical compound BrC1=CC=C2NN=CC2=C1 STVHMYNPQCLUNJ-UHFFFAOYSA-N 0.000 description 4
- 239000005711 Benzoic acid Substances 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 4
- AIZTTZZUDXUKLY-UHFFFAOYSA-N CC(C)(C)OC(C1=C(C(NCC2)N(C=CN3)C3=O)C2=NN1C(C=C1C)=CC(C)=C1Cl)=O Chemical compound CC(C)(C)OC(C1=C(C(NCC2)N(C=CN3)C3=O)C2=NN1C(C=C1C)=CC(C)=C1Cl)=O AIZTTZZUDXUKLY-UHFFFAOYSA-N 0.000 description 4
- UFIHBKDGGIQTBV-CEISFSOZSA-N CC(C)(C)OC(C1=NNC(CC(C2=CC=C(CF)C=C2)N2)=C1[C@]2(C)N(C=CN1)C1=O)=O Chemical compound CC(C)(C)OC(C1=NNC(CC(C2=CC=C(CF)C=C2)N2)=C1[C@]2(C)N(C=CN1)C1=O)=O UFIHBKDGGIQTBV-CEISFSOZSA-N 0.000 description 4
- LONYCWAGFHMSLL-FQEVSTJZSA-N CC(C)(C)OC(C1=NNC2=C1[C@@](CC(C=C1C)=CC(C)=C1Cl)(N)NCC2)=O Chemical compound CC(C)(C)OC(C1=NNC2=C1[C@@](CC(C=C1C)=CC(C)=C1Cl)(N)NCC2)=O LONYCWAGFHMSLL-FQEVSTJZSA-N 0.000 description 4
- XXOQRFZVTJTIPB-MFNFNOFVSA-N CC(C)(C)OC(C1=NNC2=C1[C@](CN(C(CN1C3(C4C5C3C36)C3C4C56NC(OC(C)(C)C)=O)O)C1=O)(C(C=C1C)=CC(C)=C1F)NCC2)=O Chemical compound CC(C)(C)OC(C1=NNC2=C1[C@](CN(C(CN1C3(C4C5C3C36)C3C4C56NC(OC(C)(C)C)=O)O)C1=O)(C(C=C1C)=CC(C)=C1F)NCC2)=O XXOQRFZVTJTIPB-MFNFNOFVSA-N 0.000 description 4
- DVFUAONPOLFTFM-DJNXLDHESA-N CC(CC1=C2C(C=O)=NN1)(N)N[C@@]2(C)C(C=C1C)=CC(C)=C1F Chemical compound CC(CC1=C2C(C=O)=NN1)(N)N[C@@]2(C)C(C=C1C)=CC(C)=C1F DVFUAONPOLFTFM-DJNXLDHESA-N 0.000 description 4
- UDYCDVNEEJEZCN-UHFFFAOYSA-N CCC(CC(C1=C2)=NNC1=CC=C2Br)O Chemical compound CCC(CC(C1=C2)=NNC1=CC=C2Br)O UDYCDVNEEJEZCN-UHFFFAOYSA-N 0.000 description 4
- RGWZIHSMBSQOCI-UHFFFAOYSA-N CCC(CC(C1=C2F)=NNC1=CC=C2Br)O Chemical compound CCC(CC(C1=C2F)=NNC1=CC=C2Br)O RGWZIHSMBSQOCI-UHFFFAOYSA-N 0.000 description 4
- YTDOZLHINUGRDD-UHFFFAOYSA-N CCC1(OCCCC1)I Chemical compound CCC1(OCCCC1)I YTDOZLHINUGRDD-UHFFFAOYSA-N 0.000 description 4
- CZGQFTCVVZOKDB-UHFFFAOYSA-N CCOC(C1=CC2=CC(C3C(C)(C)OCCC3)=CC=C2N1)=O Chemical compound CCOC(C1=CC2=CC(C3C(C)(C)OCCC3)=CC=C2N1)=O CZGQFTCVVZOKDB-UHFFFAOYSA-N 0.000 description 4
- KJAHJGKMBAAHDG-UEJVZZJDSA-N C[C@@H](C=CC1(C=O)O)NC1(C)C#N Chemical compound C[C@@H](C=CC1(C=O)O)NC1(C)C#N KJAHJGKMBAAHDG-UEJVZZJDSA-N 0.000 description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 4
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 241000282567 Macaca fascicularis Species 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 4
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- GLXAENFBPFBBOF-UHFFFAOYSA-N OC(C1=CC2=CC(Br)=CC=C2N1F)=O Chemical compound OC(C1=CC2=CC(Br)=CC=C2N1F)=O GLXAENFBPFBBOF-UHFFFAOYSA-N 0.000 description 4
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 4
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 description 4
- 235000010233 benzoic acid Nutrition 0.000 description 4
- 229960004365 benzoic acid Drugs 0.000 description 4
- 150000001639 boron compounds Chemical class 0.000 description 4
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 4
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 4
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 4
- 159000000007 calcium salts Chemical class 0.000 description 4
- 150000007942 carboxylates Chemical class 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 4
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 4
- 238000004455 differential thermal analysis Methods 0.000 description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- BJXYHBKEQFQVES-NWDGAFQWSA-N enpatoran Chemical compound N[C@H]1CN(C[C@H](C1)C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N BJXYHBKEQFQVES-NWDGAFQWSA-N 0.000 description 4
- 239000003759 ester based solvent Substances 0.000 description 4
- 239000001530 fumaric acid Substances 0.000 description 4
- 239000000174 gluconic acid Substances 0.000 description 4
- 235000012208 gluconic acid Nutrition 0.000 description 4
- 229950006191 gluconic acid Drugs 0.000 description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 229940071870 hydroiodic acid Drugs 0.000 description 4
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 4
- 229910000103 lithium hydride Inorganic materials 0.000 description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 4
- 239000011976 maleic acid Substances 0.000 description 4
- 239000001630 malic acid Substances 0.000 description 4
- 235000011090 malic acid Nutrition 0.000 description 4
- 229960002510 mandelic acid Drugs 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 4
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 4
- 235000006408 oxalic acid Nutrition 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 4
- 239000008177 pharmaceutical agent Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 230000036470 plasma concentration Effects 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 description 4
- 235000011009 potassium phosphates Nutrition 0.000 description 4
- 235000019260 propionic acid Nutrition 0.000 description 4
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 4
- 229960004889 salicylic acid Drugs 0.000 description 4
- 239000011975 tartaric acid Substances 0.000 description 4
- 235000002906 tartaric acid Nutrition 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000002411 thermogravimetry Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- LAJAFFLJAJMYLK-CVOKMOJFSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[[(7s)-4-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5h-benzo[7]annulen-3-yl]amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound N1([C@H]2CCC3=CC=C(C(=C3CC2)OC)NC=2N=C(C(=CN=2)Cl)N[C@H]2[C@H]([C@@]3([H])C[C@@]2(C=C3)[H])C(N)=O)CCOCC1 LAJAFFLJAJMYLK-CVOKMOJFSA-N 0.000 description 3
- DIXMBHMNEHPFCX-MCMMXHMISA-N (2r)-2-[5-[6-amino-5-[(1r)-1-[5-fluoro-2-(triazol-2-yl)phenyl]ethoxy]pyridin-3-yl]-4-methyl-1,3-thiazol-2-yl]propane-1,2-diol Chemical compound O([C@H](C)C=1C(=CC=C(F)C=1)N1N=CC=N1)C(C(=NC=1)N)=CC=1C=1SC([C@](C)(O)CO)=NC=1C DIXMBHMNEHPFCX-MCMMXHMISA-N 0.000 description 3
- TWYYFYNJOJGNFP-CUXYNZQBSA-N (2s,4r,5s,6s)-2-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-2-carbamoyl-4-[[(e,4s,6s)-4,6-dimethyloct-2-enoyl]oxymethyl]-5-hydroxy-1,3-dioxane-4,5,6-tricarboxylic acid Chemical compound O1[C@H](C(O)=O)[C@](C(O)=O)(O)[C@](COC(=O)/C=C/[C@@H](C)C[C@@H](C)CC)(C(O)=O)O[C@]1(C(N)=O)CCC(=C)[C@@H](OC(C)=O)[C@H](C)CC1=CC=CC=C1 TWYYFYNJOJGNFP-CUXYNZQBSA-N 0.000 description 3
- VPMIAOSOTOODMY-KJAPKAAFSA-N (4r)-6-[(e)-2-[6-tert-butyl-4-(4-fluorophenyl)-2-propan-2-ylpyridin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1/C=C/C=1C(C(C)C)=NC(C(C)(C)C)=CC=1C1=CC=C(F)C=C1 VPMIAOSOTOODMY-KJAPKAAFSA-N 0.000 description 3
- RXNPEQZHMGFNAY-GEALJGNFSA-N (5R)-4-[(1S,6R)-5-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-5-methyl-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one Chemical compound C[C@@H]1CC(=O)NC2=C1C(=NC=N2)N3CCN([C@H]4[C@@H]3C4)C(=O)[C@H](CNC(C)C)C5=CC=C(C=C5)Cl RXNPEQZHMGFNAY-GEALJGNFSA-N 0.000 description 3
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 3
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 3
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 3
- AICIYIDUYNFPRY-UHFFFAOYSA-N 1,3-dihydro-2H-imidazol-2-one Chemical compound O=C1NC=CN1 AICIYIDUYNFPRY-UHFFFAOYSA-N 0.000 description 3
- RZFJBSIAXYEPBX-UHFFFAOYSA-N 1-[4-[4-[2-[4-chloro-3-(diethylsulfamoyl)anilino]pyrimidin-4-yl]pyridin-2-yl]phenyl]-3-methylurea Chemical compound C1=C(Cl)C(S(=O)(=O)N(CC)CC)=CC(NC=2N=C(C=CN=2)C=2C=C(N=CC=2)C=2C=CC(NC(=O)NC)=CC=2)=C1 RZFJBSIAXYEPBX-UHFFFAOYSA-N 0.000 description 3
- YKYWUHHZZRBGMG-JWTNVVGKSA-N 1-methyl-2-[[(1r,5s)-6-[[5-(trifluoromethyl)pyridin-2-yl]methoxymethyl]-3-azabicyclo[3.1.0]hexan-3-yl]methyl]benzimidazole Chemical compound C1([C@@H]2CN(C[C@@H]21)CC=1N(C2=CC=CC=C2N=1)C)COCC1=CC=C(C(F)(F)F)C=N1 YKYWUHHZZRBGMG-JWTNVVGKSA-N 0.000 description 3
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 3
- VCUXVXLUOHDHKK-UHFFFAOYSA-N 2-(2-aminopyrimidin-4-yl)-4-(2-chloro-4-methoxyphenyl)-1,3-thiazole-5-carboxamide Chemical compound ClC1=CC(OC)=CC=C1C1=C(C(N)=O)SC(C=2N=C(N)N=CC=2)=N1 VCUXVXLUOHDHKK-UHFFFAOYSA-N 0.000 description 3
- MWDVCHRYCKXEBY-LBPRGKRZSA-N 3-chloro-n-[2-oxo-2-[[(1s)-1-phenylethyl]amino]ethyl]benzamide Chemical compound N([C@@H](C)C=1C=CC=CC=1)C(=O)CNC(=O)C1=CC=CC(Cl)=C1 MWDVCHRYCKXEBY-LBPRGKRZSA-N 0.000 description 3
- JOFDSYLCZIHGGO-UHFFFAOYSA-N 4-[(4-cyclohexylphenyl)methyl-[2-[[5-(dimethylamino)naphthalen-1-yl]sulfonyl-methylamino]acetyl]amino]-2-hydroxybenzoic acid Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)N(C)CC(=O)N(C=1C=C(O)C(C(O)=O)=CC=1)CC(C=C1)=CC=C1C1CCCCC1 JOFDSYLCZIHGGO-UHFFFAOYSA-N 0.000 description 3
- MSICOAYELJUIIN-UHFFFAOYSA-N 4-chloro-3,5-dimethylaniline Chemical compound CC1=CC(N)=CC(C)=C1Cl MSICOAYELJUIIN-UHFFFAOYSA-N 0.000 description 3
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 3
- RRELDGDKULRRDM-UHFFFAOYSA-N 6-[2-chloro-4-nitro-5-(oxan-4-yloxy)anilino]-3,4-dihydro-1H-quinolin-2-one Chemical compound [O-][N+](=O)c1cc(Cl)c(Nc2ccc3NC(=O)CCc3c2)cc1OC1CCOCC1 RRELDGDKULRRDM-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- MCMSJVMUSBZUCN-UHFFFAOYSA-N 9,10-dimethoxy-3-methyl-2-(2,4,6-trimethylphenyl)imino-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one Chemical compound C1=2C=C(OC)C(OC)=CC=2CCN(C(N2C)=O)C1=CC2=NC1=C(C)C=C(C)C=C1C MCMSJVMUSBZUCN-UHFFFAOYSA-N 0.000 description 3
- VCUKKMIXURRDKL-UHFFFAOYSA-N 9-(dimethylamino)-3-(4-ethylphenyl)pyrido[1,2]thieno[3,4-d]pyrimidin-4-one Chemical compound C1=CC(CC)=CC=C1N1C(=O)C(SC=2C3=C(N(C)C)C=CN=2)=C3N=C1 VCUKKMIXURRDKL-UHFFFAOYSA-N 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 3
- WEPRVOYIMNSRPF-UHFFFAOYSA-N CC(C)(C)OC(C1(NC(NCC(OC)OC)=O)N=NC2=C1C(C1=CC=C(CF)C=C1)NCC2)=O Chemical compound CC(C)(C)OC(C1(NC(NCC(OC)OC)=O)N=NC2=C1C(C1=CC=C(CF)C=C1)NCC2)=O WEPRVOYIMNSRPF-UHFFFAOYSA-N 0.000 description 3
- HTJQYHSANNXIEN-UHFFFAOYSA-N CC(C)(C)OC(C1=C(C(NCC2)N(C=CN3)C3=O)C2=NN1C1=CC=C(CF)C=C1)=O Chemical compound CC(C)(C)OC(C1=C(C(NCC2)N(C=CN3)C3=O)C2=NN1C1=CC=C(CF)C=C1)=O HTJQYHSANNXIEN-UHFFFAOYSA-N 0.000 description 3
- CYUDVWSJJHUITF-IBGZPJMESA-N CC(C)(C)OC(C1=NNC2=C1[C@@](CC1=CC=C(CF)C=C1)(N)NCC2)=O Chemical compound CC(C)(C)OC(C1=NNC2=C1[C@@](CC1=CC=C(CF)C=C1)(N)NCC2)=O CYUDVWSJJHUITF-IBGZPJMESA-N 0.000 description 3
- BPEJIRISCOGHHI-HKBQPEDESA-N CC(C)(C)OC(C1=NNC2=C1[C@](CC(N1C3=NNC4=CC(CF)=CC=C34)=CNC1=O)(C(C=C1C)=CC(C)=C1F)NCC2)=O Chemical compound CC(C)(C)OC(C1=NNC2=C1[C@](CC(N1C3=NNC4=CC(CF)=CC=C34)=CNC1=O)(C(C=C1C)=CC(C)=C1F)NCC2)=O BPEJIRISCOGHHI-HKBQPEDESA-N 0.000 description 3
- QURPNTMATIARQB-HKBQPEDESA-N CC(C)(C)OC(C1=NNC2=C1[C@](CC(N1C3=NNC4=CC=CC(CF)=C34)=CNC1=O)(C(C=C1C)=CC(C)=C1Cl)NCC2)=O Chemical compound CC(C)(C)OC(C1=NNC2=C1[C@](CC(N1C3=NNC4=CC=CC(CF)=C34)=CNC1=O)(C(C=C1C)=CC(C)=C1Cl)NCC2)=O QURPNTMATIARQB-HKBQPEDESA-N 0.000 description 3
- RWGSYOWFYDWEMP-HKBQPEDESA-N CC(C)(C)OC(C1=NNC2=C1[C@](CC(N1C3=NNC4=CC=CC(CF)=C34)=CNC1=O)(C(C=C1C)=CC(C)=C1F)NCC2)=O Chemical compound CC(C)(C)OC(C1=NNC2=C1[C@](CC(N1C3=NNC4=CC=CC(CF)=C34)=CNC1=O)(C(C=C1C)=CC(C)=C1F)NCC2)=O RWGSYOWFYDWEMP-HKBQPEDESA-N 0.000 description 3
- BVWCZHBBUXIBKI-VWLOTQADSA-N CC(C)(C)OC(C1=NNC2=C1[C@](CNC(NCC(OC)OC)=O)(C(C=C1C)=CC(C)=C1Cl)NCC2)=O Chemical compound CC(C)(C)OC(C1=NNC2=C1[C@](CNC(NCC(OC)OC)=O)(C(C=C1C)=CC(C)=C1Cl)NCC2)=O BVWCZHBBUXIBKI-VWLOTQADSA-N 0.000 description 3
- AUZUKLKUCUKPJQ-UHFFFAOYSA-N CC(C)(C1=CC=CC=C1C1)OC1OS(C(F)(F)F)(=O)=O Chemical compound CC(C)(C1=CC=CC=C1C1)OC1OS(C(F)(F)F)(=O)=O AUZUKLKUCUKPJQ-UHFFFAOYSA-N 0.000 description 3
- RWFIZTIHSWJHIT-SGFYLWESSA-N CC(C)C(OC(NC1(C2C3C1C14)C1C2C34NC(N[C@@](C)(C1=C(C2)NN=C1C(OC(C)(C)C)=O)NC2C(C=C1C)=CC(C)=C1F)=O)=O)=O Chemical compound CC(C)C(OC(NC1(C2C3C1C14)C1C2C34NC(N[C@@](C)(C1=C(C2)NN=C1C(OC(C)(C)C)=O)NC2C(C=C1C)=CC(C)=C1F)=O)=O)=O RWFIZTIHSWJHIT-SGFYLWESSA-N 0.000 description 3
- DUYMORZOIWJOME-UHFFFAOYSA-M CCC1(OCCCC1)[Zn]I Chemical compound CCC1(OCCCC1)[Zn]I DUYMORZOIWJOME-UHFFFAOYSA-M 0.000 description 3
- VMWAGAUUIQZZDC-LVZZEGJGSA-N CC[C@@H](C1)[C@@]1(C1=C(C(C2=C(C(C(N3C4=NN(C)C5=CC=CC=C45)=CNC3=O)NCC3)C3=NN2C(C=C2C)=CC(C)=C2F)=O)NC2=CC=CC(C3OCCCC3)=C12)C#N Chemical compound CC[C@@H](C1)[C@@]1(C1=C(C(C2=C(C(C(N3C4=NN(C)C5=CC=CC=C45)=CNC3=O)NCC3)C3=NN2C(C=C2C)=CC(C)=C2F)=O)NC2=CC=CC(C3OCCCC3)=C12)C#N VMWAGAUUIQZZDC-LVZZEGJGSA-N 0.000 description 3
- VYEDLODCNTYETO-FOHQGADXSA-N CN(C(C1=C(C2OCCCC2)C2=CC=CC=C2N1[C@@](COCC1=CC=CC=C1)(C1)[C@H]1C#N)=O)C1=CC=CC=C1 Chemical compound CN(C(C1=C(C2OCCCC2)C2=CC=CC=C2N1[C@@](COCC1=CC=CC=C1)(C1)[C@H]1C#N)=O)C1=CC=CC=C1 VYEDLODCNTYETO-FOHQGADXSA-N 0.000 description 3
- HRMJSGHLZCKSAA-MWKCGYCGSA-N CN(C(C1=C([C@](COCC2=CC=CC=C2)(C2)[C@H]2C(N2)=NOC2=O)C2=C(C3OCCCC3)C=CC=C2N1)=O)C1=CC=CC=C1 Chemical compound CN(C(C1=C([C@](COCC2=CC=CC=C2)(C2)[C@H]2C(N2)=NOC2=O)C2=C(C3OCCCC3)C=CC=C2N1)=O)C1=CC=CC=C1 HRMJSGHLZCKSAA-MWKCGYCGSA-N 0.000 description 3
- YFQCRNRRZIRNOS-UHFFFAOYSA-N COC(CNC(NC1NCCC2=C1C(C(O)=O)=NN2)=O)OC Chemical compound COC(CNC(NC1NCCC2=C1C(C(O)=O)=NN2)=O)OC YFQCRNRRZIRNOS-UHFFFAOYSA-N 0.000 description 3
- SKMCVYVZTOBJOP-JWIGPWBQSA-N C[C@H](CC1=C2C(N(C=C(C3=NN(C)C4=CC=CC=C34)N3)C3=O)=NN1)N[C@@]2(C)C(C=C1C)=CC(C)=C1F Chemical compound C[C@H](CC1=C2C(N(C=C(C3=NN(C)C4=CC=CC=C34)N3)C3=O)=NN1)N[C@@]2(C)C(C=C1C)=CC(C)=C1F SKMCVYVZTOBJOP-JWIGPWBQSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 3
- 108010011459 Exenatide Proteins 0.000 description 3
- HSWVJQBEXRKOBZ-QGZVFWFLSA-N FC1=C(OC2CCN(CC2)C=2N=C3C(=NC=2N[C@H]2COCC2)CN(CC3)C(C)=O)C=CC(=C1)F Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC=2N[C@H]2COCC2)CN(CC3)C(C)=O)C=CC(=C1)F HSWVJQBEXRKOBZ-QGZVFWFLSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- YLCHKYMPBDUYQV-UHFFFAOYSA-M I[Zn]C(CCC1)C11OCCCC1 Chemical compound I[Zn]C(CCC1)C11OCCCC1 YLCHKYMPBDUYQV-UHFFFAOYSA-M 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- JGHHOZATTJBKDO-UHFFFAOYSA-N O=C(C1=C(C2OCCCC2)C2=CC=CC=C2N1)NC1=CC=CC=C1 Chemical compound O=C(C1=C(C2OCCCC2)C2=CC=CC=C2N1)NC1=CC=CC=C1 JGHHOZATTJBKDO-UHFFFAOYSA-N 0.000 description 3
- MICNBXAFDIDBCM-UHFFFAOYSA-N O=C(C1=NNC2=C1CNCC2)OCC1=CC=C(CF)C=C1 Chemical compound O=C(C1=NNC2=C1CNCC2)OCC1=CC=C(CF)C=C1 MICNBXAFDIDBCM-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- KZVWEOXAPZXAFB-BQFCYCMXSA-N Temocaprilat Chemical compound C([C@H](N[C@H]1CS[C@@H](CN(C1=O)CC(=O)O)C=1SC=CC=1)C(O)=O)CC1=CC=CC=C1 KZVWEOXAPZXAFB-BQFCYCMXSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- BEXZJJQVPWJPOA-VOTSOKGWSA-N [(e)-hept-2-enyl] 6-methyl-4-(4-nitrophenyl)-2-oxo-3,4-dihydro-1h-pyrimidine-5-carboxylate Chemical compound CCCC\C=C\COC(=O)C1=C(C)NC(=O)NC1C1=CC=C([N+]([O-])=O)C=C1 BEXZJJQVPWJPOA-VOTSOKGWSA-N 0.000 description 3
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 150000001540 azides Chemical class 0.000 description 3
- ZQNPDAVSHFGLIQ-UHFFFAOYSA-N calcium;hydrate Chemical compound O.[Ca] ZQNPDAVSHFGLIQ-UHFFFAOYSA-N 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000013065 commercial product Substances 0.000 description 3
- 229940127206 compound 14d Drugs 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical group CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 description 3
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 3
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 description 3
- 229960001519 exenatide Drugs 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- BAKHWHBSTCWLSF-UHFFFAOYSA-N imidazol-2-one;hydrochloride Chemical compound Cl.O=C1N=CC=N1 BAKHWHBSTCWLSF-UHFFFAOYSA-N 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- NFPUARSXIMWASK-GOEBONIOSA-N n-[(5r,7s)-2-(3-chlorophenyl)-1-oxa-3-azaspiro[4.5]dec-2-en-7-yl]acetamide Chemical compound C1[C@@H](NC(=O)C)CCC[C@@]11OC(C=2C=C(Cl)C=CC=2)=NC1 NFPUARSXIMWASK-GOEBONIOSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 150000002941 palladium compounds Chemical class 0.000 description 3
- PENAXHPKEVTBLF-UHFFFAOYSA-L palladium(2+);prop-1-ene;dichloride Chemical compound [Pd+]Cl.[Pd+]Cl.[CH2-]C=C.[CH2-]C=C PENAXHPKEVTBLF-UHFFFAOYSA-L 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 3
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 3
- TZSZZENYCISATO-WIOPSUGQSA-N rodatristat Chemical compound CCOC(=O)[C@@H]1CC2(CN1)CCN(CC2)c1cc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)nc(N)n1 TZSZZENYCISATO-WIOPSUGQSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 description 3
- 238000004611 spectroscopical analysis Methods 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 125000003944 tolyl group Chemical group 0.000 description 3
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 2
- JRHPOFJADXHYBR-YUMQZZPRSA-N (1s,2s)-1-n,2-n-dimethylcyclohexane-1,2-diamine Chemical compound CN[C@H]1CCCC[C@@H]1NC JRHPOFJADXHYBR-YUMQZZPRSA-N 0.000 description 2
- KSOVGRCOLZZTPF-QMKUDKLTSA-N (1s,2s,3r,4r)-3-[[5-fluoro-2-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound N([C@H]1[C@H]([C@@]2([H])C[C@@]1(C=C2)[H])C(N)=O)C(C(=CN=1)F)=NC=1NC(C=C1C)=CC=C1N1CCN(C)CC1 KSOVGRCOLZZTPF-QMKUDKLTSA-N 0.000 description 2
- FOLCUFKJHSQMEL-BIXPGCQOSA-N (4-butylcyclohexyl) N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CCCCC1CCC(CC1)OC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@@H]2CCNC2=O)C=O FOLCUFKJHSQMEL-BIXPGCQOSA-N 0.000 description 2
- OSOJAZTYTIGEBM-UHFFFAOYSA-N (4-chloro-3,5-dimethylphenyl)hydrazine hydrochloride Chemical compound Cl.Cc1cc(NN)cc(C)c1Cl OSOJAZTYTIGEBM-UHFFFAOYSA-N 0.000 description 2
- OPXRKRXGKCMCPJ-UHFFFAOYSA-N (4-fluoro-3,5-dimethylphenyl)hydrazine hydrochloride Chemical compound Cl.Cc1cc(NN)cc(C)c1F OPXRKRXGKCMCPJ-UHFFFAOYSA-N 0.000 description 2
- HGNFAVXSHSUMLA-SNVBAGLBSA-N (4r)-4-(phenylmethoxymethyl)-1,3,2-dioxathiolane 2,2-dioxide Chemical compound O1S(=O)(=O)OC[C@H]1COCC1=CC=CC=C1 HGNFAVXSHSUMLA-SNVBAGLBSA-N 0.000 description 2
- OQXNUCOGMMHHNA-GSVOUGTGSA-N (4r)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide Chemical compound C[C@@H]1COS(=O)(=O)O1 OQXNUCOGMMHHNA-GSVOUGTGSA-N 0.000 description 2
- STPKWKPURVSAJF-LJEWAXOPSA-N (4r,5r)-5-[4-[[4-(1-aza-4-azoniabicyclo[2.2.2]octan-4-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound O[C@H]1C(CCCC)(CCCC)CS(=O)(=O)C2=CC=C(N(C)C)C=C2[C@H]1C(C=C1)=CC=C1OCC(C=C1)=CC=C1C[N+]1(CC2)CCN2CC1 STPKWKPURVSAJF-LJEWAXOPSA-N 0.000 description 2
- QBTROWHSMGZXCV-RQURQNPSSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecoxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QBTROWHSMGZXCV-RQURQNPSSA-N 0.000 description 2
- UXKLQDCALAWFIU-VKNDCNMPSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-tetradecoxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCCCC)C1=CC=CC=C1 UXKLQDCALAWFIU-VKNDCNMPSA-N 0.000 description 2
- 125000006647 (C3-C15) cycloalkyl group Chemical group 0.000 description 2
- QPAGOTNPJABYCP-FITNPZAZSA-N (E)-N-(oxan-4-yl)-N'-[[(3R)-1,2,3,4-tetrahydroisoquinolin-3-yl]methyl]-N'-[(8S)-5,6,7,8-tetrahydroquinolin-8-yl]but-2-ene-1,4-diamine Chemical compound O1CCC(CC1)NC\C=C\CN([C@H]1CCCC=2C=CC=NC1=2)C[C@@H]1NCC2=CC=CC=C2C1 QPAGOTNPJABYCP-FITNPZAZSA-N 0.000 description 2
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 2
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- OXTVBHDILDPYAS-UHFFFAOYSA-N 1-[4-(aminomethyl)-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-4-[3-(3-hydroxypropoxy)phenyl]-2-oxo-1,8-naphthyridin-3-yl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=C(CN)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OCCCO)=C1 OXTVBHDILDPYAS-UHFFFAOYSA-N 0.000 description 2
- RTMMSCJWQYWMNK-UHFFFAOYSA-N 2,2,2-trifluoroethyl trifluoromethanesulfonate Chemical compound FC(F)(F)COS(=O)(=O)C(F)(F)F RTMMSCJWQYWMNK-UHFFFAOYSA-N 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- PKBZCROBNDODNV-UHFFFAOYSA-N 2-(oxan-2-yl)-1H-indole Chemical compound O1C(CCCC1)C=1NC2=CC=CC=C2C1 PKBZCROBNDODNV-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- WGABOZPQOOZAOI-UHFFFAOYSA-N 2-[4-[[(3,5-dimethoxy-4-methylbenzoyl)-(3-phenylpropyl)amino]methyl]phenyl]acetic acid Chemical compound COC1=C(C)C(OC)=CC(C(=O)N(CCCC=2C=CC=CC=2)CC=2C=CC(CC(O)=O)=CC=2)=C1 WGABOZPQOOZAOI-UHFFFAOYSA-N 0.000 description 2
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 2
- FTKZKUSQFCXEEL-UHFFFAOYSA-N 2-ethyl-3-methylpyridine Chemical compound CCC1=NC=CC=C1C FTKZKUSQFCXEEL-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- YZMSYLDAOKUZKB-UHFFFAOYSA-N 4-(2-bromoethyl)-2-methylpyridine Chemical compound Cc1cc(CCBr)ccn1 YZMSYLDAOKUZKB-UHFFFAOYSA-N 0.000 description 2
- TXEBWPPWSVMYOA-UHFFFAOYSA-N 4-[3-[(1-amino-2-chloroethyl)amino]propyl]-1-[[3-(2-chlorophenyl)phenyl]methyl]-5-hydroxyimidazolidin-2-one Chemical compound NC(CCl)NCCCC1NC(=O)N(Cc2cccc(c2)-c2ccccc2Cl)C1O TXEBWPPWSVMYOA-UHFFFAOYSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- ZTVQCRFGLVAFEC-UHFFFAOYSA-N 5-(bromomethyl)-1h-indazole Chemical compound BrCC1=CC=C2NN=CC2=C1 ZTVQCRFGLVAFEC-UHFFFAOYSA-N 0.000 description 2
- RXMAYPXTBQWALE-UHFFFAOYSA-N 6-bromo-1,1-dimethyl-3,4-dihydroisochromene Chemical compound BrC=1C=C2CCOC(C2=CC=1)(C)C RXMAYPXTBQWALE-UHFFFAOYSA-N 0.000 description 2
- LPWKFUVWWQYLOD-UHFFFAOYSA-N 9-(dimethylamino)-3-(4-methylphenyl)pyrido[2,3]thieno[2,4-d]pyrimidin-4-one Chemical compound C1=2C(N(C)C)=CN=CC=2SC(C2=O)=C1N=CN2C1=CC=C(C)C=C1 LPWKFUVWWQYLOD-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- DGJMHKMYSDYOFP-MRXNPFEDSA-N C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O Chemical compound C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O DGJMHKMYSDYOFP-MRXNPFEDSA-N 0.000 description 2
- XLGFXIXXXRFQLM-UHFFFAOYSA-N CC(C(C(C=C1CCOC)=N2)=NC2=O)=C1Br Chemical compound CC(C(C(C=C1CCOC)=N2)=NC2=O)=C1Br XLGFXIXXXRFQLM-UHFFFAOYSA-N 0.000 description 2
- BOLFNMHQXHULQX-UHFFFAOYSA-N CC1COC1CS(=O)(=O)c1ccc(C)cc1 Chemical compound CC1COC1CS(=O)(=O)c1ccc(C)cc1 BOLFNMHQXHULQX-UHFFFAOYSA-N 0.000 description 2
- STIVTVWJMDMFAW-JAMMHHFISA-N C[C@@H](C=CCC1(C)C#N)N1O Chemical compound C[C@@H](C=CCC1(C)C#N)N1O STIVTVWJMDMFAW-JAMMHHFISA-N 0.000 description 2
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 2
- 229940125761 Compound 6g Drugs 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 102000020897 Formins Human genes 0.000 description 2
- 108091022623 Formins Proteins 0.000 description 2
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 2
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- XREKBPJILUHJLB-UHFFFAOYSA-N IC(CCC1)CC11OCCC1 Chemical compound IC(CCC1)CC11OCCC1 XREKBPJILUHJLB-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- ALQSHHUCVQOPAS-UHFFFAOYSA-N Pentane-1,5-diol Chemical compound OCCCCCO ALQSHHUCVQOPAS-UHFFFAOYSA-N 0.000 description 2
- 102100040918 Pro-glucagon Human genes 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 2
- XBJFCYDKBDVADW-UHFFFAOYSA-N acetonitrile;formic acid Chemical compound CC#N.OC=O XBJFCYDKBDVADW-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 229940126212 compound 17a Drugs 0.000 description 2
- 229940125873 compound 60b Drugs 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- TXWRERCHRDBNLG-UHFFFAOYSA-N cubane Chemical compound C12C3C4C1C1C4C3C12 TXWRERCHRDBNLG-UHFFFAOYSA-N 0.000 description 2
- KTHXBEHDVMTNOH-UHFFFAOYSA-N cyclobutanol Chemical compound OC1CCC1 KTHXBEHDVMTNOH-UHFFFAOYSA-N 0.000 description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 2
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- YOXHCYXIAVIFCZ-UHFFFAOYSA-N cyclopropanol Chemical compound OC1CC1 YOXHCYXIAVIFCZ-UHFFFAOYSA-N 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- SACNIGZYDTUHKB-UHFFFAOYSA-N ditert-butyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C(C)(C)C)C(C)(C)C SACNIGZYDTUHKB-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 150000002081 enamines Chemical class 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 235000012631 food intake Nutrition 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 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 2
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 2
- YRCHYHRCBXNYNU-UHFFFAOYSA-N n-[[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-(4-fluorophenyl)acetamide Chemical compound N1=CC(CNCCOC)=CC=C1C1=CC2=NC=CC(OC=3C(=CC(NC(=S)NC(=O)CC=4C=CC(F)=CC=4)=CC=3)F)=C2S1 YRCHYHRCBXNYNU-UHFFFAOYSA-N 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- PFGVNLZDWRZPJW-OPAMFIHVSA-N otamixaban Chemical compound C([C@@H](C(=O)OC)[C@@H](C)NC(=O)C=1C=CC(=CC=1)C=1C=C[N+]([O-])=CC=1)C1=CC=CC(C(N)=N)=C1 PFGVNLZDWRZPJW-OPAMFIHVSA-N 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000005930 sec-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- DVWOYOSIEJRHKW-UIRZNSHLSA-M sodium (2S)-2-[[(2S)-2-[[(4,4-difluorocyclohexyl)-phenylmethoxy]carbonylamino]-4-methylpentanoyl]amino]-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonate Chemical compound FC1(CCC(CC1)C(OC(=O)N[C@H](C(=O)N[C@H](C(S(=O)(=O)[O-])O)C[C@H]1C(NCC1)=O)CC(C)C)C1=CC=CC=C1)F.[Na+] DVWOYOSIEJRHKW-UIRZNSHLSA-M 0.000 description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- JYRWUSXRTGACLY-UHFFFAOYSA-N tert-butyl 4-[[3-(4-methylsulfonylphenyl)-[1,2]oxazolo[4,5-d]pyrimidin-7-yl]oxy]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=NC=NC2=C1ON=C2C1=CC=C(S(C)(=O)=O)C=C1 JYRWUSXRTGACLY-UHFFFAOYSA-N 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 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 2
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- RBWMYPKAPIYTJQ-VMBFOHBNSA-N (1R,2S,5S)-6,6-dimethyl-N-[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]-3-[2-[4-(trifluoromethoxy)phenoxy]acetyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide Chemical compound CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)COC3=CC=C(C=C3)OC(F)(F)F)C(=O)N[C@@H](C[C@@H]4CCNC4=O)C=O)C RBWMYPKAPIYTJQ-VMBFOHBNSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- SSJXIUAHEKJCMH-PHDIDXHHSA-N (1r,2r)-cyclohexane-1,2-diamine Chemical compound N[C@@H]1CCCC[C@H]1N SSJXIUAHEKJCMH-PHDIDXHHSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- CEPXWUHXEXKVLW-LURJTMIESA-N (2S)-2-(iodomethyl)oxane Chemical compound IC[C@@H]1CCCCO1 CEPXWUHXEXKVLW-LURJTMIESA-N 0.000 description 1
- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 description 1
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 1
- HPJGEESDHAUUQR-SKGSPYGFSA-N (2s)-2-[[(2s)-5-(diaminomethylideneamino)-2-[[(2s)-1-[(2s)-5-(diaminomethylideneamino)-2-[[(2s)-2-[[(2s)-3-naphthalen-2-yl-2-(3-pyridin-3-ylpropanoylamino)propanoyl]amino]-3-phenylpropanoyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]buta Chemical compound NC(=O)C[C@@H](C(N)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=C2C=CC=CC2=CC=1)NC(=O)CCC=1C=NC=CC=1)CC1=CC=CC=C1 HPJGEESDHAUUQR-SKGSPYGFSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- RSBQANBNDXZFIY-UHFFFAOYSA-N (3,5-dimethylphenyl)hydrazine;hydrochloride Chemical compound [Cl-].CC1=CC(C)=CC(N[NH3+])=C1 RSBQANBNDXZFIY-UHFFFAOYSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- FNHHVPPSBFQMEL-KQHDFZBMSA-N (3S)-5-N-[(1S,5R)-3-hydroxy-6-bicyclo[3.1.0]hexanyl]-7-N,3-dimethyl-3-phenyl-2H-1-benzofuran-5,7-dicarboxamide Chemical compound CNC(=O)c1cc(cc2c1OC[C@@]2(C)c1ccccc1)C(=O)NC1[C@H]2CC(O)C[C@@H]12 FNHHVPPSBFQMEL-KQHDFZBMSA-N 0.000 description 1
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 1
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 1
- DPRJPRMZJGWLHY-HNGSOEQISA-N (e,3r,5s)-7-[5-(4-fluorophenyl)-3-propan-2-yl-1-pyrazin-2-ylpyrazol-4-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)/C=C/C=1C(C(C)C)=NN(C=2N=CC=NC=2)C=1C1=CC=C(F)C=C1 DPRJPRMZJGWLHY-HNGSOEQISA-N 0.000 description 1
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 1
- 125000004867 1,1-dimethylpropylcarbonyl group Chemical group CC(CC)(C(=O)*)C 0.000 description 1
- BXTWRMNZAGYXQQ-UHFFFAOYSA-N 1,2,4-oxadiazol-3-one Chemical compound O=C1N=CON1 BXTWRMNZAGYXQQ-UHFFFAOYSA-N 0.000 description 1
- JGDQLDVVLNXDPQ-UHFFFAOYSA-N 1,2,4-oxadiazolidin-3-one Chemical compound O=C1NCON1 JGDQLDVVLNXDPQ-UHFFFAOYSA-N 0.000 description 1
- IDFLGSYEBJNWMK-UHFFFAOYSA-N 1,2-Bis(chloromethoxy)ethane Chemical compound ClCOCCOCCl IDFLGSYEBJNWMK-UHFFFAOYSA-N 0.000 description 1
- 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 1
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- MKMGUCDUYZRWRX-UHFFFAOYSA-N 1-(bromomethoxy)propane Chemical compound CCCOCBr MKMGUCDUYZRWRX-UHFFFAOYSA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- QXOGPTXQGKQSJT-UHFFFAOYSA-N 1-amino-4-[4-(3,4-dimethylphenyl)sulfanylanilino]-9,10-dioxoanthracene-2-sulfonic acid Chemical compound Cc1ccc(Sc2ccc(Nc3cc(c(N)c4C(=O)c5ccccc5C(=O)c34)S(O)(=O)=O)cc2)cc1C QXOGPTXQGKQSJT-UHFFFAOYSA-N 0.000 description 1
- MXQJQZOSVMJABL-UHFFFAOYSA-N 1-bromoindole Chemical compound C1=CC=C2N(Br)C=CC2=C1 MXQJQZOSVMJABL-UHFFFAOYSA-N 0.000 description 1
- 125000004870 1-ethylpropylcarbonyl group Chemical group C(C)C(CC)C(=O)* 0.000 description 1
- JQCSUVJDBHJKNG-UHFFFAOYSA-N 1-methoxy-ethyl Chemical group C[CH]OC JQCSUVJDBHJKNG-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- CSUGQXMRKOKBFI-UHFFFAOYSA-N 1-methylindazole Chemical compound C1=CC=C2N(C)N=CC2=C1 CSUGQXMRKOKBFI-UHFFFAOYSA-N 0.000 description 1
- 125000004678 1-methylpropylcarbonyl group Chemical group CC(CC)C(=O)* 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- NELACHBDCVNKTB-UHFFFAOYSA-N 1-oxa-2-azaspiro[2.5]octane Chemical compound C1CCCCC21ON2 NELACHBDCVNKTB-UHFFFAOYSA-N 0.000 description 1
- QBHJDAIRJCNUIK-UHFFFAOYSA-N 1-oxa-2-azaspiro[3.5]nonane Chemical compound O1NCC11CCCCC1 QBHJDAIRJCNUIK-UHFFFAOYSA-N 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 1
- XXMFJKNOJSDQBM-UHFFFAOYSA-N 2,2,2-trifluoroacetic acid;hydrate Chemical compound [OH3+].[O-]C(=O)C(F)(F)F XXMFJKNOJSDQBM-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- YRAJNWYBUCUFBD-UHFFFAOYSA-N 2,2,6,6-tetramethylheptane-3,5-dione Chemical compound CC(C)(C)C(=O)CC(=O)C(C)(C)C YRAJNWYBUCUFBD-UHFFFAOYSA-N 0.000 description 1
- QKWWDTYDYOFRJL-UHFFFAOYSA-N 2,2-dimethoxyethanamine Chemical compound COC(CN)OC QKWWDTYDYOFRJL-UHFFFAOYSA-N 0.000 description 1
- UFLFSJVTFSZTKX-UHFFFAOYSA-N 2,2-dimethylmorpholine Chemical compound CC1(C)CNCCO1 UFLFSJVTFSZTKX-UHFFFAOYSA-N 0.000 description 1
- OVSKIKFHRZPJSS-UHFFFAOYSA-N 2,4-D Chemical compound OC(=O)COC1=CC=C(Cl)C=C1Cl OVSKIKFHRZPJSS-UHFFFAOYSA-N 0.000 description 1
- NDFIHSXOLVBGJJ-UHFFFAOYSA-N 2-(1,2-dichloroethoxy)-2-methylpropane Chemical compound ClC(CCl)OC(C)(C)C NDFIHSXOLVBGJJ-UHFFFAOYSA-N 0.000 description 1
- MDNDJMCSXOXBFZ-UHFFFAOYSA-N 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane Chemical compound O1CC(C)(C)COB1B1OCC(C)(C)CO1 MDNDJMCSXOXBFZ-UHFFFAOYSA-N 0.000 description 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- QDTSINVSGKAPBV-UHFFFAOYSA-N 2-(methoxymethyl)pyridine Chemical compound COCC1=CC=CC=N1 QDTSINVSGKAPBV-UHFFFAOYSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 1
- FUSFWUFSEJXMRQ-UHFFFAOYSA-N 2-bromo-1,1-dimethoxyethane Chemical compound COC(CBr)OC FUSFWUFSEJXMRQ-UHFFFAOYSA-N 0.000 description 1
- OVXJWSYBABKZMD-UHFFFAOYSA-N 2-chloro-1,1-diethoxyethane Chemical compound CCOC(CCl)OCC OVXJWSYBABKZMD-UHFFFAOYSA-N 0.000 description 1
- CRZJPEIBPQWDGJ-UHFFFAOYSA-N 2-chloro-1,1-dimethoxyethane Chemical compound COC(CCl)OC CRZJPEIBPQWDGJ-UHFFFAOYSA-N 0.000 description 1
- LWKFOQPKUIOYJF-UHFFFAOYSA-N 2-chloro-2-(2-chloroethoxy)propane Chemical compound ClCCOC(C)(C)Cl LWKFOQPKUIOYJF-UHFFFAOYSA-N 0.000 description 1
- NUFTVEZFJWKTJY-UHFFFAOYSA-N 2-chloro-3-(iodomethyl)pyridine Chemical compound ClC1=NC=CC=C1CI NUFTVEZFJWKTJY-UHFFFAOYSA-N 0.000 description 1
- PKSPCHZIAYGSDB-UHFFFAOYSA-N 2-chloro-4-fluoro-3-iodopyridine Chemical compound FC1=CC=NC(Cl)=C1I PKSPCHZIAYGSDB-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- 125000003858 2-ethylbutoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])O*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004883 2-ethylbutylcarbonyl group Chemical group C(C)C(CC(=O)*)CC 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- FCLRDVPREJSWBM-UHFFFAOYSA-N 2-isocyanato-1,1-dimethoxyethane Chemical compound COC(OC)CN=C=O FCLRDVPREJSWBM-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000004680 2-methylbutylcarbonyl group Chemical group CC(CC(=O)*)CC 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- SBAJRGRUGUQKAF-UHFFFAOYSA-N 3-(2-cyanoethylamino)propanenitrile Chemical compound N#CCCNCCC#N SBAJRGRUGUQKAF-UHFFFAOYSA-N 0.000 description 1
- VGOALPIDEXVYQI-UHFFFAOYSA-N 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-n-[3-imidazol-1-yl-5-(trifluoromethyl)phenyl]-4-methylbenzamide Chemical compound C1=C(C#CC=2N3N=CC=CC3=NC=2)C(C)=CC=C1C(=O)NC(C=C(C=1)C(F)(F)F)=CC=1N1C=CN=C1 VGOALPIDEXVYQI-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- IXHXKHYKFCCVRN-UHFFFAOYSA-N 3-[2-(3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-1H-imidazol-2-one Chemical compound Cc1cc(C)cc(c1)-n1nc2CCNCc2c1-n1cc[nH]c1=O IXHXKHYKFCCVRN-UHFFFAOYSA-N 0.000 description 1
- RWXMIZKCMYTINL-UHFFFAOYSA-N 3-[2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-1H-imidazol-2-one hydrochloride Chemical compound Cl.Cc1cc(cc(C)c1F)-n1nc2CCNCc2c1-n1cc[nH]c1=O RWXMIZKCMYTINL-UHFFFAOYSA-N 0.000 description 1
- UNSHMXUHOHBLIQ-UHFFFAOYSA-N 3-[4-chloro-3-(2-methylphenoxy)naphthalen-1-yl]-6-(trifluoromethyl)-1H-pyrimidine-2,4-dione Chemical compound ClC1=C(C=C(C2=CC=CC=C12)N1C(NC(=CC1=O)C(F)(F)F)=O)OC1=C(C=CC=C1)C UNSHMXUHOHBLIQ-UHFFFAOYSA-N 0.000 description 1
- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical compound CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 description 1
- ARSUQHZDPBOKDP-UHFFFAOYSA-N 4,4,6-trimethyl-1,3,2-dioxaborinane Chemical compound CC1CC(C)(C)OBO1 ARSUQHZDPBOKDP-UHFFFAOYSA-N 0.000 description 1
- UEBSWKNVDRJVHN-UHFFFAOYSA-N 4,4,6-trimethyl-2-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)-1,3,2-dioxaborinane Chemical compound O1C(C)CC(C)(C)OB1B1OC(C)(C)CC(C)O1 UEBSWKNVDRJVHN-UHFFFAOYSA-N 0.000 description 1
- AVVLVCYNVBXDSH-UHFFFAOYSA-N 4-[(4,6-dimethoxy-1,3,5-triazin-2-yl)methyl]morpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC(C[NH+]2CCOCC2)=N1 AVVLVCYNVBXDSH-UHFFFAOYSA-N 0.000 description 1
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 1
- PHCLIPMSNVUELH-UHFFFAOYSA-N 4-bromo-2,3-dimethylpyridine Chemical compound CC1=NC=CC(Br)=C1C PHCLIPMSNVUELH-UHFFFAOYSA-N 0.000 description 1
- IQTHEAQKKVAXGV-UHFFFAOYSA-N 4-ditert-butylphosphanyl-n,n-dimethylaniline Chemical compound CN(C)C1=CC=C(P(C(C)(C)C)C(C)(C)C)C=C1 IQTHEAQKKVAXGV-UHFFFAOYSA-N 0.000 description 1
- DQAZPZIYEOGZAF-UHFFFAOYSA-N 4-ethyl-n-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]piperazine-1-carboxamide Chemical compound C1CN(CC)CCN1C(=O)NC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(C#C)=C1 DQAZPZIYEOGZAF-UHFFFAOYSA-N 0.000 description 1
- IGNFILTZSIUWBS-UHFFFAOYSA-N 4-fluoro-3,5-dimethylaniline Chemical compound CC1=CC(N)=CC(C)=C1F IGNFILTZSIUWBS-UHFFFAOYSA-N 0.000 description 1
- YGZGPBBDOIPGMN-UHFFFAOYSA-N 4-fluoro-3,5-dimethylaniline hydrochloride Chemical compound Cl.Cc1cc(N)cc(C)c1F YGZGPBBDOIPGMN-UHFFFAOYSA-N 0.000 description 1
- CTPMPYIKWARWDI-UHFFFAOYSA-N 4-iodo-2,2-dimethyloxane Chemical compound CC1(C)CC(I)CCO1 CTPMPYIKWARWDI-UHFFFAOYSA-N 0.000 description 1
- SQCYBMMCCQLJDP-UHFFFAOYSA-N 4-iodo-N,N,3-trimethylpyridin-2-amine Chemical compound CN(C)c1nccc(I)c1C SQCYBMMCCQLJDP-UHFFFAOYSA-N 0.000 description 1
- 125000000439 4-methylpentoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004875 4-methylpentylcarbonyl group Chemical group CC(CCCC(=O)*)C 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- MLKOZNHTOALBRP-UHFFFAOYSA-N 4h-pyrazolo[4,3-c]pyridine Chemical compound C1N=CC=C2N=NC=C12 MLKOZNHTOALBRP-UHFFFAOYSA-N 0.000 description 1
- ZDHQVQVNOIWLNX-UHFFFAOYSA-N 5-(7-chloro-10h-benzo[1,2]cyclohepta[2,4-c][1,3]thiazol-10-yl)-1-methyl-4-sulfanylidenepyrimidin-2-one Chemical compound S=C1NC(=O)N(C)C=C1C1C2=CC=C(Cl)C=C2C=CC2=C1N=CS2 ZDHQVQVNOIWLNX-UHFFFAOYSA-N 0.000 description 1
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 1
- IXYOZIVSKCRKCT-UHFFFAOYSA-N 6-(bromomethyl)-1h-benzimidazole Chemical compound BrCC1=CC=C2N=CNC2=C1 IXYOZIVSKCRKCT-UHFFFAOYSA-N 0.000 description 1
- WFFUVYLIAPPPGM-UHFFFAOYSA-N 6-oxaspiro[4.5]decane Chemical compound C1CCCC21OCCCC2 WFFUVYLIAPPPGM-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 241001209435 Actus Species 0.000 description 1
- 208000000230 African Trypanosomiasis Diseases 0.000 description 1
- 241001514645 Agonis Species 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 241000272478 Aquila Species 0.000 description 1
- 101100096578 Arabidopsis thaliana SQD2 gene Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241001134740 Blastocrithidia Species 0.000 description 1
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 1
- HDOFJXMWZYQDME-UHFFFAOYSA-N CC(C)(C)OC(C1(N)N=NC2=C1C(C(C=C1C)=CC(C)=C1F)NCC2)=O Chemical compound CC(C)(C)OC(C1(N)N=NC2=C1C(C(C=C1C)=CC(C)=C1F)NCC2)=O HDOFJXMWZYQDME-UHFFFAOYSA-N 0.000 description 1
- IFVWAAFBKLPYJT-UHFFFAOYSA-N CC(C)(C)OC(C1(N)N=NC2=C1C(C1=CC(C)=CC(C)=C1)NCC2)=O Chemical compound CC(C)(C)OC(C1(N)N=NC2=C1C(C1=CC(C)=CC(C)=C1)NCC2)=O IFVWAAFBKLPYJT-UHFFFAOYSA-N 0.000 description 1
- QKCVBBTXZYCCET-UHFFFAOYSA-N CC(C)(C)OC(C1(NC(NCC(OC)OC)=O)N=NC2=C1C(C(C=C1C)=CC(C)=C1F)NCC2)=O Chemical compound CC(C)(C)OC(C1(NC(NCC(OC)OC)=O)N=NC2=C1C(C(C=C1C)=CC(C)=C1F)NCC2)=O QKCVBBTXZYCCET-UHFFFAOYSA-N 0.000 description 1
- NGJRBHYTOFDQNO-UHFFFAOYSA-N CC(C)(C)OC(C1=C(C(NCC2)N(C=CN3)C3=O)C2=NN1C1=CC(C)=CC(C)=C1)=O Chemical compound CC(C)(C)OC(C1=C(C(NCC2)N(C=CN3)C3=O)C2=NN1C1=CC(C)=CC(C)=C1)=O NGJRBHYTOFDQNO-UHFFFAOYSA-N 0.000 description 1
- JYKQRGGKMWFURM-UCSBTNPJSA-N CC(C)(C)OC(C1=NNC(C2)=C1[C@](C)(C1=CC=C(CF)C=C1)NC2NC(NCC(OC)OC)=O)=O Chemical compound CC(C)(C)OC(C1=NNC(C2)=C1[C@](C)(C1=CC=C(CF)C=C1)NC2NC(NCC(OC)OC)=O)=O JYKQRGGKMWFURM-UCSBTNPJSA-N 0.000 description 1
- LMBKUOVHODZBPU-UHFFFAOYSA-N CC(C)C(OC(NC1(C2C3C1C14)C1C2C34C(O)=O)=O)=O Chemical compound CC(C)C(OC(NC1(C2C3C1C14)C1C2C34C(O)=O)=O)=O LMBKUOVHODZBPU-UHFFFAOYSA-N 0.000 description 1
- ICDLBPWTCABADR-UHFFFAOYSA-N CC(C)C(OC(NN(C(OC(C)(C)C)=O)C(C=C1C)=CC(C)=C1F)=O)=O Chemical compound CC(C)C(OC(NN(C(OC(C)(C)C)=O)C(C=C1C)=CC(C)=C1F)=O)=O ICDLBPWTCABADR-UHFFFAOYSA-N 0.000 description 1
- LKOYWVQUYHEJRR-UHFFFAOYSA-N CC(C)C(OC(OC(OC(C)(C)C)=O)=O)=O Chemical compound CC(C)C(OC(OC(OC(C)(C)C)=O)=O)=O LKOYWVQUYHEJRR-UHFFFAOYSA-N 0.000 description 1
- SAMZYBRWJKCKHB-OGDGHAERSA-N CC(C1)N[C@](C)(C(C(C=C2C)=CC(C)=C2F)=O)C2=C1NN=C2N(CC(OC)OC)C(N)=O Chemical compound CC(C1)N[C@](C)(C(C(C=C2C)=CC(C)=C2F)=O)C2=C1NN=C2N(CC(OC)OC)C(N)=O SAMZYBRWJKCKHB-OGDGHAERSA-N 0.000 description 1
- QVLSGLFIXYIZIO-UHFFFAOYSA-N CC(C=NC=C1)=C1OCI Chemical compound CC(C=NC=C1)=C1OCI QVLSGLFIXYIZIO-UHFFFAOYSA-N 0.000 description 1
- IEXKNBWBFFUPBQ-UHFFFAOYSA-N CC(CC(O)=O)COC(C=C1)=CC=C1OCBr Chemical compound CC(CC(O)=O)COC(C=C1)=CC=C1OCBr IEXKNBWBFFUPBQ-UHFFFAOYSA-N 0.000 description 1
- UGIHWYOQWONUQZ-UHFFFAOYSA-N CC1(C)OB(C2OC(C)(C)C3=CC=CC=C3C2)OC1(C)C Chemical compound CC1(C)OB(C2OC(C)(C)C3=CC=CC=C3C2)OC1(C)C UGIHWYOQWONUQZ-UHFFFAOYSA-N 0.000 description 1
- OZOIRVWWHXMGPN-UHFFFAOYSA-L CC1=CC=CC=C1.[O-]OOO[O-].[K+].[K+] Chemical compound CC1=CC=CC=C1.[O-]OOO[O-].[K+].[K+] OZOIRVWWHXMGPN-UHFFFAOYSA-L 0.000 description 1
- AGHDPRSYXHCRDU-UHFFFAOYSA-N CC1C(CC(C2=C3)=NNC2=CC=C3Br)OC1 Chemical compound CC1C(CC(C2=C3)=NNC2=CC=C3Br)OC1 AGHDPRSYXHCRDU-UHFFFAOYSA-N 0.000 description 1
- OFTMHSLXCVMRLT-UHFFFAOYSA-N CC1C(CC(C2=C3F)=NNC2=CC=C3Br)OC1 Chemical compound CC1C(CC(C2=C3F)=NNC2=CC=C3Br)OC1 OFTMHSLXCVMRLT-UHFFFAOYSA-N 0.000 description 1
- FOZKHPSTBVOWEV-SXBQZSJRSA-N CCC1=NC=CC(C)=C1C1=CC=C2NC(C(OCC)=O)=C([C@]3([C@@H](C)C3)C(N3)=NOC3=O)C2=C1 Chemical compound CCC1=NC=CC(C)=C1C1=CC=C2NC(C(OCC)=O)=C([C@]3([C@@H](C)C3)C(N3)=NOC3=O)C2=C1 FOZKHPSTBVOWEV-SXBQZSJRSA-N 0.000 description 1
- OMMXGJJDHWYCHY-UHFFFAOYSA-N CN(C)C1=NC(C2=CC=C(CBr)C=C2)=CC=N1 Chemical compound CN(C)C1=NC(C2=CC=C(CBr)C=C2)=CC=N1 OMMXGJJDHWYCHY-UHFFFAOYSA-N 0.000 description 1
- UJHYPFVYHZYQNC-UHFFFAOYSA-N COC(CNC(C1=NC=CN1)=O)OC Chemical compound COC(CNC(C1=NC=CN1)=O)OC UJHYPFVYHZYQNC-UHFFFAOYSA-N 0.000 description 1
- QCMHGCDOZLWPOT-FMNCTDSISA-N COC1=C(CC[C@@H]2CCC3=C(C2)C=CC(=C3)[C@H]2CC[C@](N)(CO)C2)C=CC=C1 Chemical compound COC1=C(CC[C@@H]2CCC3=C(C2)C=CC(=C3)[C@H]2CC[C@](N)(CO)C2)C=CC=C1 QCMHGCDOZLWPOT-FMNCTDSISA-N 0.000 description 1
- WUZBOJXXYMKMMF-UHFFFAOYSA-N COC1=CC2=NC=3N(C(N(C(C=3N2C=C1)=O)CCC)=O)CCCCNC(=O)C1=CC=C(C=C1)S(=O)(=O)F Chemical compound COC1=CC2=NC=3N(C(N(C(C=3N2C=C1)=O)CCC)=O)CCCCNC(=O)C1=CC=C(C=C1)S(=O)(=O)F WUZBOJXXYMKMMF-UHFFFAOYSA-N 0.000 description 1
- VMDGYRZLTRGWQU-UHFFFAOYSA-N COCCC(C1=C2F)=NNC1=CC=C2Br Chemical compound COCCC(C1=C2F)=NNC1=CC=C2Br VMDGYRZLTRGWQU-UHFFFAOYSA-N 0.000 description 1
- DFIPCMYGSHLKJB-PQSMIZASSA-N C[C@@H](C1)[C@]1(C(N1)=NOC1=O)C(C=C1)=C(C(C2OCCCC2)=C(C(O)=O)N2)C2=C1F Chemical compound C[C@@H](C1)[C@]1(C(N1)=NOC1=O)C(C=C1)=C(C(C2OCCCC2)=C(C(O)=O)N2)C2=C1F DFIPCMYGSHLKJB-PQSMIZASSA-N 0.000 description 1
- NJVLNTRRLNRIGJ-BLVKFPJESA-N C[C@H](CC1=C2C(N(C=CN3)C3=O)=NN1)N[C@@]2(C)C(C=C1C)=CC(C)=C1F Chemical compound C[C@H](CC1=C2C(N(C=CN3)C3=O)=NN1)N[C@@]2(C)C(C=C1C)=CC(C)=C1F NJVLNTRRLNRIGJ-BLVKFPJESA-N 0.000 description 1
- UYGCHYJUAQEVKI-UHFFFAOYSA-M C[C@]1(OCCCC1)[Zn]I Chemical compound C[C@]1(OCCCC1)[Zn]I UYGCHYJUAQEVKI-UHFFFAOYSA-M 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- MMMPAMNMNPUPLM-UHFFFAOYSA-N ClC1=NC=CC(C2=CC=C(CBr)C=C2)=N1 Chemical compound ClC1=NC=CC(C2=CC=C(CBr)C=C2)=N1 MMMPAMNMNPUPLM-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 1
- 239000005751 Copper oxide Substances 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 239000004287 Dehydroacetic acid Substances 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- UMUKFAPAFXWHJM-UHFFFAOYSA-N FC(CC(C1=C2)=NNC1=CC=C2Br)(F)F Chemical compound FC(CC(C1=C2)=NNC1=CC=C2Br)(F)F UMUKFAPAFXWHJM-UHFFFAOYSA-N 0.000 description 1
- PLDYVEFYLOCRIZ-UHFFFAOYSA-N FC(CC(C1=C2F)=NNC1=CC=C2Br)(F)F Chemical compound FC(CC(C1=C2F)=NNC1=CC=C2Br)(F)F PLDYVEFYLOCRIZ-UHFFFAOYSA-N 0.000 description 1
- 206010017711 Gangrene Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- YVUNGVQHMNNCGW-UHFFFAOYSA-N ICOCC1=CC=NC=C1 Chemical compound ICOCC1=CC=NC=C1 YVUNGVQHMNNCGW-UHFFFAOYSA-N 0.000 description 1
- 206010023379 Ketoacidosis Diseases 0.000 description 1
- 208000007976 Ketosis Diseases 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 229920002884 Laureth 4 Polymers 0.000 description 1
- 208000004554 Leishmaniasis Diseases 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- SQFXOQQZNWJJHO-UHFFFAOYSA-N N#CCC(C1=C2)=C(C(O)=O)NC1=CC=C2Br Chemical compound N#CCC(C1=C2)=C(C(O)=O)NC1=CC=C2Br SQFXOQQZNWJJHO-UHFFFAOYSA-N 0.000 description 1
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 1
- ZNSPHKJFQDEABI-NZQKXSOJSA-N Nc1nc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)cc(n1)N1CCC2(CN[C@@H](C2)C(O)=O)CC1 Chemical compound Nc1nc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)cc(n1)N1CCC2(CN[C@@H](C2)C(O)=O)CC1 ZNSPHKJFQDEABI-NZQKXSOJSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- SUHDFMFNQZUUPL-UHFFFAOYSA-N O=C(C1=CC2=CC=CC=C2N1)N1N=C(CCNC2)C2=C1 Chemical compound O=C(C1=CC2=CC=CC=C2N1)N1N=C(CCNC2)C2=C1 SUHDFMFNQZUUPL-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- DLSWIYLPEUIQAV-UHFFFAOYSA-N Semaglutide Chemical compound CCC(C)C(NC(=O)C(Cc1ccccc1)NC(=O)C(CCC(O)=O)NC(=O)C(CCCCNC(=O)COCCOCCNC(=O)COCCOCCNC(=O)CCC(NC(=O)CCCCCCCCCCCCCCCCC(O)=O)C(O)=O)NC(=O)C(C)NC(=O)C(C)NC(=O)C(CCC(N)=O)NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)C(CC(C)C)NC(=O)C(Cc1ccc(O)cc1)NC(=O)C(CO)NC(=O)C(CO)NC(=O)C(NC(=O)C(CC(O)=O)NC(=O)C(CO)NC(=O)C(NC(=O)C(Cc1ccccc1)NC(=O)C(NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)C(C)(C)NC(=O)C(N)Cc1cnc[nH]1)C(C)O)C(C)O)C(C)C)C(=O)NC(C)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NC(CC(C)C)C(=O)NC(C(C)C)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CCCNC(N)=N)C(=O)NCC(O)=O DLSWIYLPEUIQAV-UHFFFAOYSA-N 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical group [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 241000222714 Trypanosomatidae Species 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- NELWQUQCCZMRPB-UBPLGANQSA-N [(2r,3r,4r,5r)-4-acetyloxy-5-(4-amino-5-ethenyl-2-oxopyrimidin-1-yl)-2-methyloxolan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1N1C(=O)N=C(N)C(C=C)=C1 NELWQUQCCZMRPB-UBPLGANQSA-N 0.000 description 1
- KPFBUSLHFFWMAI-HYRPPVSQSA-N [(8r,9s,10r,13s,14s,17r)-17-acetyl-6-formyl-3-methoxy-10,13-dimethyl-1,2,7,8,9,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1C[C@@H]2[C@](CCC(OC)=C3)(C)C3=C(C=O)C[C@H]2[C@@H]2CC[C@](OC(C)=O)(C(C)=O)[C@]21C KPFBUSLHFFWMAI-HYRPPVSQSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- HGDWHTASNMRJMP-UHFFFAOYSA-N [1-(hydroxyamino)-1-oxo-5-(3-phenoxyphenyl)pentan-2-yl]phosphonic acid Chemical compound ONC(=O)C(P(O)(O)=O)CCCC1=CC=CC(OC=2C=CC=CC=2)=C1 HGDWHTASNMRJMP-UHFFFAOYSA-N 0.000 description 1
- IAGRTVXFXZYJOX-UHFFFAOYSA-N [NH-]N1CC(C#N)=CCC1.[K+] Chemical compound [NH-]N1CC(C#N)=CCC1.[K+] IAGRTVXFXZYJOX-UHFFFAOYSA-N 0.000 description 1
- JGFFTJDJHXLDNJ-UHFFFAOYSA-L [O-]OOO[O-].[K+].[K+] Chemical compound [O-]OOO[O-].[K+].[K+] JGFFTJDJHXLDNJ-UHFFFAOYSA-L 0.000 description 1
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- DCBMHXCACVDWJZ-UHFFFAOYSA-N adamantylidene Chemical group C1C(C2)CC3[C]C1CC2C3 DCBMHXCACVDWJZ-UHFFFAOYSA-N 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001278 adipic acid derivatives Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 230000002862 amidating effect Effects 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 150000001483 arginine derivatives Chemical class 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 210000000467 autonomic pathway Anatomy 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000005872 benzooxazolyl group Chemical group 0.000 description 1
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- LASLVGACQUUOEB-UHFFFAOYSA-N bicyclo[1.1.0]butane Chemical compound C1C2CC21 LASLVGACQUUOEB-UHFFFAOYSA-N 0.000 description 1
- LPCWKMYWISGVSK-UHFFFAOYSA-N bicyclo[3.2.1]octane Chemical compound C1C2CCC1CCC2 LPCWKMYWISGVSK-UHFFFAOYSA-N 0.000 description 1
- OOSCHYDNHHSIKU-UHFFFAOYSA-N bicyclo[4.3.2]undecane Chemical compound C1CC2CCCC1CCCC2 OOSCHYDNHHSIKU-UHFFFAOYSA-N 0.000 description 1
- TWONWILUDBHKQU-UHFFFAOYSA-N bicyclo[5.2.0]nonane Chemical compound C1CCCCC2CCC21 TWONWILUDBHKQU-UHFFFAOYSA-N 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- UORVGPXVDQYIDP-BJUDXGSMSA-N borane Chemical compound [10BH3] UORVGPXVDQYIDP-BJUDXGSMSA-N 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- SIIVGPQREKVCOP-UHFFFAOYSA-N but-1-en-1-ol Chemical compound CCC=CO SIIVGPQREKVCOP-UHFFFAOYSA-N 0.000 description 1
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical class [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001734 carboxylic acid salts Chemical class 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 229910000175 cerite Inorganic materials 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 229960002242 chlorocresol Drugs 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
- LSZLYWSRWXFMOI-UHFFFAOYSA-N cobalt(2+);5,10,15,20-tetraphenylporphyrin-22,24-diide Chemical compound [Co+2].C1=CC(C(=C2C=CC([N-]2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3[N-]2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 LSZLYWSRWXFMOI-UHFFFAOYSA-N 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940125876 compound 15a Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 229910000431 copper oxide Inorganic materials 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- DRNAQRXLOSUHBQ-UHFFFAOYSA-N cphos Chemical compound CN(C)C1=CC=CC(N(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 DRNAQRXLOSUHBQ-UHFFFAOYSA-N 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- BNXQBNHLBJCJGP-UHFFFAOYSA-N cyanomethyl 1h-indole-2-carboxylate Chemical compound C1=CC=C2NC(C(OCC#N)=O)=CC2=C1 BNXQBNHLBJCJGP-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 235000019258 dehydroacetic acid Nutrition 0.000 description 1
- 229940061632 dehydroacetic acid Drugs 0.000 description 1
- JEQRBTDTEKWZBW-UHFFFAOYSA-N dehydroacetic acid Chemical compound CC(=O)C1=C(O)OC(C)=CC1=O JEQRBTDTEKWZBW-UHFFFAOYSA-N 0.000 description 1
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 125000005131 dialkylammonium group Chemical group 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- VBXDEEVJTYBRJJ-UHFFFAOYSA-N diboronic acid Chemical compound OBOBO VBXDEEVJTYBRJJ-UHFFFAOYSA-N 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- AJDPNPAGZMZOMN-UHFFFAOYSA-N diethyl (4-oxo-1,2,3-benzotriazin-3-yl) phosphate Chemical compound C1=CC=C2C(=O)N(OP(=O)(OCC)OCC)N=NC2=C1 AJDPNPAGZMZOMN-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 125000005442 diisocyanate group Chemical group 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- CNXMDTWQWLGCPE-UHFFFAOYSA-N ditert-butyl-(2-phenylphenyl)phosphane Chemical group CC(C)(C)P(C(C)(C)C)C1=CC=CC=C1C1=CC=CC=C1 CNXMDTWQWLGCPE-UHFFFAOYSA-N 0.000 description 1
- REWLCYPYZCHYSS-UHFFFAOYSA-N ditert-butyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical group COC1=CC=C(OC)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C(C)(C)C)C(C)(C)C REWLCYPYZCHYSS-UHFFFAOYSA-N 0.000 description 1
- CRHWEIDCXNDTMO-UHFFFAOYSA-N ditert-butylphosphane Chemical compound CC(C)(C)PC(C)(C)C CRHWEIDCXNDTMO-UHFFFAOYSA-N 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- LCFXLZAXGXOXAP-DAXSKMNVSA-N ethyl (2z)-2-cyano-2-hydroxyiminoacetate Chemical compound CCOC(=O)C(=N/O)\C#N LCFXLZAXGXOXAP-DAXSKMNVSA-N 0.000 description 1
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 description 1
- LWRLKENDQISGEU-UHFFFAOYSA-N ethyl 5-bromo-1h-indole-2-carboxylate Chemical compound BrC1=CC=C2NC(C(=O)OCC)=CC2=C1 LWRLKENDQISGEU-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- UKJFVOWPUXSBOM-UHFFFAOYSA-N hexane;oxolane Chemical compound C1CCOC1.CCCCCC UKJFVOWPUXSBOM-UHFFFAOYSA-N 0.000 description 1
- 208000029080 human African trypanosomiasis Diseases 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000005945 imidazopyridyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- QBZXOWQOWPHHRA-UHFFFAOYSA-N lithium;ethane Chemical compound [Li+].[CH2-]C QBZXOWQOWPHHRA-UHFFFAOYSA-N 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 150000002689 maleic acids Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- KTMKRRPZPWUYKK-UHFFFAOYSA-N methylboronic acid Chemical compound CB(O)O KTMKRRPZPWUYKK-UHFFFAOYSA-N 0.000 description 1
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 206010062198 microangiopathy Diseases 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- TVVSQWIXBFOVHM-UHFFFAOYSA-N n-[4-(bromomethoxy)phenyl]acetamide Chemical compound CC(=O)NC1=CC=C(OCBr)C=C1 TVVSQWIXBFOVHM-UHFFFAOYSA-N 0.000 description 1
- XAYGBKHKBBXDAK-UHFFFAOYSA-N n-[4-[4-(cyclopropylmethyl)piperazine-1-carbonyl]phenyl]quinoline-8-sulfonamide Chemical compound C=1C=C(NS(=O)(=O)C=2C3=NC=CC=C3C=CC=2)C=CC=1C(=O)N(CC1)CCN1CC1CC1 XAYGBKHKBBXDAK-UHFFFAOYSA-N 0.000 description 1
- DSBJAYRCGNAJQG-UHFFFAOYSA-N n-ethyl-n-propylpropanamide Chemical compound CCCN(CC)C(=O)CC DSBJAYRCGNAJQG-UHFFFAOYSA-N 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- GSJRUEBQWPLHSN-UHFFFAOYSA-N n-methylmethanamine;oxolane Chemical compound CNC.C1CCOC1 GSJRUEBQWPLHSN-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006252 n-propylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 230000023187 negative regulation of glucagon secretion Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000004533 oil dispersion Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000005475 oxolanyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical class OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940099429 polyoxyl 40 stearate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- 150000003297 rubidium Chemical class 0.000 description 1
- 108010060325 semaglutide Proteins 0.000 description 1
- 229950011186 semaglutide Drugs 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 201000002612 sleeping sickness Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- UOENJXXSKABLJL-UHFFFAOYSA-M sodium;8-[(2-hydroxybenzoyl)amino]octanoate Chemical compound [Na+].OC1=CC=CC=C1C(=O)NCCCCCCCC([O-])=O UOENJXXSKABLJL-UHFFFAOYSA-M 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 229940100515 sorbitan Drugs 0.000 description 1
- 229960005078 sorbitan sesquioleate Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005458 thianyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl 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
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000005503 thioxanyl group Chemical group 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- 238000002096 two-dimensional nuclear Overhauser enhancement spectroscopy Methods 0.000 description 1
- 125000002948 undecyl 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])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
The present invention provides a compound represented by formula (I) in which an indole ring or a pyrrolo[2,3-b]pyridine ring and a pyrazolopyridine skeleton are bonded using a substituent, or a salt of the compound; solvates thereof; and prophylactic or therapeutic agents for non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus), obesity, and the like in which said compound, salt, or solvate is used as an active ingredient. (In the formula, X, Y, Q1, Q2, R1, R2, R3, R4, R5, R6, R7, R8, R9, n1, n2, Z1, and Z2represent substances indicated in the present specification.) diabetes mellitus (type 2 diabetes mellitus), obesity, and the like in which said compound, salt, or solvate is used as an active ingredient. (In the formula, X, Y, Q1, Q2, R1, R2, R3, R4, R5, R6, R7, R8, R9, n1, n2, Z1, and Z2represent substances indicated in the present specification.)
Description
DESCRIPTION
PYRAZOLOPYRIDINE DERIVATIVE HAVING GLP-1 RECEPTOR AGONIST EFFECT
TECHNICAL FIELD
The present invention relates to a compound which is a GLP-1 receptor agonist
having the same effect as GLP-1, a salt thereof, or a solvate of either the compound or a salt
of the compound. The present invention further relates to a preventative agent or a
therapeutic agent for non-insulin-dependent diabetes mellitus (Type 2 diabetes) or obesity
comprising such a compound, a salt or a solvate as an active ingredient.
BACKGROUND ART
Glucagon-like peptide-1 (GLP-1) is an incretin secreted from L cells in the small
intestine when nutrients pass through the digestive tract, and it is known that the GLP-1
demonstrates a wide variety of effects through the GLP-1 receptor, such as promotion of
glucose dependent insulin secretion, inhibition of glucagon secretion, delaying of gastric
emptying, suppression of feeding. Although GLP-1 analog is already commercialized as a
therapeutic agent for diabetes, and seen as one of the most effective therapeutic agent for
diabetes due to its potent effect in HbA1c redcution and weight loss, all of them require an
invasive subcutaneous administration. As such, development of a GLP-1 receptor agonist
that can be non-invasively administered is awaited. Attempts were made, for example, to
improve the bioavailability at the time of oral administration of a GLP-1 analog: Semaglutide
by using an absorbefacient (sodium N-(8-(2-hydroxybenzoyl)amino)caprylate: SNAC)
(Patent Document 1) and to develop a low molecular GLP-1 receptor agonist (Patent
Documents 2 and 3), but a further improvement is required in medicinal properties including
activity, metabolic stability and bioavailability.
The following two compounds for a chemical library are known as 2-[(2,4,6,7-
tetrahydro-5H-pyrazolo[4,3-c]pyridineyl)carbonyl]-1H-indol.
[Chemical Formula 1]
Further, Patent Document 4 describes the following pyrazolopyridine derivative as a
compound that is useful in the prevention/therapy of sleeping sickness, leishmaniasis or the
like caused by eukaryote: such as blastocrithidia (e.g. Trypanosomatidae) parasitizing the
patient.
[Chemical Formula 2]
CITATION LIST
PATENT LITERATURE
Patent Document 1:
Patent Document 2:
Patent Document 3:
Patent Document 4:
SUMMARY OF INVENTION
TECHNICAL PROBLEM
The problem to be solved by the present invention is to provide a compound which
is a GLP-1 receptor agonist having the same effect as GLP-1 peptide that may be non-
invasively administered and has an improved activity, metabolic stability and bioavailability,
a salt thereof, or a solvate of either the compound or a salt of the compound, and also to
provide a preventative agent or a therapeutic agent for non-insulin-dependent diabetes
mellitus (Type 2 diabetes) or obesity comprising such a compound, salt or solvate as an
active ingredient.
SOLUTION TO PROBLEM
The present inventors studied extensively to solve this problem and found that a
compound represented by Formula (I), in which the indole ring and the pyrazolopyridine
structure are bound to each other through a substituent, has the same effect as GLP-1 peptide
as a GLP-1 receptor agonis, and thus completed the present invention.
In other words, the following invention is provided as one aspect of the present
invention.
[1] A compound represented by Formula (I):
[Chemical Formula 3]
wherein, X is –N= or –CR =; R is selected from a hydrogen atom, a halogen atom,
and C alkyl;
Y is selected from -C(=O)-, -CHR-, and -S(=O) -; R is a hydrogen atom or C
2 1-6
alkyl;
Q is C aryl or 5 to 10 membered heteroaryl, wherein C aryl and 5 to 10
6-10 6-10
membered heteroaryl are optionally substituted with one to five substituents independently
selected from a halogen atom, C alkyl (wherein C alkyl is optionally substituted with one
1-6 1-6
or more halogen atoms), and C alkoxy;
Q is 3 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl, wherein 3 to
12 membered heterocyclyl and 5 to 10 membered heteroaryl are optionally substituted with
one to three substituents independently selected from a halogen atom, C alkyl (wherein C
1-6 1-6
Qa Qb
alkyl is optionally substituted with one or more halogen atoms), C alkoxy, and -NR R ,
and further, two C alkyl groups together with a carbon atom to which they are attached
Qa Qb
may form C carbocyclic ring; and R and R are independently selected from a hydrogen
atom, C alkyl, and (C alkyl)calbonyl;
1-6 1-6
1 2 3
R , R and R are each independently selected from a hydrogen atom and C alkyl
(wherein, C alkyl is optionally substituted with one or more substituents independently
selected from a halogen atom, C alkoxy, and hydroxy);
4 5 6
R , R and R are independently selected from a hydrogen atom, a halogen atom,
and C alkyl;
R and R are independently a hydrogen atom or C alkyl, wherein C alkyl is
1-6 1-6
optionally substituted with one or more substituents independently selected from a halogen
atom and C cycloalkyl, or R and R together with a carbon atom to which they are
3-15
attached may form C cycloalkane ring, or C cycloalkane ring formed by R and R
3-15 3-15
together is optionally substituted with one to three C alkyl, wherein C alkyl is optionally
1-6 1-6
substituted with one or more substituents independently selected from a halogen atom,
7a 7b 7a 7b
hydroxy, -NR R , C alkoxy, and 3 to 12 membered heterocyclyl, and R and R are
independently selected from a hydrogen atom, C alkyl, and (C alkyl)carbonyl;
1-6 1-6
n1 is an integer of 0 to 3; n2 is an integer of 0 to 5;
R is selected from a group represented by Formula (IIa), (IIb), (IIc), (IId):
[Chemical Formula 4]
9f 9g 9h 9a 9b 9c 9d 9g
-CO R , and -C(=O)-NR R ; and R , R , R , R , and R are each independently selected
from a hydrogen atom, C alkyl (wherein C alkyl is optionally substituted with one or
1-6 1-6
more substituents independently selected from a halogen atom and C alkoxy), and (C
1-6 1-6
alkyl)carbonyl, R is a hydrogen atom, or C alkyl that is optionally substituted with one or
9f 9h
more halogen atoms, R is a hydrogen atom or C alkyl, R is a hydrogen atom, C alkyl,
1-6 1-6
9i 9i
(C alkyl)carbonyl, cyano, or -S(=O) -R ; n3 is an integer of 0 to 2, R is C alkyl;
1-6 n3 1-6
Z is selected from a group represented by Formula (IIIa), (IIIb), (IIIc), (IIId), and (IIIe):
[Chemical Formula 5]
za zb
wherein R is selected from a hydrogen atom, C alkyl, and (C alkyl)carbonyl, R and
1-6 1-6
R are independently a hydrogen atom or C alkyl, n4 is an integer of 1 to 3, n5 and n6 are
independently an integer of 0 to 10 (* represents a binding position with a pyrazolopyridine
structure, ** represents a binding position with Z );
Z is selected from C alkyl, C cycloalkyl, 3 to 12 membered heterocyclyl, C
1-6 3-15 6-10
aryl and 5 to 10 membered heteroaryl, wherein C cycloalkyl, 3 to 12 membered
3-15
heterocyclyl, C aryl, and 5 to 10 membered heteroaryl are optionally substituted with one
6-10
to five substituents independently selected from Group A:
Group A: a) oxo,
b) a halogen atom,
c) cyano,
zd ze zd ze
d) -NR R ; wherein R and R are independently selected from a hydrogen atom,
C alkyl and (C alkyl)carbonyl, wherein C alkyl is optionally substituted with one or
1-6 1-6 1-6
more substituents independently selected from hydroxy, a halogen atom and C alkoxy,
zf zg zf zg
e) -C(=O)-NR R ; wherein R and R are independently selected from a hydrogen
atom, C alkyl and (C alkyl)carbonyl, wherein C alkyl is optionally substituted with one
1-6 1-6 1-6
or more substituents independently selected from hydroxy, a halogen atom and C alkoxy,
zh zh
f) -S(=O) -R ; wherein n7 is an integer of 0 to 2, R is a hydrogen atom or C
n7 1-6
alkyl,
g) C alkyl; wherein C alkyl is optionally substituted with one or more
1-6 1-6
zi zj
substituent independently selected from a halogen atom, hydroxy, -NR R , C alkoxy, and
zi zj
3 to 12 membered heterocyclyl, wherein R and R are independently a hydrogen atom or C
alkyl, and wherein 3 to 12 membered heterocyclyl is optionally substituted with one or more
substituents independently selected from hydroxy, C alkyl and 3 to 12 membered
heterocyclyl,
h) C alkoxy; wherein C alkoxy is optionally substituted with one or more
1-6 1-6
substituent independently selected from hydroxy, a halogen atom, and C alkoxy,
i) 3 to 12 membered heterocyclyl; wherein 3 to 12 membered heterocyclyl is
optionally substituted with one or more substituents independently selected from C alkyl
and (C alkyl)carbonyl,
j) C aryl; wherein C aryl is optionally substituted with one or more (C
6-10 6-10 1-6
alkyl)carbonyl, and
k) 5 to 10 membered heteroaryl; wherein 5 to 10 membered heteroaryl is optionally
substituted with one or more substituents independently selected from C alkyl, C alkoxy,
1-6 1-6
zk zl zk zl
-NR R , and 3 to 12 membered heterocyclyl, wherein R and R are independently selected
from a hydrogen atom, C alkyl and (C alkyl)carbonyl, and wherein 3 to 12 membered
1-6 1-6
heterocyclyl is optionally substituted with one or more substituents independently selected
from C alkyl and (C alkyl)carbonyl;
1-6 1-6
a salt thereof, or a solvate of either the compound or a salt of the compound.
[2] The compound according to [1], a salt thereof, or a solvate of either the
compound or a salt of the compound, wherein Q is phenyl or pyridyl, and phenyl or pyridyl
is substituted with one to four substituents independently selected from a halogen atom and
C alkyl.
[3] The compound according to either [1] or [2], a salt thereof, or a solvate of
either the compound or a salt of the compound, wherein R and R are both a hydrogen atom;
7 8 7 8 7 8
R and R are both C alkyl; R is a hydrogen atom and R is C alkyl; or R and R
1-6 1-6
together with a carbon atom to which they are attached form C cycloalkane ring, wherein
C cycloalkane ring that has been formed is optionally substituted with one to two C
3-8 1-6
alkyl, and C alkyl is optionally substituted with one or more substituents independently
selected from hydroxy, C alkoxy, and 3 to 12 membered heterocyclyl.
[4] The compound according to any one of [1] to [3], a salt thereof, or a solvate of
either the compound or a salt of the compound, wherein Z is selected from C alkyl, C
1-6 3-15
cycloalkyl, 3 to 12 membered heterocyclyl, C aryl, and 5 to 10 membered heteroaryl,
6-10
wherein C cycloalkyl, 3 to 12 membered heterocyclyl, C aryl, and 5 to 10 membered
3-15 6-10
heteroaryl are optionally substituted with one to four substituents independently selected
from Group B:
Group B: a) oxo,
b) a halogen atom,
zd1 zel zd1 ze1
c) -NR R ; wherein R and R are independently selected from a hydrogen
atom, C alkyl and (C alkyl)carbonyl, and C alkyl is optionally substituted with one or
1-6 1-6 1-6
more C alkoxy,
zh1 zh1
d) -S(=O) -R ; wherein n7 is an integer of 0 to 2, R is C alkyl,
n7 1-6
e) C alkyl; wherein C alkyl is optionally substituted with one or more
1-6 1-6
zi zj
substituents independently selected from a halogen atom, hydroxy, -NR R , C alkoxy, and
zi zj
3 to 12 membered heterocyclyl, wherein R and R are independently a hydrogen atom or C
alkyl, and wherein 3 to 12 membered heterocyclyl is optionally substituted with one or more
substituents independently selected from hydroxy, C alkyl and 3 to 12 membered
heterocyclyl,
f) C alkoxy; wherein C alkoxy is optionally substituted with one or more
1-6 1-6
hydroxy,
g) 3 to 12 membered heterocyclyl; wherein 3 to 12 membered heterocyclyl is
optionally substituted with one or more (C alkyl)carbonyl,
h) 5 to 10 membered heteroaryl; wherein 5 to 10 membered heteroaryl is optionally
zk1 zl1
substituted with one or more substituents independently selected from C alkyl, -NR R ,
zk1 zl1
and R and R are independently selected from a hydrogen atom and C alkyl.
[5] The compound according to any one of [1] to [4], a salt thereof, or a solvate of
either the compound or a salt of the compound, wherein Y is -C(=O)-.
[6] The compound according to any one of [1] to [5], a salt thereof, or a solvate of
either the compound or a salt of the compound, wherein R is a hydrogen atom.
[7] The compound according to any one [1] to [6], a salt thereof, or a solvate of
either the compound or a salt of the compound, wherein n1 and n2 are both 0.
[8] The compound according to any one of [1] to [7], a salt thereof, or a solvate of
either the compound or a salt of the compound, wherein R is represented by Formula (IIb):
[Chemical Formula 6]
[9] The compound according to any one of [1] to [8], a salt thereof, or a solvate of
either the compound or a salt of the compound, wherein X is -N=, -CH=, or -CF=.
[10] The compound according to any one of [1] to [9], a salt thereof, or a solvate
of either the compound or a salt of the compound, wherein Z is represented by Formula
(IIIa):
[Chemical Formula 7]
(* represents a binding position with a pyrazolopyridine structure, ** represents a binding
position with Z ).
[11] A pharmaceutical composition comprising the compound according to any
one of [1] to [10], a salt thereof, or a solvate of either the compound or a salt of the
compound as an active ingredient.
[12] A preventive agent or a therapeutic agent for non-insulin-dependent diabetes
mellitus (Type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin dependent
diabetes mellitus (Type 1 diabetes), diabetic complication, obesity, hypertension,
hyperlipidemia, arteriosclerosis, coronary heart disease, brain infarction, non-alcoholic
steatohepatitis, Parkinson's disease, or dementia, wherein the preventative agent or the
therapeutic agent comprises the compound according to any one of [1] to [10], a salt thereof,
or a solvate of either the compound or a salt of the compound as an active ingredient. An
example of dementia is Alzheimer’s disease.
[13] A preventive agent or a therapeutic agent for non-insulin-dependent diabetes
mellitus (Type 2 diabetes) or obesity comprising the compound according to any one of [1] to
, a salt thereof, or a solvate of either the compound or a salt of the compound as an active
ingredient.
[14] Use of the compound according to any one of [1] to [10], a salt thereof, or a
solvate of either the compound or a salt of the compound in the manufacture of a medicament
for preventing or treating non-insulin-dependent diabetes mellitus (Type 2 diabetes),
hyperglycemia, impaired glucose tolerance, insulin dependent diabetes mellitus (Type 1
diabetes), diabetic complication, obesity, hypertension, hyperlipidemia, arteriosclerosis,
coronary heart disease, brain infarction, non-alcoholic steatohepatitis, Parkinson's disease, or
dementia. Described herein is a method for preventing or treating non-insulin-dependent
diabetes mellitus (Type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin
dependent diabetes mellitus (Type 1 diabetes), diabetic complication, obesity, hypertension,
hyperlipidemia, arteriosclerosis, coronary heart disease, brain infarction, non-alcoholic
steatohepatitis, Parkinson's disease, or dementia, which comprises administering an effective
amount of the compound according to any one of [1] to [10], a salt thereof, or a solvate of
either the compound or a salt of the compound to a subject. An example of dementia is
Alzheimer’s disease.
[15] Use of the compound according to any one of [1] to [10], a salt thereof, or a
solvate of either the compound or a salt of the compound in the manufacture of a medicament
for preventing or treating non-insulin-dependent diabetes mellitus (Type 2 diabetes) or
obesity. Described herein is a method for preventing or treating non-insulin-dependent
diabetes mellitus (Type 2 diabetes) or obesity, which comprises administering an effective
amount of the compound according to any one of [1] to [10], a salt thereof, or a solvate of
either the compound or a salt of the compound to a subject.
ADVANTAGEOUS EFFECTS OF INVENTION
The compound, a salt thereof, or a solvate of either the compound or a salt of the
compound of the present invention is has an effect similar to GLP-1 peptide as a GLP-1
receptor agonist, and provides a non-peptide agent for preventing or treating non-insulin-
dependent diabetes mellitus (Type 2 diabetes) or obesity which is expected to provide a
sufficient bioavailability through oral administration.
BRIEF DESCRIPTION OF DRAWINGS
Fig. 1 shows the result of measurement by X-ray powder diffractometry of the
crystal of a sodium salt hydrate of Compound 1 obtained in Example 163 (Sample 160a).
The vertical axis shows the diffraction intensity and the horizontal axis shows the diffraction
angle 2θ (º).
Fig. 2 shows the result of measurement by X-ray powder diffractometry of the
crystal of a sodium salt hydrate of Compound 1 obtained in Example 163 (Sample 160b).
The vertical axis shows the diffraction intensity and the horizontal axis shows the diffraction
angle 2θ (º).
Fig. 3 shows the result of measurement by X-ray powder diffractometry of the
crystal of Example Compound 66 obtained in Example 163 (Sample 161a). The vertical
axis shows the diffraction intensity and the horizontal axis shows the diffraction angle 2θ (º).
Fig. 4 shows the result of measurement by X-ray powder diffractometry of the
crystal of Example Compound 66 obtained in Example 163 (Sample 161b). The vertical
axis shows the diffraction intensity and the horizontal axis shows the diffraction angle 2θ (º).
Fig. 5 shows the result of measurement by X-ray powder diffractometry of the
crystal of a calcium salt hydrate of Example Compound 67 obtained in Example 163 (Sample
162a). The vertical axis shows the diffraction intensity and the horizontal axis shows the
diffraction angle 2θ (º).
Fig. 6 shows the result of measurement by X-ray powder diffractometry of the
crystal of a calcium salt hydrate of Example Compound 67 obtained in Example 163 (Sample
162b). The vertical axis shows the diffraction intensity and the horizontal axis shows the
diffraction angle 2θ (º).
Fig. 7 shows the result of thermogravimetry/ differential thermal analysis of the
crystal of a sodium salt hydrate of Compound 1 obtained in Example 164. The horizontal
axis shows temperature (ºC), and the right vertical axis shows the weight change (%) of the
sample in thermogravimetry. The left vertical axis shows the heat flow observed in the
differential thermal analysis.
Fig. 8 shows the result of thermogravimetry/ differential thermal analysis of the
crystal of a calcium salt hydrate of Example Compound 67 obtained in Example 164. The
horizontal axis shows temperature (ºC), and the right vertical axis shows the weight change
(%) of the sample in thermogravimetry. The left vertical axis shows the heat flow observed
in the differential thermal analysis.
Fig. 9 shows the impact of Example Compound 67 and exenatide against insulin
secretion after intravenous administration of glucose in male cynomolgus monkeys. The
area under the curve of insulin is shown by a mean value ± standard error (n=6). Each
pharmaceutical agent was administered in a crossover design. * indicates that the value of
the group shows a statistically significant difference versus that of vehicle group at P<0.025 ,
and ** indicates that the value of the group shows a statistically significant difference versus
that of vehicle group at P<0.005 (Williams test). The concentration of each drug is amean
value of the measured plasma concentration of the drug.
Fig. 10 shows the impact of Example Compound 67 and exenatide against plasma
glucose levels after intravenous administration of glucose in male cynomolgus monkeys.
The area under the curve of plasma glucose is shown by a mean value ± standard error (n=6).
Each pharmaceutical agent was administered in a crossover design. * indicates that the
value of the group shows a statistically significant difference versus that of vehicle group at
P<0.025, and ** indicates that the value of the group shows a statistically significant
difference versus that of vehicle group at P<0.005 (Williams test). The concentration of
each drug is a mean value of the measured plasma concentration of drug.
Fig. 11 shows the impact of Example Compound 67 and exenatide against the food
intake of male cynomolgus monkeys. The food intake is shown by a mean value ± standard
deviation (n=6). Each pharmaceutical agent was administered in a crossover design. *
indicates that the value of the group shows a statistically significant difference versus that of
vehicle group at P<0.025, and ** indicates that the value of the group shows a statistically
significant difference versus that of vehicle group at P<0.005 (Williams test).
Fig. 12 shows the time profile of the plasma concentrations for the drug after oral
administration of this substance to male cynomolgus monkeys. Plasma concentrations are
represented by mean values of n=2 for each dosage.
DESCRIPTION OF EMBODIMENTS
The present invention is further described below without being limited thereby.
Definition
The term “a halogen atom” in the present invention means a fluorine atom, a
chlorine atom, a bromine atom, an iodine atom and the like. A halogen atoms that is
preferred as a substituent of aryl in the present invention (e.g. R when X in Formula (I) is -
CR =) is a fluorine atom and a chlorine atom. A halogen atoms that is preferred as a
substituent of alkyl in the present invention (e.g. a substituent of C - alkyl when the C
1 6 6-10
aryl or the 5 to 10 membered heteroaryl of Q is substituted with C - alkyl) is a fluorine
atom and a chlorine atom. Specific examples of C - alkyl having a halogen atom as a
substituent include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
pentafluoroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, heptafluoropropyl, 3,3,3-
trifluoropropyl, 2,3-dichloropropyl, 1-fluorobromopropyl, 4-bromobutyl, 3,3,3,4,4-
pentafluorobutyl, 4,4-dichlorobutyl, 5-iodopentyl, 5,5-difluoropentyl, 6-chlorohexyl, and
6,6,6-trifluorohexyl.
The term “C - alkyl” in the present invention is a straight chain or brached chain
alkyl group with 1 to 6 carbons. Examples include methyl, ethyl, n-propyl, i-propyl, n-
butyl, i-butyl, sec-butyl, t-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-
dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, and 2-ethylbutyl.
The term “C alkoxy” in the present invention means a group: C - alkyl-O- group,
1-6 1 6
of which C - alkyl is already defined. Examples include methoxy, ethoxy, n-propoxy, i-
propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, 1-methylpropoxy, n-pentyloxy,
isopentyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-
methylpentyloxy, and 2-ethylbutoxy.
The term “(C - alkyl)carbonyl” in the present invention means a group: (C -
1 6 1 6
alkyl)-C(O)- group, of which C - alkyl is already defined. Examples include
methylcarbonyl (acetyl), ethylcarbonyl (propionyl), n-propylcarbonyl, i-propylcarbonyl, n-
butylcarbonyl, i-butylcarbonyl, sec-butylcarbonyl, t-butylcarbonyl, 1-methylpropylcarbonyl,
n-pentylcarbonyl, isopentylcarbonyl, 2-methylbutylcarbonyl, 1,1-dimethylpropylcarbonyl, 1-
ethylpropylcarbonyl, n-hexylcarbonyl, 4-methylpentylcarbonyl, and 2-ethylbutylcarbonyl.
The term “C aryl” in the present invention means an aromatic carbocyclic group,
6-10
and it may contain a non-aromatic portion in addition to the aromatic portion. The ring may
be monocyclic, or it may be a bicyclic aryl that is condensed with a benzene ring or a
monocyclic aryl ring. Examples include phenyl, 1-naphthyl, 2-naphthyl, azulenyl,
isochromanyl, 2,4-dihydro-1H-isoquinolinonyl, and 1,3-dihydrobenzimidazolonyl. A
preferable example is phenyl.
The term “heteroaryl” in the present invention means an aromatic 5 to 10 membered
cyclic group that comprise, among atoms constituting a ring, one or more hetero atoms
selected from a nitrogen atom, an oxygen atom and a sulfur atom, and it may contain a non-
aromatic portion in addition to the aromatic portion. The ring may be monocyclic, or it may
be a bicyclic heteroaryl that is condensed with a benzene ring or a monocyclic heteroaryl
ring. Examples include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,
isothiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl,
pyrimidyl, pyridazinyl, pyrazinyl , triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl,
benzothiazolyl, benzooxazolyl, benzooxadiazolyl, benzoimidazolyl, indolyl, isoindolyl,
indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl,
indolizinyl, imidazopyridyl, benzoisoxazolyl, and benzoisothiazolyl.
The term “heterocyclyl” in the present invention means a non-aromatic cyclic group
comprising one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms, and it
may be completely saturated or partly unsaturated. The ring may be a monocyclic ring, a
bicyclic ring or a spiro ring of 3 to 12 members, preferably 3 to 10 members. Examples
include oxetanyl, azetidinyl, 3,7-dioxaazabicyclo[3.3.1]nonanyl, piperazinyl , piperidinyl,
morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 2-oxa
azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2-thia
azaspiro[3.3]heptyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrazolidinyl, thianyl,
oxanyl, thioxanyl, indolinyl, isoindolinyl, tetrahydroindolinyl, quinuclidinyl, azepinyl, and
tropanyl.
The term “C - cycloalkyl” of the present invention means a monovalent group
3 15
derived by removing any single hydrogen atom from a cyclic saturated aliphatic hydrocarbon
having 3 to 15 carbons. Also, the term “C - cycloalkyl” means a cycloalkyl of three to
eight carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and cyclooctyl. Also, the term “C - cycloalkyl” means a cycloalkyl of 3 to 6
carbons. When two groups together form a C - cycloalkane ring, the resulting group is
3 15
bivalent. Examples include cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-
diyl, cyclohexane-1,1-diyl, cycloheptane-1,1-diyl, and cyclooctane-1,1-diyl.
When the two groups on two carbon atoms are combined to form a C - carbocyclic
ring, the resulting ring forms a condensed ring. Examples include ring structures such that
the two carbon atoms are linked by -CH -, -CH CH -, -CH CH CH -, -CH CH CH CH -, -
2 2 2 2 2 2 2 2 2 2
CH CH CH CH CH -, and -CH CH CH CH CH CH -.
2 2 2 2 2 2 2 2 2 2 2
In addition, the cycloalkane ring, the carbocyclic ring, the cyclic hydrocarbon in the
cycloalkyl may be a cross-linked ring. Examples of cross-linked rings in the C -
3 15
cycloalkyl include bicyclo[1.1.0]butane, bicyclo[3.2.1]octane, bicyclo[5.2.0]nonane,
2,6 2,5
bicyclo[4.3.2]undecane, tricyclo[2.2.1.0 ]heptane, tricyclo[4.3.1.1 ]undecane,
3,7 3,7
tricyclo[3.3.1.1 ]decane (adamantane), tricyclo[3.3.1.1 ]decaneylidene (2-
2,5 3,8 4,7
adamantylidene), pentacyclo[4.2.0.0 .0 .0 ]octane (cubane), and examples of C -
3 15
cycloalkyl include bicyclo[1.1.0]butyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl,
2,6 2,5
bicyclo[4.3.2]undecyl, tricyclo[2.2.1.0 ]heptyl, tricyclo[4.3.1.1 ]undecyl, adamantyl, 2-
adamantylidenyl, and cubanyl.
The present invention provides a compound represented by Formula (I), a salt
thereof, or a solvate of either the compound or a salt of the compound.
[Chemical Formula 8]
X is –N= or –CR =; R is selected from a hydrogen atom, a halogen atom, and C
alkyl. X is preferably -N=, -CH=, or -CF=, more preferably -CH=.
Y is selected from -C(=O)-, -CHR-, and -S(=O) -; R is a hydrogen atom or C
2 1-6
alkyl.
Q is C aryl or 5 to 10 membered heteroaryl, wherein C aryl and 5 to 10
6-10 6-10
membered heteroaryl are optionally substituted with one to five substituents independently
selected from a halogen atom, C alkyl (wherein C alkyl is optionally substituted with one
1-6 1-6
or more halogen atoms), and C alkoxy. Q is preferably phenyl or pyridyl, wherein
phenyl or pyridyl is substituted with one to four substituents independently selected from a
halogen atom and C alkyl. More preferably Q is phenyl substituted with two to three
substituents independently selected from a halogen atom and C alkyl.
Q is 3 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl, wherein 3 to
12 membered heterocyclyl and 5 to 10 membered heteroaryl are optionally substituted with
one to three substituents independently selected from a halogen atom, C alkyl (wherein C
1-6 1-6
Qa Qb
alkyl is optionally substituted with one or more halogen atoms), C alkoxy, and -NR R ,
and two C alkyl groups together with a carbon atom to which they are attached may form
Qa Qb
C carbocyclic ring; and R and R are independently selected from a hydrogen atom, C
3-8 1-6
alkyl, and (C alkyl)calbonyl. Preferably, Q is i) 6 membered heterocyclyl, wherein 6
membered heterocyclyl is optionally substituted with one or more C alkyl, and two C
1-6 1-6
alkyl groups together with a carbon atom to which they are attached may form C
carbocyclic ring, or ii) 5 to 6 membered heteroaryl, wherein 5 to 6 membered heteroaryl is
optionally substituted with one to three substituents independently selected from a halogen
Qc Qd Qc Qd
atom, C alkyl, C alkoxy, and -NR R , and R and R are independently selected
1-6 1-6
from a hydrogen atom and C alkyl. Preferably, Q is 5 to 6 membered heterocyclyl or
heteroaryl, wherein the 5 to 6 membered heterocyclyl and 5 to 6 membered heteroaryl are
optionally substituted with one to three C alkyl.
1 2 3
R , R and R are each independently selected from a hydrogen atom and C alkyl
(wherein, C alkyl is optionally substituted with one or more substituents independently
selected from a halogen atom, C alkoxy, and hydroxy). Preferably, the combination of
1 2 3 1 2
R , R and R is selected from: all hydrogen atoms; R is a hydrogen atom, R is a hydrogen
3 1 2 3
atom, and R is C alkyl; and R is a hydrogen atom, R is C alkyl, and R is C alkyl.
1-6 1-6 1-6
4 5 6
R , R and R are independently selected from a hydrogen atom, a halogen atom,
4 5 6
and C alkyl. It is preferred that R , R and R are independently a hydrogen atom or a
4 5 6
fluorine atom. More preferably, the combination of R , R , and R are: all hydrogen atoms;
4 5 6
or R is a hydrogen atom, R is a hydrogen atom, and R is a fluorine atom.
R and R are independently a hydrogen atom or C alkyl, wherein C alkyl is
1-6 1-6
optionally substituted with one or more substituents independently selected from a halogen
atom and C cycloalkyl, or R and R together with a carbon atom to which they are
3-15
attached may form C cycloalkane ring, wherein C cycloalkane ring formed by
3-15 3-15
combining R and R is optionally substituted with one to three C alkyl, wherein C alkyl
1-6 1-6
is optionally substituted with one or more substituents independently selected from a halogen
7a 7b 7a 7b
atom, hydroxy, -NR R , C alkoxy, and 3 to 12 membered heterocyclyl, and R and R
are independently selected from a hydrogen atom, C alkyl, and (C alkyl)carbonyl.
1-6 1-6
Preferably R and R together with a carbon atom to which they are attached form C
cycloalkane ring, wherein the C cycloalkyl thus formed is optionally substituted with one
or more C alkyl, wherein C alkyl is optionally substituted with one or more hydroxy.
1-6 1-6
The C cycloalkyl is preferably C cycloalkyl. A preferable C cycloalkyl is, for
3-8 3-6 3-6
example, cyclopentyl.
n1 is an integer of 0 to 3; n2 is an integer of 0 to 5. n1 and n2 are each preferably 0
to 2, more preferably 0 to 1, and even more preferably 0. Also, the combination of n1 and
n2 is preferably 0 and 0, 0 and 1, 0 and 2, 1 and 0, 1 and 1, 2 and 0, more preferably 0 and 0,
0 and 1, 1 and 0, 2 and 0, and even more preferably 0 and 0.
R is selected from a group represented by Formula (IIa), (IIb), (IIc), (IId):
[Chemical Formula 9]
9f 9g 9h 9a 9b 9c 9d 9g
-CO R , and -C(=O)-NR R ; and R , R , R , R , and R are each independently selected
from a hydrogen atom, C alkyl (wherein C alkyl is optionally substituted with one or
1-6 1-6
more substituents independently selected from a halogen atom and C alkoxy), and (C
1-6 1-6
alkyl)carbonyl, R is a hydrogen atom, or C alkyl that is optionally substituted with one or
more substituents independently selected from a halogen atom, R is a hydrogen atom or C
9h 9i
alkyl, R is a hydrogen atom, C alkyl, (C alkyl)carbonyl, cyano, or -S(=O) -R ; n3 is an
1-6 1-6 n3
integer of 0 to 2, and R is C alkyl.
Z is selected from a group represented by Formula (IIIa), (IIIb), (IIIc), (IIId), and
(IIIe):
[Chemical Formula 10]
za zb
wherein R is selected from a hydrogen atom, C alkyl, and (C alkyl)carbonyl, R
1-6 1-6
and R are independently a hydrogen atom or C alkyl, n4 is an integer of 1 to 3, n5 and n6
are independently an integer of 0 to 10.
* represents a binding position with a pyrazolopyridine structure, ** represents a
binding position with Z .
Z is selected from C alkyl, C cycloalkyl, 3 to 12 membered heterocyclyl, C
1-6 3-15 6-10
aryl and 5 to 10 membered heteroaryl, wherein C cycloalkyl, 3 to 12 membered
3-15
heterocyclyl, C aryl, and 5 to 10 membered heteroaryl are optionally substituted with one
6-10
to five substituents independently selected from Group A.
Group A: a) oxo,
b) a halogen atom,
c) cyano,
zd ze zd ze
d) -NR R ; wherein R and R are independently selected from a
hydrogen atom, C alkyl and (C alkyl)carbonyl, wherein C alkyl is optionally
1-6 1-6 1-6
substituted with one or more substituents independently selected from hydroxy, a
halogen atom and C alkoxy,
zf zg zf zg
e) -C(=O)-NR R ; wherein R and R are independently selected from a
hydrogen atom, C alkyl and (C alkyl)carbonyl, wherein C alkyl is optionally
1-6 1-6 1-6
substituted with one or more substituents independently selected from hydroxy, a
halogen atom and C alkoxy,
zh zh
f) -S(=O) -R ; wherein n7 is an integer of 0 to 2, R is a hydrogen atom
or C alkyl,
g) C alkyl; wherein C alkyl is optionally substituted with one or more
1-6 1-6
zi zj
substituents independently selected from a halogen atom, hydroxy, -NR R , C
zi zj
alkoxy, and 3 to 12 membered heterocyclyl, wherein R and R are independently a
hydrogen atom or C alkyl, and wherein 3 to 12 membered heterocyclyl is
optionally substituted with one or more substituents independently selected from
hydroxy, C alkyl and 3 to 12 membered heterocyclyl,
h) C alkoxy; wherein C alkoxy is optionally substituted with one or
1-6 1-6
more substituents independently selected from hydroxy, a halogen atom, and C
alkoxy,
i) 3 to 12 membered heterocyclyl; wherein 3 to 12 membered heterocyclyl
is optionally substituted with one or more substituents independently selected from
C alkyl and (C alkyl)carbonyl,
1-6 1-6
j) C aryl; wherein C aryl is optionally substituted with one or more
6-10 6-10
(C alkyl)carbonyl, and
k) 5 to 10 membered heteroaryl; wherein 5 to 10 membered heteroaryl is
optionally substituted with one or more substituents independently selected from C
zk zl zk
alkyl, C alkoxy, -NR R , and 3 to 12 membered heterocyclyl, wherein R and
6 1-6
R are independently selected from a hydrogen atom, C alkyl and (C
1-6 1-6
alkyl)carbonyl, and wherein 3 to 12 membered heterocyclyl is optionally substituted
with one or more substituents independently selected from C alkyl and (C
1-6 1-6
alkyl)carbonyl.
zd ze zf zg
When the C alkyl in R , R , R and R is substituted with hydroxy, C alkyl is
1-6 1-6
preferably C alkyl, and more preferably C alkyl.
2-6 2-4
When the C alkoxy is substituted with hydroxy, C alkyl is preferably C alkyl,
1-6 1-6 2-6
and more preferably C alkyl.
Preferably, Z is selected from i) C cycloalkyl that is optionally substituted with
3-15
zd ze
one or more -NR R , ii) C aryl that is optionally substituted with one to three substituents
6-10
independently selected from Group C, and iii) 5 to 10 membered heteroaryl that is optionally
substituted with one to three substituents independently selected from Group D.
More preferably, Z is selected from i) C aryl that is optionally substituted with
6-10
one to three substituents independently selected from Group C, and ii) 5 to 10 membered
heteroaryl that is optionally substituted with one to three substituents independently selected
from Group D.
Group C: a) a halogen atom,
zd2 ze2 zd2 ze2
b) -NR R ; wherein R and R are independently selected from a
hydrogen atom, C alkyl and (C alkyl)carbonyl, wherein C alkyl is optionally
1-6 1-6 1-6
substituted with one or more C alkoxy,
zh1 zh1
c) -S(=O) -R ; wherein n7 is an integer of 0 to 2, R is C alkyl,
n7 1-6
d) C alkyl;
e) C alkoxy; wherein C alkoxy is optionally substituted with one or
1-6 1-6
more hydroxy,
f) 5 to 10 membered heteroaryl; wherein 5 to 10 membered heteroaryl is
optionally substituted with one or more substituents independently selected from -
zk1 zl1 zk1 zl1
NR R , wherein R and R are independently selected from a hydrogen atom
and C alkyl.
Group D: a) oxo,
b) a halogen atom,
c) C alkyl; wherein C alkyl is optionally substituted with one or more
1-6 1-6
substituents independently selected from a halogen atom, hydroxy, C alkoxy, and
3 to 12 membered heterocyclyl, wherein 3 to 12 membered heterocyclyl is optionally
substituted with one or more C alkyl, and
d) 3 to 12 membered heterocyclyl.
The compound represented by Formula (I) of the present invention is preferably
such that Z is a group represented by Formula (IIIa), Y is -C(=O)-, R is a group represented
9b 7 8
by Formula (IIb), R is a hydrogen atom, R and R together with a carbon atom to which
they are attached form C cycloalkane ring that is substituted with one to three C alkyl,
3-15 1-6
and the one to three C alkyl is unsubstituted.
Next, examples of the production method of a compound represented by Formula
(I), a salt thereof, or a solvate of either the compound or a salt of the compound are explained
by the following schemes.
The compound represented by Formula (I), a salt thereof, or a solvate of either the
compound or a salt of the compound are produced by conducting i) General production
method A1 or General production method A2, ii) General production method B, and iii)
General production method C. This production method is one example of a preferable
production method of a compound of Formula (I), in which Z is a group represented by
Formula (IIIa), Y is represented by -C(=O)-, R is a group represented by Formula (IIb), and
R is a hydrogen atom, that is, a compound represented by Formula (Ia).
It is also an example of a preferable production method for a copound in which R
and R together with a carbon atom to which they are attached form a C - cycloalkane ring
3 15
substituted with 1 to 3 C - alkyl groups, wherein the alkyl groups are not substituted.
Note that in a case in which a starting material or a target product of a given step
undergoes an undesirable chemical transformation under the reaction condition of that step, it
is possible to obtain the target product of that step by protecting or deprotecting a functional
group. T.W.Greene, P.G.M.Wuts, Protective Groups in Organic Synthesis, Fourth Edition,
John Wiley&Sons, Inc., New York (2007) may be referred to in order to select the protecting
group and the method of protection and deprotection. Some examples of the protection and
deprotection of a functional group are shown in the scheme below.
<General production method A1>
Compound f may be synthesized by the General production method A1 illustrated
by the following scheme.
[Chemical Formula 11]
2 1a 3a
wherein, P is a hydrogen atom or C - alkyl, P is a protective group of amino, P
3b 3a 3b
and P are independently C - alkyl, or P and P together with oxygen atoms to which they
are attached and a carbon atom to which the oxygen atoms are attached may form 5 to 7
1 2 2 1
membered 1,3-dioxacycloalkane ring, Y is cyano or -CO-OP , Y is =O or =NH, and X is a
leaving group.
A protective group of amino includes for example formyl, (C - alkyl)carbonyl
(acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.), carbamoyl, C
alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, sec-
butoxycarbonyl, t-butoxycarbonyl, etc.), substituted silyl (trimethylsilyl, triethylsilyl,
triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, etc.), aralkyloxycarbonyl
(benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, etc.), allyl, and aralkyl.
The leaving group includes, for example, a halogen atom, acetyloxy,
trifluoroacetyloxy, methanesulfonyloxy, paratoluenesulfonyloxy.
Step A1-1a:
Compound a1 may be obtained by reacting Compound a with a base.
Examples of the base include metal hydrides such as sodium hydride, potassium
hydride, lithium hydride; and metal alkoxides such as potassium t-butoxide, sodium t-
butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithium t-
pentoxide. A metal alkoxide such as potassium t-butoxide is preferred.
Examples of the solvent include ether-based solvents such as tetrahydrofuran (THF),
diethyl ether, and dioxane, and THF is preferred.
The reaction temperature is normally -30ºC to 30ºC, preferably -10ºC to 10ºC.
The reaction time is normally 15 min. to 5 h., preferably 30 min. to 3h.
Compound a1 may be isolated, or it may be subjected to step A1-1b without being
isolated.
Compound a may be obtained as a commercial product from Aldlab Chemicals,
LLC or Tokyo Chemical Industry Co., Ltd. It may also be synthesized by referring to
Bioorganic Medicinal Chemistry, 1999, 7, 795-809, or CN 103086955.
Note that Compound a1 may be obtained as an alkali metal salt such as a potassium
salt by being brought into contact with a base used in the reaction, and such salt may be
subjected to the next step.
Step A1-1b:
Compound a1 may be reacted with Compound a2 to obtain Compound b. This
reaction may preferably be performed in the presence of an acid.
Examples of the acid include, for example, acids such as hydrochloric acid, acetic
acid, methanesulfonic acid, p-toluenesulfonic acid, and salts of a weak base and a strong acid
such as pyridine-hydrochloric acid salt.
Examples of the solvent include hydrocarbon-based solvents (hexane, heptane,
benzene, toluene, xylene, etc.) and alcohol-based solvents (methanol, ethanol, etc.).
Further, water may exist in the reaction mixture.
The reaction temperature is normally 40ºC to 200ºC, preferably 60ºC to 150ºC.
The reaction time is normally 6 min. to 30 h., preferably 30 min. to 3 h.
Compound a2 may be commercially obtained as a salt with hydrogen chloride
attached to it from Alfa Aesar, etc. By referring to Synlett, 2011, 17, 2555-2558,
Compound a2 whose hydrazine portion is protected with t-butoxycarbonyl may be put to use
after it is deprotected with an acid such as methanesulfonic acid. Also, by referring to
Journal of Medicinal Chemistry 2003, 46, 1546-1553, Compound a2 may be synthesized by
using compound: Q -NH as the starting compound.
Step A1-2:
Compound b may be reacted with Compound b1 or Compound b2 in the presence of a
base to obtain Compound c.
Examples of the base include tertiary amines (triethylamine, N-methylmorpholine,
diisopropylethylamine, DBU, DABCO, etc.), nitrogen-containing aromatic compounds
(pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine , pyrazine, pyridazine, etc.), metal
hydrides such as sodium hydride, potassium hydride, lithium hydride; and metal alkoxides
such as potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide,
sodium t-pentoxide, and lithium t-pentoxide. When using Compound b2, a metal alkoxide
such as potassium t-butoxide is preferred.
Examples of solvents that may be used include alcohol-based solvents such as
methanol, and ethanol; ether-based solvents such as THF, and diethyl ether; ester-based
solvents such as ethyl acetate, and methyl acetate; nitrile-based solvents such as acetonitrile,
benzonitrile, and benzyl cyanide; amide-based solvents such as N,N-dimethyl acetamide
(DMA), N,N-dimethylimidazolidinone (DMI), and DMF. An amide-based solvent such as
DMA is preferred.
The reaction temperature is normally -50ºC to 70ºC, preferably -30ºC to 50ºC.
The reaction time is normally 15 min. to 72 h., preferably 1 h. to 30 h.
Compound b1 may be commercially obtained from Enamine LTD., etc. By
referring to , Compound b1 may be synthesized by reacting compound:
3a 3b
H NCH CH(OP )(OP ) and phosgene or triphosgene Compound b2 may be commercially
2 2 .
obtained from UkrOrgSyntez Ltd., etc. By referring to WO 99/50262, Compound b2 may
3a 3b
be synthesized by reacting compound: H NCH CH(OP )(OP ) and diisocyanate such as
Step A1-3:
Compound c may be reacted with an acid to obtain Compound d.
Examples of the acid include inorganic acid (hydrochloric acid, hydrobromic acid,
hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acid (methanesulfonic acid,
benzenesulfonic acid, toluenesulfonic acid, etc.), and carboxylic acid (formic acid (FA),
acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid, succinic acid,
malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic acid, fluoroacetic acid,
trifluoroacetic acid (TFA), tartaric acid, propionic acid, glutaric acid, etc.).
Examples of the solvent include ether-based solvents (ether, tetrahydrofuran (THF),
dioxane, dimethoxyethane, cyclopentylmethyl ether, etc.), aromatic hydrocarbon-based
solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), aliphatic hydrocarbon-
based solvents (pentane, hexane, heptane, octane, cyclohexane, etc.), amide-based solvents
(N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methylpyrrolidone), alcohol-based
solvents (methanol, ethanol, 2,2,2-trifluoroethanol, n-propanol, isopropanol, n-butanol, sec-
butanol, pentanol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol,
ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, etc.), acetate ester-based
solvents (methyl acetate, ethyl acetate, isopropyl acetate), acetonitrile, and a mixed solvent
thereof. An ether-based solvent such as tetrahydrofuran is preferred.
The reaction temperature is normally 0ºC to 100ºC, preferably 10ºC to 80ºC.
The reaction time is normally 10 min. to 20h., preferably 30 min. to 5 h.
Step A1-4:
a) When Z is C - alkyl, C - cycloalkyl and 3 to 12 membered heterocyclyl,
1 6 3 15
Compound d may be reacted with Compound d1 in the presence of a base to obtain
Compound e.
Examples of the base include metal hydrides such as sodium hydride, potassium
hydride, and lithium hydride; metal alkoxides such as potassium t-butoxide, sodium t-
butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithium t-
pentoxide; and metal alkyls such as butyllithium, and ethyllithium.
Examples of the solvent include ether-based solvents (ether, tetrahydrofuran (THF),
dioxane, dimethoxyethane, cyclopentylmethyl ether, etc.), aromatic hydrocarbon-based
solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), aliphatic hydrocarbon-
based solvents (pentane, hexane, heptane, octane, cyclohexane, etc.), and amide-based
solvents (N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methylpyrrolidone, etc.).
An amide-based solvent such as N,N-dimethyl acetamide is preferred.
The reaction temperature is normally 0ºC to 150ºC, preferably 20ºC to 120ºC.
The reaction time is normally 15 min. to 24h., preferably 30 min. to 5 h.
b) When Z is C aryl and 5 to 10 membered heteroaryl, Compound d may be
6-10
reacted with Compound d1 in the presence of a base, a copper catalyst and a ligand, to obtain
Compound e.
Examples of the base include a weak basic inorganic salt (sodium carbonate,
potassium carbonate, potassium phosphate, cesium carbonate, etc.), and organic base (triethyl
amine, pyridine, tetrabutylammonium fluoride, etc.). A weak basic inorganic salt such as
potassium carbonate is preferred.
Examples of the copper catalyst include copper iodide (I), copper bromide (I),
copper chloride (I), copper acetate (I), copper oxide (II), and copper
trifluoromethanesulfonate (I), and copper iodide (I) is preferred.
Examples of the ligand include phenanthroline, quinolinol, 2,2,6,6-
tetramethylheptane-3,5-dione, and diamines such as N,N´-dimethylethane-1,2-diamine, trans-
cyclohexane-1,2-diamine, and trans-N,N´-dimethylcyclohexane-1,2-diamine, and trans-N,N´-
dimethylcyclohexane-1,2-diamine is preferred.
Examples of the solvent include ether-based solvents (ether, tetrahydrofuran (THF),
dioxane, dimethoxyethane, cyclopentylmethyl ether, etc.), aromatic hydrocarbon-based
solvents (benzene, toluene, xylene, quinoline, chlorobenzene, etc.), aliphatic hydrocarbon-
based solvents (pentane, hexane, heptane, octane, cyclohexane, etc.), amide-based solvents
(N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methylpyrrolidone, etc.), alcohol-
based solvents (methanol, ethanol, 2,2,2-trifluoroethanol, n-propanol, isopropanol, n-butanol,
sec-butanol, pentanol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol,
ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, etc.), acetate ester-based
solvents (methyl acetate, ethyl acetate, isopropyl acetate, etc.), and acetonitrile, and an
amide-based solvent such as N-methylpyrrolidone is preferred.
The reaction temperature is normally 30ºC to 200ºC, preferably 60ºC to 160ºC.
The reaction time is normally 1 h. to 15 h., preferably 3 h. to 9 h.
Step A1-5:
Compound e may be deprotected to obtain Compound f.
When the protective group P is C alkoxycarbonyl such as t-butoxycarbonyl, it is
preferable to use an acid for deprotection.
Examples of the acid include inorganic acid (hydrogen chloride, hydrobromic acid,
hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acid (methanesulfonic acid,
benzenesulfonic acid, toluene sulfonic acid, etc.), and carboxylic acid (formic acid, acetic
acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid, succinic acid, malonic
acid, gluconic acid, mandelic acid, benzoic acid, salicylic acid, fluoroacetic acid ,
trifluoroacetic acid, tartaric acid, propionic acid, glutaric acid, etc.).
Examples of the solvent include ether-based solvents (tetrahydrofuran,
methyltetrahydrofuran, diethyl ether, t-butylmethyl ether, diisopropyl ether,
cyclopentylmethyl ether, 1,2-dimethoxyethane, etc.), hydrocarbon-based solvents (hexane,
heptane, benzene, toluene, etc.), amide-based solvents (N,N-dimethyl formamide, N,N-
dimethyl acetamide, N-methylpyrrolidone, etc.), and halogen-based solvents
(dichloromethane, chloroform, carbon tetrachloride, etc.), and an amide-based solvent such
as N-methylpyrrolidone is preferred.
The reaction temperature is normally 0ºC to 200ºC, preferably 10ºC to 120ºC.
The reaction time is normally 30 min. to 10 h., preferably 1 h. to 6 h.
Note that Compound f may be obtained as a salt with the acid used in the reaction,
and such salt may be subjected to the next step.
<General production method A2>
2 zd ze
When Z is a bulky group such as C - cycloalkyl that is substituted with -NR R , it
3 15
is possible to synthesize Compound p corresponding to Compound f by General production
method A2 as illustrated by the following scheme.
[Chemical Formula 12]
In the formulae, Z is non-substituted C - cycloalkyl or 3 to 12 membered
3 15
heterocyclyl.
1a 2a
P and P are protective groups of amino,
2 3 4 5
X , X , X and X are each independently a leaving group,
10a 10b 10a 10b
R and R are independently C - alkyl, or R and R together with oxygen
atoms to which they are attached and a carbon atom to which the oxgen atoms are attached
may form a 5 to 7 membered 1,3-dioxacycloalkane ring.
Examples of the protective group of amino include formyl, (C - alkyl)carbonyl
(acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.), carbamoyl, C
alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, sec-
butoxycarbonyl, t-butoxycarbonyl, etc.), substituted silyl (trimethylsilyl, triethylsilyl,
triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, etc.), aralkyloxycarbonyl
(benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, etc.), allyl, aralkyl.
Examples of the leaving group include a halogen atom, acetyloxy,
trifluoroacetyloxy, methanesulfonyloxy, and paratoluenesulfonyloxy.
Step A2-1:
Compound g may be reacted with an azide in the presence of a base, to obtain
Compound h.
Examples of the base include tertiary amines (triethylamine, N-methylmorpholine,
diisopropylethylamine, DBU, DABCO, etc.).
Examples of the azide include metal azides such as sodium azide, trimethylsilyl
azide, and diphenylphosphoryl azide, and diphenylphosphoryl azide is preferred.
Examples of the solvent include ether-based solvents (tetrahydrofuran,
methyltetrahydrofuran, diethyl ether, t-butylmethyl ether, diisopropyl ether,
cyclopentylmethyl ether, 1,2-dimethoxyethane, etc.), hydrocarbon-based solvents (hexane,
heptane, benzene, toluene, etc.), and amide-based solvents (N,N-dimethyl formamide, N,N-
dimethyl acetamide, N-methylpyrrolidone), and a hydrocarbon-based solvent such as toluene
is preferred.
The reaction temperature is normally 0ºC to 150ºC, preferably 10ºC to 100ºC.
The reaction time is normally 1 h. to 10 h., preferably 2 h. to 6 h.
Compound g is described in, for example, Journal of the American Chemical
Society, 2016, 138, 1698-1708 and . It may also be commercially
obtained from Enamine Ltd.
Step A2-2:
Compound b obtained in Step A1-1b may be reacted with Compound h in the
presence of a base, to obtain Compound i.
Examples of the base include tertiary amines (triethylamine, N-methylmorpholine,
diisopropylethylamine, DBU, DABCO, etc.), and nitrogen-containing aromatic compounds
(pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine , pyrazine, pyridazine, etc.).
Examples of the solvent include ether-based solvents such as tetrahydrofuran (THF),
diethyl ether, dioxane; and hydrocarbon-based solvents such as hexane, heptane, benzene,
toluene, etc. A base such as pyridine may also be used as the solvent.
The reaction temperatureis normally 0ºC to 60ºC, preferably 5ºC to 45ºC.
The reaction time is normally 30 min. to 50 h., preferably 2 h. to 10 h.
Step A2-3:
Compound i may be reacted with Compound i1 or Compound i2 in the presence of a
base to obtain Compound j.
The base includes a weak basic inorganic salt (sodium carbonate, potassium
carbonate, cesium carbonate, etc.), and metal hydrides (sodium hydride, potassium hydride,
etc.), and a weak basic inorganic salt such as cesium carbonate is preferred.
Examples of Compound i1 include 1,2-dichloromethoxyethane, 1,2-dichloro
ethoxyethane, ans 1,2-dichloroi-propoxyethane, and 1,2-dichlorot-butoxyethane, and
1,2-dichloroethoxyethane is preferred. Compound i1 may be commercially obtained
from Tokyo Chemical Industry Co., Ltd. or FCH Group.
Examples of Compound i2 include 2-chloro-1,1-dimethoxyethane, 2-chloro-1,1-
diethoxyethane, 2-bromo-1,1-dimethoxyethane, and 2-bromo-1,1-ethoxyethane. Compound
i2 may be commercially obtained from Tokyo Chemical Industry Co., Ltd.
Examples of the solvent include alcohol-based solvents such as methanol, ethanol;
ether-based solvents such as THF, diethyl ether; ester-based solvents such as ethyl acetate,
methyl acetate; nitrile-based solvents such as acetonitrile, benzonitrile, benzyl cyanide; and
amide-based solvents such as N,N-dimethyl acetamide (DMA), N,N-dimethyl
imidazolidinone (DMI), DMF. An amide-based solvent such as DMA is preferred.
The reaction temperature is normally 0ºC to 60ºC, preferably 20ºC to 45ºC.
The reaction time is normally 1 h. to 72 h., preferably 12 min. to 35 h.
Step A2-4:
Compound j may be reacted with acid to obtain Compound k.
Examples of the acid include an inorganic acid (hydrochloric acid, hydrobromic
acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), a sulfonic acid (methanesulfonic
acid, benzenesulfonic acid, toluenesulfonic acid, etc.), and a carboxylic acid (formic acid,
acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid, succinic acid,
malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic acid, fluoroacetic acid,
trifluoroacetic acid, tartaric acid, propionic acid, glutaric acid, etc.), and a sulfonic acid such
as methanesulfonic acid is preferred.
Examples of the solvent include ether-based solvents such as tetrahydrofuran (THF),
diethyl ether, and dioxane, and THF is preferred.
The reaction temperature is normally 0ºC to 100ºC, preferably 20ºC to 80ºC.
The reaction time is normally 15 min. to 6 h., preferably 30 min. to 3 h.
Step A2-5:
Compound k may be reacted with Compound k1 in the presence of a base, to obtain
Compound l.
Examples of Compound k1 include C alkyl halides such as methyl iodide, and
(C - alkyl)carbonyl halides such as acetyl chloride. When R is (C - alkyl)carbonyl, it is
1 6 1 6
preferred to use an acid anhydride that is represented as ((C - alkyl)carbonyl) O, for
1 6 2
example, an acetic anhydride in place of Compound k1.
Examples of the base include metal hydrides such as sodium hydride, potassium
hydride, and lithium hydride; and metal alkoxides such as potassium t-butoxide, sodium t-
butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, and lithium t-
pentoxide. A metal alkoxide such as potassium pentoxide is preferred.
Examples of the solvent includes ether-based solvents such as tetrahydrofuran
(THF), diethyl ether, dioxane; and hydrocarbon-based solvents such as hexane, heptane,
benzene, toluene. THF is preferred.
The reaction temperature is normally -50ºC to 50ºC, preferably -40ºC to 40ºC.
The reaction time is normally 1 min. to 2 h., preferably 3 min. to 30 min.
Step A2-6:
Compound l may be deprotected to obtain Compound m.
An appropriate reagent or reaction condition may be selected according to the type
of the protective group in deprotection. When the protective group is t-butoxycarbonyl, a
reaction with an acid is preferred.
Examples of the acid include inorganic acid (hydrochloric acid, hydrobromic acid,
hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acid (methanesulfonic acid,
benzenesulfonic acid, toluenesulfonic acid, etc.), and carboxylic acid (formic acid, acetic
acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid, succinic acid, malonic
acid, gluconic acid, mandelic acid, benzoic acid, salicylic acid, fluoroacetic acid,
trifluoroacetic acid, tartaric acid, propionic acid, glutaric acid, etc.), and carboxylic acid such
as trifluoroacetic acid is preferred.
Examples of the solvent include ether-based solvents such as diethyl ether, THF,
dimethoxyethane, etc.; halogen-based solvents such as dichloromethane (CH Cl ),
chloroform, carbon tetrachloride; N,N-dimethylformamide; and acetonitrile. A halogen-
based solvent such as CH Cl is preferred.
The reaction temperature is normally 0ºC to 60ºC, preferably 10ºC to 40ºC.
The reaction time is normally 30 min. to 10 h., preferably 1 h. to 5 h.
Note that Compound m may be obtained as a salt with the acid used in the reaction,
and such salt may be subjected to Step A2-7.
Step A2-7:
An amino in Compound m may be protected to obtain Compound n.
An appropriate reagent or reaction condition may be selected according to the type
of protective group in protection. When the protective group is C alkoxycarbonyl, a
reaction with a base is preferred.
Examples of the compound used for protection include methoxycarbonyl chloride,
ethoxycarbonyl chloride, 2,2,2-trichloroethoxycarbonyl chloride, benzoyl chloride (Z-Cl), 9-
fluorenylmethyloxycarbonyl chloride (Fmoc-Cl), and di-t-butyl dicarbonate, and di-t-butyl
dicarbonate is preferred.
Examples of the base include tertiary amines (triethylamine, N-methylmorpholine,
diisopropylethylamine, DBU, DABCO, etc.), and nitrogen-containing aromatic compounds
(pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine , pyrazine, pyridazine, etc.), and a
tertiary amine such as triethyl amine is preferred.
Examples of the solvent includes ether-based solvents such as diethyl ether, THF,
dimethoxyethane, etc.; halogen-based solvents such as dichloromethane (CH Cl ),
chloroform, carbon tetrachloride; N,N-dimethylformamide; and acetonitrile. A halogen-
based solvent such as CH Cl is preferred.
The reaction temperature is normally 0ºC to 60ºC, preferably 15ºC to 40ºC.
The reaction time is normally 30 min. to 20 h., preferably 1 h. to 5 h.
Step A2-8:
Compound n may be reacted with Compound n1 in the presence of a base to obtain
Compound o.
Examples of Compound n1 include C alkyl halides such as methyl iodide, and (C
1-6 1-
alkyl)carbonyl halide such as acetyl chloride. When R is C alkyl, it is preferred that
6 1-6
C alkyl is either not substituted or substituted with C alkoxy.
1-6 1-6
This step is performed similarly to Step A2-5, and the base, and solvent used in the
reaction, and reaction temperature, reaction time are similar to Step A2-5.
Step A2-9:
Compound o may be deprotected to obtain Compound p.
An appropriate reagent or reaction condition may be selected according to the type
of protective group in deprotection. When the protective group P is C alkoxycarbonyl
such as t-butoxycarbonyl, deprotection using an acid is preferred.
This step is performed similarly to Step A1-5, and the acid, and solvent used in the
reaction, and reaction temperature, reaction time are similar to Step A1-5.
<General production method B>
It is possible to synthesize Compound bf by General production method B as
illustrated by the following scheme.
[Chemical Formula 13]
21 21a 21b, 21a 21b
In the formulae, P is hydroxy, C - alkoxy, or -NR R and R and R are
independently a hydrogen atom, C alkyl or C aryl,
1-6 6-10
21 21a
X is a hydrogen atom, a halogen atom, or -Zn-X ,
X is a bromine atom or an iodine atom, and
X is a leaving group.
The leaving group includes, for example, a halogen atom, acetyloxy,
trifluoroacetyloxy, methanesulfonyloxy, paratoluenesulfonyloxy.
Step B-1:
Compound ba may be reacted with Compound ba1 in the presence of a paradium
catalyst to obtain Compound bb.
The complex formed in the reaction mixture by separately adding a palladium
compound and a ligand may be used as the palladium catalyst. The complex that has been
prepared separately may be used. Examples of the ligand include 4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene, trimethylenebis(diphenylphosphine), 2-(di-t-
butylphosphino)biphenyl, 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl, 2-(di-t-
butylphosphino)-2’,4’,6’-triisopropyl-3,6-dimethoxy-1,1’-biphenyl, and 2-di-t-
butylphosphino-2’,4’,6’-triisopropylbiphenyl. Examples of palladium compounds that may
be combined with a ligand include, for example, di-μ-chlorobis[(η-allyl)palladium(II)],
tetrakis(triphenylphosphine)palladium(0).
Examples of the palladium catalyst that may be used with the present step include
tris(dibenzylideneacetone)dipalladium(0), 5,10,15,20-tetraphenyl-21H,23H-porphine
Cobalt(II), palladium(II) acetate, bis(di-t-butyl(4-
dimethylaminophenyl)phosphine)dichloropalladium(II), [1,1’-
bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct,
dichlorobis(triphenylphosphine)palladium(II), palladium hydroxide,
tetrakis(triphenylphosphine)palladium(0), and di-μ-chlorobis[(η-allyl)palladium(II)]. It is
preferred to use a complex formed from a palladium compound of di-μ-chlorobis[(η-
allyl)palladium(II)] and a ligand of 2-(di-t-butylphosphino)-2’,4’,6’-triisopropyl-1,1’-
biphenyl as a catalyst in Step 11.
Note that the step may be performed in the presence of a base.
Examples of the base includes a weak basic inorganic salt (sodium carbonate,
potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, calcium acetate,
etc.), metal hydrides (sodium hydride, potassium hydride, etc.), and metal alkoxides
(potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium
t-pentoxide, lithium t-pentoxide, etc.).
Examples of the reaction solvent include ether-based solvents such as
tetrahydrofuran (THF), diethyl ether, dioxane, etc.; amide-based solvents such as N,N-
dimethyl acetamide (DMA), N,N-dimethylimidazolidinone (DMI), DMF. The solvent may
be a mixture with water.
The reaction temperature is normally 10ºC to 200ºC, preferably 40ºC to 130ºC.
The reaction time is normally 1 min. to 20 h., preferably 10 min. to 10 h.
Compound ba may be obtained commercially from Aurora Fine Chemicals. It may
also be synthesized by referring to Synthetic Communications, 39(14), 2506-2515, 2009. It
may also be obtained by esterfying or amidating Compound ba in which -COP is -COOH.
21 21a
Compound ba1 whose X is -Zn-X may be obtained commercially from Focus
Synthesis LLC. It may be synthesized by referring to .
Step B-2:
Compound bb may be reacted with Compound bb1 in the presence of a base to
obtain Compound bc.
Examples of the base include metal hydrides such as sodium hydride, potassium
hydride, etc., and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide,
potassium hydroxide, and cesium hydroxide, and potassium hydroxide is preferred.
Examples of the reaction solvent include amide-based solvents such as N,N-
dimethyl acetamide (DMA), N,N-dimethylimidazolidinone (DMI), and DMF, and DMI is
preferred. The solvent may be a mixture with water.
The reaction temperature is normally -10ºC to 100ºC, preferably 0ºC to 45ºC.
The reaction time is normally 30 min. to 10 h., preferably 1 h. to 5 h.
Compound bb may be obtained commercially from Aquila Pharmatech LLC. It
may be synthesized by referring to , Organic Letters, 7(18), 3965-3968,
2005, or US 5998438.
Step B-3:
Compound bc may be reacted with hydroxyamine (H NOH) to obtain Compound
Examples of the reaction solvent include aprotic polar solvents such as
dimethylsulfoxide (DMSO), dimethylformamide, dimethylacetamide, and 1-methyl
pyrrolidinone, and alcohol-based solvents such as methanol and ethanol, and DMSO is
preferred. The solvent may be a mixture with water.
The reaction temperature is normally -10ºC to 100ºC, preferably 20ºC to 45ºC.
The reaction time is normally 2 h. to 72 h., preferably 3 h. to 36 h.
Compound bd may be subjected to Step B-4 without being isolated or purified.
Step B-4:
Compound bd may be reacted with triphosgene, chloro-carbonic acid ester (methyl
chlorocarbonate, ethyl chlorocarbonate, isopropyl chlorocarbonate, etc.), carbonyl
diimidazole, etc., preferably carbonyl diimidazole in the presence of a base, to obtain
Compound be.
Examples of the base include tertiary amines (triethyl amine, N-methylmorpholine,
diisopropylethylamine, 1,8-diazabicycloundecene (DBU), DABCO, etc.), and metal
hydroxides (sodium hydroxide, potassium hydroxide), and a tertiary amine such as DBU is
preferred.
Examples of the solvent include aprotic polar solvents such as dimethylsulfoxide
(DMSO), dimethylformamide, dimethylacetamide, and 1-methylpyrrolidinone, alcohol-
based solvents such as methanol and ethanol, and ether-based solvents such as
tetrahydrofuran (THF), diethyl ether, and dioxane, and DMSO is preferred.
The reaction temperature is normally -10ºC to 100ºC, preferably 20ºC to 45ºC.
The reaction time is normally 10 min. to 10 h., preferably 15 min. to 2 h.
Step B-5:
Compound be that is protected with P may be deprotected using a base to obtain
Compound bf.
Examples of the base include alkali metal hydroxides such as lithium hydroxide,
sodium hydroxide, potassium hydroxide, and cesium hydroxide; and metal alkoxides such as
potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium
t-pentoxide, and lithium t-pentoxide.
Examples of the solvent include alcohol-based solvents such as methanol, ethanol,
methoxy ethanol, t-butylalcohol; ether-based solvents such as THF, diethyl ether; and amide-
based solvents such as N,N-dimethyl acetamide (DMA), N,N-dimethylimidazolidinone
(DMI), and DMF. The solvent may also be a mixture with water.
The reaction temperature is normally -20ºC to 120ºC, preferably 20ºC to 100ºC.
The reaction time is normally 20 min. to 10 h., preferably 30 min. to 5 h.
Note that the order of Steps B-1, B-2, B-3, B-4 and B-5 may be changed. For
example, Compound ba may be sequentally subjected to Step B-2, and Step B-1 to obtain
Compound bc. Compound ba may be sequentially subjected to Step B-2, Step B-3, Step B-
4, Step B-5, and Step B-1 to obtain Compound bf. Compund ba may be sequentially
subjected to Step B-2, Step B-3, Step B-4, Step B-1 and Step B-5 to obtain Compound bf.
Step B-Aa and Step B-Ab:
Further when X is a halogen atom, Compound ba may be subjected to the
following Step B-Aa and Step B-Ab to obtain Compound bb, and Compound bb may also be
subjected to Step B-2.
[Chemical Formula 14]
Qc Qd
In the formulae, R and R are independently a hydrogen atom or C alkyl, or
Qc Qd
R and R together with oxygen atoms to which they are attached and a carbon atom to
which the oxygen atomes are attached may form 1,3,2-dioxaborolanyl or 1,3,2-
dioxaborinanyl.
Step B-Aa:
Compound ba may be reacted with Compound ba2 or Compound Ba3 in the
presence of a palladium catalyst to obtain an organic boron Compound baa. This step may
be performed in the presence of a base.
This step is performed similarly to Step B-1, and the palladium catalyst, the base,
the solvent used in the reaction, or the reaction temperature, reaction time are similar to Step
B-1.
Examples of Compound ba2 include pinacol borane, 4,6,6-trimethyl-1,3,2-
dioxaborinane. Compound ba3 includes, for example, diboronic acid, pinacol
diborane(4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane)), bis(neopentyl
glycolato)diboron, and bis(hexylene glycolato)diboron. These compounds may be obtained
as a commercial product from Tokyo Chemical Industry Co., Ltd. By referring to Journal
of the American Chemical Society, 131(45), 16346-16347, 2009 or Organic Synthesis, 77,
176-185, 2000, they may also be synthesized using i) pinacol and ii) diborane, BH ・THF
complex or BH ・dimethyl sulfide complex.
The organic boron compound baa may be subjected to Step B-Ab without being
isolated.
Step B-Ab:
An organic boron compound baa may be reacted with Compound ba1 in the
presence of base to obtain Compound bb.
Examples of the base include a weak basic inorganic salt (sodium carbonate,
potassium carbonate, cesium carbonate, sodium acid carbonate, potassium acid carbonate,
etc.), and sodium carbonate is preferred.
The solvent used in the reaction or the reaction temperature, reaction time is the
same as Step B-1.
Note that a transformation of Compound ba1 to an organic boron compound similar
to the transformation of Compound ba to Compound baa, followed by a reaction thereof with
Compound ba also provides Compound bb.
Step B-B:
Further, when Compound bb1 is represented by X -(CH ) -CH -CN, Compound
2 n1 2
bca corresponding to Compuond bc obtained in Step B-2 may be subjected to Step B-B, that
is, reacted with Compound bc1 in the presence of a base to give Compound bcb
corresponding to Compound bc, in which R and R together with a carbon atom to which
they are attached form C cycloalkane ring, and C cycloalkane ring formed by
3-15 3-15
combining R and R may be substituted with one to three C alkyls, and the resulting
compound may be subjected to Step B-3.
[Chemical Formula 15]
7c 7e 7d
In the formulae, R , R and R existing in a number of n8 are each independently a
hydrogen atom or C alkyl, and n8 is an integer of 0 to 3.
The base includes, for example, metal hydrides such as sodium hydride, potassium
hydride, lithium bis(trimethylsilyl)amide (LiHMDS), and sodium bis(trimethylsilyl)amide
(NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide
(LDA), and lithium 2,2,6,6-tetramethylpyrrolidide, and KHMDS is preferred.
The solvent includes, for example, ether-based solvents such as THF, diethyl ether
and dioxane, amide-based solvents such as N,N-dimethyl acetamide (DMA), N,N-
dimethylimidazolidinone (DMI), DMF, N,N'-dimethylpropyleneurea (DMPU), and an amide-
based solvent such as DMPU is preferred.
The reaction temperature is, for example, -20ºC to 40ºC, preferably -10ºC to 10ºC.
The reaction time is, for example, 30 min. to 8 h., preferably 1 h. to 4 h.
Compound bc1 may be obtained as a commercial product from CGeneTech. Inc. It
may also be synthesized by referring to Organic Letters, 12(17), 3938-3941, 2010.
<General production method C>
Step C-1:
[Chemical Formula 16]
Compound f (or Compound p) and Compound bf may be condensed using a
condensation agent in the presence of a base, and Compound (Ia) may be obtained.
Examples of the condensation agent include BOP-based condensation agents such as
benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP),
benzotriazolyloxy-tris(pyrrolizino)phosphonium hexafluorophosphate (PyBOP(Registered
Trademark)), PyAOP, BroP, PyCloP, PyBroP(Registered Trademark), DEPBT; 4-(4,6-
dimethoxy-1,3,5-triazinyl)methylmorpholinium chloride n-hydrate (DMT-MM), 2-(1H-
benzotriazolyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU),
[dimethylamino(triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylazanium
hexafluorophosphate (HATU), and ethyl (hydroxyimino)cyanoacetate (Oxyma). HATU is
preferred.
Examples of the base include tertiary amines (triethyl amine, N-methylmorpholine,
diisopropylethylamine, DBU, DABCO, etc.), and nitrogen-containing aromatic compounds
(pyridine, dimethylaminopyridine, picoline, (2,6-)lutidine , pyrazine, pyridazine, etc.), and a
tertiary amine such as diisopropylethylamine is preferred.
Examples of the solvent include ether-based solvents such as THF, diethyl ether and
dioxane, aprotic polar solvents such as dimethylsulfoxide (DMSO), dimethylformamide
(DMF), dimethylacetamide, and 1-methylpyrrolidinone, and an aprotic polar solvent such
as DMF is preferred.
The reaction temperature is, for example, 0ºC to 80ºC, preferably 20ºC to 60ºC.
The reaction time is, for example, 1 min. to 10 h., preferably 30 min. to 5 h.
Note that Compound (Ia) may be obtained by changing the order of the steps, for
example, by sequentially subjecting Compound d to Step A1-5, Step C-1, Step A1-4,
sequentially subjecting Compound ba to Step B-2, Step B-3, Step B-4, Step B-5, Step C-1,
and Step B-1.
Further, the compound represented by Formula (I) may be brought in contact with or
reacted with an acid or base that may be used in the production of pharmaceutical
preparations to obtain the salt thereof. The salt may be any pharmaceutically acceptable
salt, and examples of such salts include inorganic acid salts (hydrochloric acid salt,
hydrobromic acid salt, hydroiodic acid salt, sulfuric acid salt, phosphoric acid salt, etc.),
sulfonic acid salts (methanesulfonic acid salt, ethanesulfonic acid salt, benzenesulfonic acid
salt, toluene sulfonic acid salt, etc.), carboxylic acid salts (formic acid salt, acetic acid salt,
oxalic acid salt, maleic acid salt, fumaric acid salt, citric acid salt, malic acid salt, succinic
acid salt, malonic acid salt, gluconic acid salt, mandelic acid salt, benzoic acid salt, salicylic
acid salt, fluoroacetic acid salt, trifluoroacetic acid salt, tartaric acid salt, propionic acid salt,
glutaric acid salt, adipic acid salt, nicotinic acid salt, etc.), alkali metal salts (lithium salt,
sodium salt, potassium salt, cesium salt, rubidium salt, etc.), alkali earth metal salts
(magnesium salt, calcium salt, etc.), ammonium salts (ammonium salt, alkylammonium salt,
dialkylammonium salt, trialkylammonium salt, tetraalkylammonium salt, etc.), and basic
amino acid salts (lysine salt, arginine salt, etc.), and alkali metal salts and alkali earth metal
salts are preferred, and sodium salts and calcium salts are even more preferred. For
example, the free form of a compound represented by Formula (I) may be suspended or
dissolved in alcohol, such as methanol, and ethanol, or acetonitrile, acetone,
dimethylsulfoxide, etc. and a basic aqueous solution containing sodium ion from sodium
hydroxide, etc., a methanol solution containing sodium methoxide, or an ethanol solution
containing sodium ethoxide is added thereto, to obtain a sodium salt of a compound
represented by Formula (I). The reaction temperature is, for example, 0ºC to 80ºC,
preferably 20ºC to 60ºC.
The compound represented by Formula (1) or a salt thereof may be a solvate, or a
non-solvate. The solvent contained in a solvate may be either water or an organic solvent.
Alcohols (e.g. methanol, ethanol, n-propanol), dimethylformamide, acetonitrile, acetone,
dimethylsulfoxide may be used as the organic solvent. The compound represented by
Formula (I) and a salt thereof may be preferably used in the form of a hydrate, and it is also
preferably used in the form of a non-solvate. The proportion of the solvent molecule
(preferably a water molecule) against a single molecule compound represented by Formula
(I) or a salt thereof is, for example, 0.1 to 10, and 0.5 to 6 is more preferred. Further, the
proportion may fluctuate by humidity, the production method, and the production season.
The solvate of a compound represented by Formula (I) or a salt thereof may be
obtained by a common method, such as precipitating the compound represented by Formula
(1) or a salt thereof from a solvent. Further, the hydrate may be obtained by precipitating a
compound represented by Formula (I) or a salt thereof from a water-containing organic
solvent.
The solvate of a compound represented by Formula (I) or a salt thereof may be
transformed to a compound represented by Formula (I) or a salt thereof by a common method
such as heating under reduced pressure.
A compound used as a pharmaceutical agent is preferably the compound represented
by Formula (I) per se (free form), a hydrate of the free form, a salt of the free form, and a
hydrate of salt, more preferably, a free form, a hydrate of the free form, a sodium salt of the
free form, a hydrate of a sodium salt, a calcium salt of the free form, and a hydrate of the
calcium salt.
The compound represented by Formula (I) or a salt thereof, or a solvate of either the
compound or a salt of the compound, of the present invention may be used in a form of a
crystal, or in an amorphous state.
The present invention includes all stereoisomers of the compound represented by
Formula (I) (e.g. enantiomer, diastereomer (including cis- and trans- geometric isomer)), the
racemic form of the isomers, and other mixtures. For example, the compound of the present
invention may have one or more asymmetric center, and the present invention includes a
racemic mixture, a diastereomer mixture, and enantiomers of such compound.
The present invention includes an embodiment in which an atom constituting the
compound molecule of the present invention represented by Formula (I) is an isotope, and
includes an embodiment in which at least one atom is substituted with an atom having the
same atomic number (proton number) and a different mass number (sum of protons and
neutrons). Examples of isotopes included in the compound of the present invention include
hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorous atom, sulfur atom,
2 3 13 14 15 17 18 31
fluorine atom, chlorine atom, which respectively include H, H, C, C, N, O, O, P,
32 35 18 36
P, S, F, Cl. In particular, radioisotopes which emit radiation as they decay, such as
3 14
H or C, are useful in pharmaceutical preparations or in vivo topographic tests of
compounds. The stable isotope neither decays nor changes in their amount, nor have
radioactivity, so they can be used safely. When the atom constituting the compound
molecule of the present invention is an isotope, it may be transformed according to the
common method by replacing the reagent used in synthesis with a reagent containing the
corresponding isotope.
The compound of the present invention, a salt thereof, or a solvent of these has a
GLP1 receptor agonist effect and a blood glucose level reduction effect, and it may be used
for the prevention or therapy of non-insulin-dependent diabetes mellitus (Type 2 diabetes),
hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus (Type 1
diabetes), diabetic complication, obesity, hypertension, hyperlipidemia, arteriosclerosis,
myocardial infarction, coronary heart disease, brain infarction, non-alcoholic steatohepatitis,
Parkinson's disease, or dementia, by administering it to patients in the form of a
pharmaceutical composition in pharmacologically effective amount by an appropriate
administration method.
“Diabetes” in the present invention is a state or a disease in which the metabolism
for generating and using glucose becomes deficient due to a failure in maintaining an
appropriate blood glucose level in the body, and encompasses insulin-dependent diabetes
mellitus (Type 1 diabetes) and non-insulin-dependent diabetes mellitus (Type 2 diabetes).
“Hyperglycemia” refers to a state in which the plasma glucose level while fasting or
after administration of glucose is higher than the normal value (e.g. 80 to 110 mg/dL in
human while fasting), and it is a typical symptom of diabetes.
“Impaired glucose tolerance” includes insulin-resistant impaired glucose tolerance
and insulin hyposecretion.
“Diabetic complication” is a complication caused by diabetes or hyperglycemia, and
it may be acute complex or chronic complex. The term “acute complex” includes
ketoacidosis, and infectious disease (e.g. skin infection, soft tissue infection, biliary system
infection, respiratory system infection, urinary tract infection), and the “chronic complex”
includes, for example, microangiopathy (e.g. nephropathy, retinopathy), neuropathy (e.g.
sensory nerve disorder, motor nerve disorder, autonomic nerve disorder), and gangrene.
Major diabetes complexes include diabetic retinopathy, diabetic nephropathy, and diabetic
neuropathy. “Coronary heart disease” includes myocardial infarction and angina pectoris.
“Dementia” includes, for example, Alzheimer's disease, vascular dementia, and
diabetic dementia.
The administration method may be systemic administration including oral
administration, rectal administration, intravenous administration, intramuscular
administration, subcutaneous administration, intravaginal administration, intraperitoneal
administration, intravesical administration, and aspiration, as well as local administration by
ointment, gels, and cream.
When using the compound of the present invention, a salt thereof, or a solvate of
either the compound or a salt of the compound in the form of a pharmaceutical composition,
it is normally formulated into a certain pharmaceutical formulation (dosage form).
Examples of such pharmaceutical formulations include a tablet, a capsule, granules, powders,
subtle granules, pills, aqueous or non-aqueous solution or suspension. Further, the
compound of the present invention, a salt thereof, or a solvate of either the compound or a
salt of the compound may also be used in the form of various controlled release preparations.
Examples of such controlled release preparations include, for example, those to be imbedded
in the body, those applied to the oral mucosa or nasal mucosa. The solution or suspension
may be filled in containers suited for dividing into respective administration amounts to be
stored.
The various pharmaceutical formulations may be produced by a well known method
by mixing the compound of the present invention, a salt thereof, or a solvate of either the
compound or a salt of the compound and a pharmaceutically acceptable additive. Examples
of such additives include, for example, an excipient, a lubricant (a coating agent), a binding
agent, a disintegrator, a stabilizer, correctives, a base, a dispersant, a diluent, a surfactant, or
an emulsifier.
Examples of an excipient include starch (starch, potato starch, corn starch, etc.),
lactose, crystalline cellulose, and dicalcium phosphate.
Examples of a lubricant (coating agent) include ethyl cellulose, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, shellac, talc, carnauba wax, and paraffin.
Examples of a binding agent include polyvinyl pyrrolidone, macrogol, and
compounds that are the same as the above excipient.
Examples of a disintegrator include chemically modified starch and cellulose, such
as croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone,
and compounds that are the same as the above excipient.
Examples of a stabilizer include para-oxybenzoates such as methyl paraben, and
propyl paraben; benzalkonium chloride; phenols such as phenol, and cresol; thimerosal;
dehydroacetic acid; and sorbic acid.
Examples of a correctives include sweetener, acidulant, and flavor, that are normally
used.
Examples of a base include fats such as lard; vegetable oil such as olive oil and
sesame oil; higher alcohols such as stearyl alcohol, and cetanol; animal oil; lanolin acid;
Vaseline; paraffin; bentonite; glycerin; and glycol oil.
Examples of a dispersant include cellulose derivative (Arabic rubber, tragacanth,
methyl cellulose, etc.), stearic acid polyesters, sorbitan sesquioleate, aluminum monostearate,
sodium alginate, polysorbate, and sorbitan fatty acid ester.
Examples of the solvent or diluent in a liquid formulation include phenol,
chlorocresol, purified water, distilled water, etc.
Examples of a surfactant or emulsifier include polysorbate 80, polyoxyl 40 stearate,
lauromacrogol.
The content of the compound of the present invention, a salt thereof, or a solvate of
either the compound or a salt of the compound in the pharmaceutical formulation differs by
the dosage form, but it is generally 0.01 to 100 wt%.
The pharmaceutical formulation may contain one type or two or more types of the
compound of the present invention, a salt thereof, or a solvate of either the compound or a
salt of the compound.
When using the compound of the present invention, a salt thereof, or a solvate of
either the compound or a salt of the compound as a preventative agent or a therapeutic agent
for non-insulin-dependent diabetes mellitus (Type 2 diabetes) or obesity, the amount to be
administered may be appropriately determined according to the severity of the symptom, the
age, the body weight, the relative health state, whether other drugs are combined, and the
method of administration. For example, when the subject of administration is a
homeotherm, particularly a human, the dosage per day is 0.01 to 10000 mg, preferably 0.1 to
1000 mg, in oral administration, and 0.001 to 3000 mg, preferably 0.01 to 300 mg in a non-
oral administration. Note that the above dosage may be administered once per a day to a
few weeks, or it may be divided into two or more times per day.
The effective amount of the compound of the present invention, a salt thereof, or a
solvate of either the compound or a salt of the compound means a therapeutic effective
amount or a preventative effective amount, and it may be appropriately determined according
to the severity of the symptom, the age, the body weight, the relative health state, whether
other drugs are combined, and the method of administration
EXAMPLES
The content of the present invention is explained in more detail by the following
Examples and Reference Examples. All starting materials and reagents were obtained from
commercial suppliers or synthesized by commonly known methods. A room temperature
(rt) is a temperature of 5 to 35ºC. The silica gels that were used were SHOKO Scientific
Purif-Pack(Registered Trademerk) SI 60 μm (Shoko Scientific Co., Ltd.), Biotage
(Registered Trademark) SNAP Ultra Silica Cartridge (Biotage), or SNAP KP-Sil Cartridge
(Biotage), reversed-phase silica gel was Wakosil (Registered Trademark) 25C18 (Wako Pure
Chemical Industries, Ltd.), or Biotage (Registered Trademark) SNAP Ultra C18 Cartridge
(Biotage). The HPLC purification of the compound was performed using AutoPurification
HPLC/MS System (Waters) or Preprative HPLC system with injection/fractionation function
(gilson). The H-NMR spectrum was measured using or not using Me Si as an inner
reference material, and using ECP-400 (JEOL), Agilent 400-MR (Agilent Technologies
Japan, Ltd), AVANCE3 300MHz (Bruker) or AVANCE3 600MHz Cryo-TCI (Bruker)
(s=singlet, brs=broad singlet, d=doublet, t=triplet, q=quartet, dd=double doublet, ddd=double
double doublet, m=multiplet). The chemical shift of the NMR data uses Me Si or
deuterized solvent as a reference, and is presented using ppm (parts per million, δ), and the
coupling constant (J) was shown using Hz (Hertz). LC/MS was carried out by measuring
the retention time and performing mass spectrometry using the device and the analysis
condition of Table 1. Microwave was irradiated using InitiatorTM (Biotage). The mass
spectrometry in LC/MS was performed using the following mass spectrometers: SQD
(Waters), SQD2 (Waters), 2020 (Shimadzu), or 2010EV (Shimadzu).
[Table 1]
Table 1. Device and Analysis Condition used for LC/MS
LC/MS
Analysis
Device Column Mobile phase, gradient and flow rate
Condition
Speed Core C18 0.1%FA H O/0.1%FA MeCN
nexera/20
SMD-FA05-1 2.1mmI.D.x50mm, =95/5→0/100(1.5 min.)→0/100(0.5
2.7μm min.), 1 mL/min.
Metoric Core C18 0.1%FA H O/0.1%FA MeCN
nexera/20
SMD-FA05-2 2.1mmI.D.x50mm, =95/5→0/100(1.5min.)→0/100(0.5
2.7μm min.), 1 mL/min.
nexera/20 Ascentis Express C18 0.1%FA H O/0.1%FA MeCN
SMD-FA05-3
2.1mmI.D.x50mm, =95/5→0/100(1.5 min.)→0/100(0.7
2.7μm min.), 1 mL/min.
Speed Core C18 0.1%FA H O/0.1%FA MeCN
SMD-FA05- nexera/20
2.1mmI.D.x50mm, =05/95→0/100(4.5 min.)→0/100(0.5
long 20
2.7μm min.), 1 mL/min.
Phenomenex kinetex
0.1%FA H O/0.1%FA MeCN
UFLCXR C18
SMD-FA10-1 =90/10→0/100(1.2 min.)→0/100(0.5
/2020 3.0mmI.D.x50mm,
min.), 1.5 mL/min.
2.6μm
Kinetex XB-C18 0.1%FA H O/0.1%FA MeCN
UFLCXR
SMD-FA10-2 3.0mmI.D.x50mm, =90/10→0/100(1.2 min.)→0/100(0.5
/2020
2.6μm min.), 1.5 mL/min.
Kinetex XB-C18 0.1%FA H2O/0.1%FA MeCN
UFLCXR
SMD-FA10-3 3.0mmI.D.x50mm, =90/10→0/100(1.1 min.)→0/100(0.7
/2020
2.6μm min.), 1.5 mL/min.
Acquity BEH C18 0.1%FA H O/0.1%FA MeCN
UFLCXR
SMD-FA10-4 2.1mmI.D.x50mm, =90/10→0/100(1.1 min.)→0/100(0.5
/2020
1.7μm min.), 0.7 mL/min.
Accucore 0.1%FA H2O/0.1%FA MeCN
Nexera/2
SMD-FA10-5 2.1mmI.D.x50mm, =90/10→0/100(1.1 min.)→0/100(0.5
2.7μm min.), 1.0 mL/min.
Kinetex XB-C18 0.1%FA H O/0.1%FA MeCN
SMD- UFLCXR
3.0mmI.D.x50mm,2. =90/10→40/60(4.0 min.)→5/95(0.5
FA1060-1 /2020
6μm min.), 1.5 mL/min.
Phenomenex kinetex
0.1%FA H O/0.1%FA MeCN
SMD-FA10- UFLCXR C18
=90/10→0/100(4.5 min.)→0/100(1.3
long /2020 3.0mmI.D.x50mm,2.
min.), 1.1 mL/min.
Ascentis Express C18 0.05%TFA H O /0.05%TFA MeCN
SMD- nexera/20
2.1mmI.D.x50mm, =95/5→0/100(1.5 min.)→0/100(0.5
TFA05-1 20
2.7μm min.), 1 mL/min.
Metoric Core C18 0.05%TFA H O /0.05%TFA MeCN
SMD- nexera/20
2.1mmI.D.x50mm, =95/5→0/100(1.5 min.)→0/100(0.5
TFA05-2 20
2.7μm min.), 1 mL/min.
Kinetex 1.7u C18 0.05%TFA H O /0.05%TFA MeCN
SMD- nexera/20
2.1mmI.D.x50mm, =95/5→0/100(1.5 min.)→0/100(0.5
TFA05-3 20
1.7μm min.), 1 mL/min.
Ascentis Express C18 0.05%TFA H2O /0.05%TFA MeCN
SMD- nexera/20
2.1mmI.D.x50mm, =95/5→0/100(1.1 min.)→0/100(0.5
TFA05-4 20
2.7μm min.), 1 mL/min.
Shim-pack XR-ODS 0.05%TFA H O/0.05%TFA MeCN
SMD- UFLCXR
3.0mmI.D.x50mm, =95/5→0/100(1.2 min.)→0/100(1.0
TFA05-5 /2020
2.2μm min.), 1 mL/min.
Shim-pack XR-ODS 0.05%TFA H O/0.05%TFA MeCN
SMD- UFLCXR
3.0mmI.D.x50mm,2. =95/5→0/100(2.2 min.)→0/100(1.0
TFA05-6 /2020
2μm min.), 1 mL/min.
Ascentis Express RP-
0.1%FA H O/0.1%FA MeCN
SMD-FA05- nexera/20 Amide
=95/5→0/100(1.5 min.)→0/100(0.5
RP 20 2.1mmI.D.x50mm,
min.), 1 mL/min.
2.7μm
Ascentis Express RP-
0.1%FA H O/0.1%FA MeCN
SMD-FA50- nexera/20 Amide
=50/50→0/100(1.0 min.)→0/100(1.0
RP 20 2.1mmI.D.x50mm,
min.), 1 mL/min.
2.7μm
Ascentis Express RP-
0.05%TFA H O/0.05%TFA MeCN
SMD- nexera/20 Amide
=95/5→0/100(1.5 min.)→0/100(0.5
TFA05-RP 20 2.1mmI.D.x50mm,
min.), 1 mL/min.
2.7μm
Ascentis Express RP-
0.05%TFA H O/0.05%TFA MeCN
SMD- nexera/20 Amide
=50/50→0/100(1 min.)→0/100(1
TFA50-RP 20 2.1mmI.D.x50mm,
min.), 1ml/min.
2.7μm
Aquity
Ascentis Express C18 0.1%FA H O/0.1%FA MeCN
UPLC-I-
SQD-FA05-1 2.1mmI.D.x50mm, =95/5→0/100(1.0 min.)→0/100(0.4
Class/SQ
2.7μm min.), 0.9 mL/min.
Aquity Ascentis Express RP-
0.1%FA H2O/0.1%FA MeCN
UPLC-I- Amide
SQD-FA05-2 =95/5→0/100(1.0 min.)→0/100(0.4
Class/SQ 2.1mmI.D.x50mm,
min.), 1 mL/min.
D 2.7μm
Aquity Ascentis Express C18 0.1%FA H O/0.1%FA MeCN
SQD-FA05-3 UPLC/S 2.1mmI.D.x50mm, =95/5→0/100(1.0 min.)→0/100(0.4
QD 2.7μm min.), 1 mL/min.
Aquity Ascentis Express C18 0.1%FA H O/0.1%FA MeCN
SQD-FA05-4 UPLC/S 2.1mmI.D.x50mm, =95/5→0/100(1.0 min.)→0/100(0.4
QD2 2.7μm min.), 1 mL/min.
Aquity Ascentis Express RP-
0.1%FA H O/0.1%FA MeCN
SQD- UPLC-I- Amide
=50/50→0/100(0.7 min.)→0/100(0.7
FA50―1 Class/SQ 2.1mmI.D.x50mm,
min.), 1 mL/min.
D 2.7μm
Aquity
Ascentis Express C18 10mMAcONH H O/MeOH
UPLC-I-
SQD-AA05-1 2.1mmI.D.x50mm, =95/5→0/100(1 min.)→100(0.4
Class/SQ
5μm min.), 1 mL/min.
Aquity Ascentis Express C18 10mMAcONH H O/MeOH
SQD-AA05-2 UPLC/S 2.1mmI.D.x50mm, =95/5→0/100(1 min.)→100(0.4
QD 2.7μm min.), 1 mL/min.
Aquity Ascentis Express C18 10mMAcONH H O/MeOH
SQD-AA50-1 UPLC/S 2.1mmI.D.x50mm, =50/50→0/100(0.7 min.)→100(0.7
QD 2.7μm min.), 1 mL/min.
Aquity
Ascentis Express C18 0.1%FA H O/0.1%FA MeCN
SQD-FA05- UPLC-I-
2.1mmI.D.x50mm, =95/5→0/100(4.5 min.)→0/100(0.5
long Class/SQ
2.7μm min.), 1 mL/min.
Aquity
Ascentis Express C18 0.1%FA H O/0.1%FA MeCN
SQD- UPLC-I-
2.1mmI.D.x50mm, =95/5→5/50(4.5 min.)→0/100(0.01
FA0550-long Class/SQ
2.7μm min.)→0/100(0.49 min.), 1 mL/min.
Aquity
Ascentis Express C18 10mMAcONH H O /MeOH
SQD-AA50- UPLC-I-
2.1mmI.D.x50mm, =50/50→0/100(4.5 min.)→100(0.5
long Class/SQ
5μm min.), 1 mL/min.
Aquity
Ascentis Express C18 10mMAcONH H O /MeOH
SQD- UPLC-I-
2.1mmI.D.x50mm, =95/5→50/50(4.5 min.)→0/100(0.01
AA0550-long Class/SQ
5μm min.)→0/100(0.49 min.), 1 mL/min.
<Example 1> Synthesis of 3-[(1S,2S)[2-[2-(3,5-dimethylphenyl)[3-(1-
methylindazolyl)oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine
carbonyl](2-ethylmethylpyridinyl)indolyl]methylcyclopropyl]-4H-1,2,4-
oxadiazolone (Compound 1)
[Chemical Formula 17]
<Step 1-1>
Potassium [(5-Cyano-1,2,3,6-tetrahydropyridinyl)amide] (Compound 1b)
To a tetrahydrofuran (THF) (179 mL) solution of 3-(2-
cyanoethylamino)propanenitrile (Compound 1a, 22.0 g, 179 mmol) was added a THF
solution (179 mL) of 1M potassium tert-butoxide and the mixture was stirred at room
temperature for 1 h. The reaction mixture was filtered by washing with THF (50 mL), and
then the filtrate was dried under reduced pressure to obtain the titled Compound 1b (23.8 g,
yield 83%) as a light brown solid.
LC/MS Mass Spectrometery: m/z 124 ([M+H] ).
LC/MS Retention Time: 0.14 min. (Analysis Condition:SMD-FA05-1).
H-NMR (400MHz, MeOH-d ) δ:3.33 (2H, t, J=1.3 Hz), 2.90 (2H, t, J=5.9 Hz), 2.21
(2H, tt, J=5.9, 1.3 Hz).
<Step 1-2>
tert-Butyl 3-amino(3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-
-carboxylate (Compound 1d)
To an ethanol (57.9 mL) solution of 3,5-dimethylphenylhydrazine hydrochloride
(Compound 1c, 5.00 g, 29.0 mmol) and Compound 1b obtained in Step 1-1 (4.67 g, 29.0
mmol) was added 2N hydrochloric acid (23.2 mL, 46.3 mmol), and the mixture was stirred at
50ºC for 1 h. After the reaction mixture was cooled to 0ºC, 5M sodium hydroxide aqueous
solution (9.27 mL, 46.3 mmol) and di-tert-butyl dicarbonate (6.64 g, 30.4 mmol) were added
and the mixture was stirred at 0ºC for 1 h. Water was added to the reaction mixture and
extraction was performed using ethyl acetate, then the organic layer was washed with brine
and dried with anhydrous magnesium sulfate. After filtration, the filtrate was concentrated
under reduced pressure, and the residue was purified by a silica gel column chromatography
(ethyl acetate/hexane=0:1 to 1:1) to obtain the titled Compound 1d (7.82 g, yield 79%) as a
pale yellow solid.
LC/MS Mass Spectrometry: m/z 343 ([M+H] ) 。
LC/MS retention time: 0.99 min. (Analysis condition: SMD-FA05-3).
<Step 1-3>
tert-Butyl 3-(2,2-dimethoxyethylcarbamoylamino)(3,5-dimethylphenyl)-6,7-
dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate(Compound 1f)
To a pyridine (7.39 mL) solution of Compound 1d (2.53 g, 7.39 mmol) obtained in
Step 1-2 was added 2-isocyanato-1,1-dimethoxyethane (Compound 1e, 1.94 g, 14.8 mmol),
and the mixture was stirred at room temperature. After 3 hours and 15 minutes,
diethylamine (1.08 g, 14.8 mmol) was added and the mixture was stirred at room temperature
for 5 min., then water (50.6 mL) was added, and the resulting mixture was stirred at room
temperature for 20 min. The reaction mixture that had become a suspension was filtered,
and the obtained solid was washed with water (12.7 mL) then dried under reduced pressure to
obtain the titled Compound 1f (3.20 g, yield 91%) as a pale yellow solid.
LC/MS mass spectrometry: m/z 474 ([M+H] ).
LC/MS retention time: 0.78 min. (Analysis Condition: SQD-FA05-1).
<Step 1-4>
3-[2-(3,5-Dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinyl]-1H-
imidazolone (Compound 1g)
To Compound 1f (158 mg, 0.334 mmol) obtained in Step 1-3 was added formic acid
(3.84 mL, 100 mmol), and the mixture was stirred at room temperature for 21 h. The
reaction mixture was concentrated under reduced pressure, and toluene was added and the
solvent was removed by evaporation under reduced pressure. Dichloromethane (1 mL) was
added to the resuide to dissolve the residue, and then hydrogen chloride (4M dioxane
solution, 0.835 mL, 3.34 mol) was added at room temperature. The reaction mixture was
concentrated under reduced pressure. Toluene was added and the solvent was removed by
evaporation under reduced pressure to obtain a crude product (176 mg) of the titled
Compound 1g.
LC/MS mass spectrometry: m/z 310 ([M+H] ).
LC/MS retention time: 0.39 min. (Analysis Condition: SQD-FA05-3).
<Step 1-5>
4-Bromoethylmethylpyridine (Compound 1i)
A THF (75.0 mL) solution of 4-bromo-2,3-dimethylpyridine (Compound 1h, 7.05 g,
37.9 mmol) was cooled to -78ºC, and then 1.11 M lithium diisopropylamide n-hexane-THF
solution (35.8 mL, 39.8 mmol) was added slowly. The reaction mixture was stirred at -78ºC
for 5 min., and then iodomethane (2.84 mL, 45.5 mmol) was added. The reaction mixture
was stirred at -78ºC for 5 min., and warmed slowly to room temperature. Then, the reaction
mixture was stirred for 30 min. and the solvent was removed by evaporation under reduced
pressure. The residue was purified by silica gel column chromatography (dichloromethane
/ethyl acetate), and the titled Compound 1i (6.98 g, yield 92%) was obtained as an orange oil-
like material.
LC/MS mass spectrometry: m/z 200 ([M+H] ).
LC/MS retention time: 0.38 min. (Analysis Condition: SQD-FA05-3).
<Step 1-6>
Ethyl 5-bromo[(1S, 2S)cyanomethylcyclopropyl]indolecarboxylate
(Compound 1l)
The N,N’-dimethylpropyleneurea (117 mL) solution of ethyl 5-bromo
(cyanomethyl)indolecarboxylate (Compound 1j, 3.60 g, 11.7 mmol) and (4R)methyl-
1,3,2-dioxathiolane 2,2-dioxide (Compound 1k, 4.86 g, 35.2 mmol) was deaerated under
reduced pressure, then nitrogen was introduced in the vessel and the mixture was cooled to
0ºC. Under nitrogen atmosphere, a THF solution (46.9 mL, 46.9 mmol) of 1.0 M potassium
bis(trimethylsilyl)amide was added dropwise slowly. The reaction mixture was stirred at
0ºC for 2.5 h., then formic acid (5.30 mL, 141 mmol) was added and extraction was
performed using a mixture of hexane/ethyl acetate (1:3). The organic layer was washed
three times with water, twice with a saturated aqueous solution of sodium hydrogen
carbonate, and once with brine, and then dried with sodium sulfate. After filtration, the
filtrate was concentrated under reduced pressure and the residue was purified by silica gel
column chromatography (ethyl acetate/hexane =1:19 to 1:4) to obtain the titled Compound 1l
(1.70 g, yield 42%) as a white solid.
LC/MS mass spectrometry: m/z 347 ([M+H] ).
LC/MS retention time: 0.69 min. (Analysis Condition: SQD-AA50-1).
<Step 1-7>
Ethyl 1-[(1S,2S)cyanomethylcyclopropyl] (2-ethylmethylpyridin
yl)indolecarboxylate (Compound 1m)
The dioxane (44 mL) suspension of Compound 1l (2.70 g, 7.78 mmol) obtained in
Step 1-6, 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (2.17 g, 8.55 mmol) and
potassium acetate (1.15 g, 11.7 mmol) were deaerated under reduced pressure, and then
nitrogen was introduced in the vessel. Under nitrogen atmosphere, 1,1’-bis
(diphenylphosphino)ferrocene-palladium (II) dichloride-dichloromethane complex (1.29 g,
1.56 mmol) was added, and the mixture was stirred at 100ºC for 3 h. After the solution was
cooled to room temperature, 4-bromoethylmethylpyridine (Compound 1i, 2.33 g, 11.7
mmol), sodium carbonate (2.47 g, 23.3 mmol), and water (7.4 mL) were added to the
solution, and then the solution was subjected to deaeration under reduced pressure.
Nitrogen was introduced in the vessel, and the solution was stirred at 100ºC for 2 h. The
solution was cooled to room temperature, and then water (5.4 mL), and N-acetyl cysteine
(0.635 g, 3.89 mmol) were added. The mixture was stirred for 0.5 h. The reaction mixture
was subjected to extraction with ethyl acetate, and the organic layer was washed once with
brine, and then drided using sodium sulfate. After filtration, the filtrate was concentrated
under reduced pressure and the residue was purified by silica gel column chromatography
(ethyl acetate/hexane =1:19 to 2:3) to obtain the titled Compound 1m (2.92 g, yield 97%) as
a pale yellow gum-like product.
LC/MS mass spectrometry: m/z 388 ([M+H] ).
LC/MS retention time: 1.06 min. (Analysis Condition: SQD-AA05-2).
<Step 1-8>
Ethyl 5-(2-ethylmethylpyridinyl)[(1S,2S)methyl(5-oxo-4H-1,2,4-
oxadiazolyl)cyclopropyl]indolecarboxylate (Compound 1n)
To a dimethylsulfoxide (DMSO) (2.9 mL) solution of Compound 1m (0.225 g, 0.581
mmol) obtained in Step 1-7 was added 50% hydroxyamine aqueous solution (0.356 mL, 5.81
mmol), and the mixture was stirred at room temperature for 17 h. Ethyl acetate (50 mL)
was added, the mixture was washed with water (10 mL) and brine (10 mL), and then dried
with magnesium sulfate. After the mixture was filtered, the filtrate was concentrated under
reduced pressure, and the obtained residue was dissolved in DMSO (1.9 mL). Then,
carbonyl diimidazole (188 mg, 1.16 mmol) and 1,8-diazabicycloundecene (0.219 mL, 1.45
mmol) were added and the resulting mixture was stirred at room temperature for 0.5 h.
Formic acid was added to the mixture, which was then purified by reversed-phase
chromatography (acetonitrile/water, 0.1% formic acid) to obtain the titled Compound 1n (169
mg, yield 65%) as a white powder.
LC/MS mass spectrometry: m/z 447 ([M+H] ).
LC/MS retention time: 0.80 min. (Analysis Condition: SMD-FA05-3).
<Step 1-9>
-(2-Ethylmethylpyridinyl)[(1S,2S)methyl(5-oxo-4H-1,2,4-oxadiazol
yl)cyclopropyl]indolecarboxylic acid (Compound 1o)
To a DMSO (40 mL) solution of Compound 1n (3.61 g, 8.08 mmol) obtained in Step
1-8 was added 2M sodium hydroxide aqueous solution (10.1 mL, 20.2 mmol), and the
mixture was stirred at room temperature for 1.5 h. Formic acid was added to the mixture,
which was then purified by reversed-phase chromatography (acetonitrile/water, 0.1% formic
acid) to obtain the titled Compound 1o (3.38 g, yield 100%) as a white powder.
LC/MS mass spectrometry: m/z 419 ([M+H] ).
LC/MS retention time: 0.83 min. (Analysis Condition: SQD-AA05-2).
<Step 1-10>
3-[(1S,2S)[2-[2-(3,5-dimethylphenyl) (2-oxo-1H-imidazolyl)-6,7-dihydro-
4H-pyrazolo[4,3-c]pyridinecarbonyl] (2-ethylmethylpyridinyl)indolyl]
methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound 1p)
To a N,N’-dimethylformamide (DMF) (24.1 mL) solution of Compound 1g (1.25 g,
3.61 mmol) obtained in Step 1-4, Compound 1o (1.59 g, 3.80 mmol) obtained in Step 1-9,
and [dimethylamino(triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylazanium
hexafluorophosphate (1.51 g, 3.98 mmol) was added diisopropylethylamine (3.15 mL, 18.1
mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture
was directly purified by reversed-phase column chromatography (acetonitrile/water, 0.1%
formic acid) and the titled Compound 1p (2.44 g, yield 95%) was obtained as a light brown
foam.
LC/MS mass spectrometry: m/z 710 ([M+H] ).
LC/MS retention time: 0.85 min. (Analysis Condition: SMD-FA05-3).
<Step 1-11>
3-[(1S,2S)[2-[2-(3,5-Dimethylphenyl)[3-(1-methylindazolyl)oxoimidazol-
1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl](2-ethylmethylpyridin
yl)indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound 1)
To a N-methylpyrrolidone (0.188 mL) suspension of Compound 1p (20 mg, 0.028
mmol) obtained in Step 1-10, 5-bromomethylindazole (Compound 1q, 11.9 mg, 0.056
mmol), (1S,2S)N,2-N-dimethylcyclohexane-1,2-diamine (1.6 mg, 0.011 mmol) and
potassium carbonate (11.7 mg, 0.085 mmol) was added copper (I) iodide (1.1 mg, 0.0056
mmol) at room temperature, and the mixture was stirred under nitrogen atmosphere at 130ºC
for 3 h. The reaction mixture was purified by reversed-phase silica gel chromatography
(acetonitrile/water, 0.1% formic acid), and the titled Compound 1 (17.2 mg, yield 73%) was
obtained as a light brown foam.
LC/MS mass spectrometry: m/z 840 ([M+H] ).
LC/MS retention time: 1.12 min. (Analysis Condition: SMD-TFA05-3).
<Examples 2 to 50>
An operation similar to Step 1-11 of Example 1 was performed using a combination of
the 2-oxoimidazole compound shown in Table 2-2 and the halogen compound shown in
Table 2-3 below, as well as an appropriate reagent, and Example Compounds 2 to 50 shown
in Table 2-1 were obtained by the following reaction.
[Chemical Formula 18]
[Table 2-1]
Table 2-1. The Obtained Example Compounds 2 to 50
LC/MS LC/MS
Analysis retention mass
Structure Compound
Condition time spectrometry
(min.) (m/z)
3-[(1S,2S)[5-(2-ethyl
methylpyridinyl)[2-
(4-fluoro-3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
SMD- 858
2 oxoimidazolyl]-6,7- 1.15
TFA05-3 ([M+H] )
dihydro-4H-pyrazolo[4,3-
c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-(2-ethyl
methylpyridinyl)[2-
(4-fluoro-3,5-
dimethylphenyl)[3-(3-
methyl-1,2-benzothiazol
SMD- 875
3 yl)oxoimidazolyl]- 1.22
TFA05-3 ([M+H] )
6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
Example
3-[(1S,2S)[5-(2-ethyl
methylpyridinyl)[2-
(4-fluoro-3,5-
dimethylphenyl)[3-(3-
fluoromethoxyphenyl)-
SMD- 852
4 2-oxoimidazolyl]-6,7- 1.21
TFA05-3 ([M+H] )
dihydro-4H-pyrazolo[4,3-
c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[3-[3-(1,3-
dimethylindazolyl)
oxoimidazolyl](4-
fluoro-3,5-
dimethylphenyl)-6,7-
SMD- 872
dihydro-4H-pyrazolo[4,3- 1.18
TFA05-3 ([M+H] )
c]pyridinecarbonyl]
(2-ethylmethylpyridin-
4-yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(4-
fluoro-3,5-
dimethylphenyl)[3-[1-
(2-hydroxy
methylpropyl)indazol
yl]oxoimidazolyl]-
SMD- 919
6 6,7-dihydro-4H- 1.40
TFA05-2 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl](2-methoxy
methylpyridinyl)indol-
1-yl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-(2,2-
dimethylmorpholinyl)-
2-[2-(4-fluoro-3,5-
dimethylphenyl)[3-[1-
(2-methoxyethyl)indazol-
SMD- 896
7 5-yl]oxoimidazolyl]- 1.32
TFA05-3 ([M+H] )
6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(4-
fluoro-3,5-
dimethylphenyl)[2-oxo-
3-[1-[(3R)-oxolan
yl]indazolyl]imidazol
SMD- 879
8 yl]-6,7-dihydro-4H- 1.38
TFA05-2 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
N-[4-[3-[2-(4-fluoro-3,5-
dimethylphenyl)[1-
[(1S,2S)methyl(5-
oxo-4H-1,2,4-oxadiazol
yl)cyclopropyl](oxan
SMD- 929
9 yl)indolecarbonyl]-6,7- 1.33
TFA05-2 ([M+H] )
dihydro-4H-pyrazolo[4,3-
c]pyridinyl]
oxoimidazolyl]
methoxyphenyl]-N-(3-
methoxypropyl)acetamide
3-[(1S,2S)[2-[2-(4-
fluoro-3,5-
dimethylphenyl)[2-oxo-
3-[1-(2,2,2-
trifluoroethyl)indazol
SMD- 891
yl]imidazolyl]-6,7- 1.47
TFA05-2 ([M+H] )
dihydro-4H-pyrazolo[4,3-
c]pyridinecarbonyl]
(oxanyl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-
dimethylphenyl)[3-[1-
(2-methoxyethyl)indazol-
-yl]oxoimidazolyl]-
4-methyl-6,7-dihydro-4H- SMD- 919
11 1.49
pyrazolo[4,3-c]pyridine TFA05-2 ([M+H] )
carbonyl](2-methoxy
methylpyridinyl)indol-
1-yl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-
dimethylphenyl)methyl-
3-[3-(1-methylindazol
yl)oxoimidazolyl]-
6,7-dihydro-4H- SMD- 874
12 1.45
pyrazolo[4,3-c]pyridine TFA05-1 ([M+H] )
carbonyl](2-methoxy
methylpyridinyl)indol-
1-yl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-
dimethylphenyl)[3-[1-
(2-hydroxy
methylpropyl)indazol
yl]oxoimidazolyl]
SMD- 932
13 methyl-6,7-dihydro-4H- 1.42
TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl](2-methoxy
methylpyridinyl)indol-
1-yl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-
dimethylphenyl)methyl-
3-[2-oxo[1-[(3S)-
oxolanyl]indazol
yl]imidazolyl]-6,7- SMD- 918
14 1.15
dihydro-4H-pyrazolo[4,3- TFA05-1 ([M+H] )
c]pyridinecarbonyl]
(3-fluoromethylpyridin-
4-yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-[2-
(dimethylamino)
methylpyridinyl]
[(4S)(4-fluoro-3,5-
dimethylphenyl)methyl-
3-[3-(1-methylindazol SQD- 887
0.75
yl)oxoimidazolyl]- FA05-1 ([M+H] )
6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-
dimethylphenyl)[3-[1-
(2-methoxyethyl)indazol-
-yl]oxoimidazolyl]-
SMD- 882
16 4-methyl-6,7-dihydro-4H- 1.45
TFA05-2 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-
dimethylphenyl)methyl-
3-[3-[1-[(3-methyloxetan-
3-yl)methyl]indazolyl]-
SMD- 908
17 2-oxoimidazolyl]-6,7- 1.45
TFA05-2 ([M+H] )
dihydro-4H-pyrazolo[4,3-
c]pyridinecarbonyl]
(oxanyl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-
dimethylphenyl)methyl-
3-[3-(3-methyl-1,2-
benzothiazolyl)
SMD- 854
18 oxoimidazolyl]-6,7- 1.50
TFA05-1 ([M+H] )
dihydro-4H-pyrazolo[4,3-
c]pyridinecarbonyl]
(oxanyl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-
dimethylphenyl)[3-[4-
(2-hydroxyethoxy)
methylphenyl]
oxoimidazolyl] SMD- 857
19 1.36
methyl-6,7-dihydro-4H- TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-
dimethylphenyl)[3-[4-
(1-hydroxy
methylpropanyl)oxy
methoxyphenyl]
SMD- 901
oxoimidazolyl] 1.40
TFA05-1 ([M+H] )
methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine
carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)[3-
(4-ethylsulfonylphenyl)
oxoimidazolyl](4-
fluoro-3,5-
dimethylphenyl)methyl-
SMD- 875
21 6,7-dihydro-4H- 1.37
TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-
dimethylphenyl)methyl-
3-[2-oxo[1-[(3S)-
oxolanyl]indazol
SMD- 893
22 yl]imidazolyl]-6,7- 1.40
TFA05-1 ([M+H] )
dihydro-4H-pyrazolo[4,3-
c]pyridinecarbonyl]
(oxanyl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-
dimethylphenyl)[3-(4-
fluoromethylindazol
yl)oxoimidazolyl]
SMD- 855
23 methyl-6,7-dihydro-4H- 1.41
TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)[3-
(1,1-dimethyl-3,4-
dihydroisochromenyl)-
2-oxoimidazolyl](4-
fluoro-3,5-
dimethylphenyl)methyl- SMD- 867
24 1.52
6,7-dihydro-4H- TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)[3-
[4-[6-
(dimethylamino)pyrimidin-
4-yl]methylphenyl]
oxoimidazolyl](4-
fluoro-3,5-
SMD- 918
dimethylphenyl)methyl- 1.12
TFA05-1 ([M+H] )
6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine
carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-
dimethylphenyl)[3-[1-
(2-fluoroethyl)indazol
yl]oxoimidazolyl]
SMD- 869
26 methyl-6,7-dihydro-4H- 1.39
TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-
dimethylphenyl)[3-(6-
fluoromethylindazol
yl)oxoimidazolyl]
SMD- 855
27 methyl-6,7-dihydro-4H- 1.39
TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-
dimethylphenyl)[3-[4-
fluoro(2,2,2-
trifluoroethyl)indazol
yl]oxoimidazolyl] SMD- 923
28 1.44
methyl-6,7-dihydro-4H- TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-
dimethylphenyl)[3-[4-
fluoro[(3-methyloxetan-
3-yl)methyl]indazolyl]-
2-oxoimidazolyl] SMD- 925
29 1.40
methyl-6,7-dihydro-4H- TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-
dimethylphenyl)[3-[4-
fluoro(2-hydroxy
methylpropyl)indazol
yl]oxoimidazolyl] SMD- 913
1.36
methyl-6,7-dihydro-4H- TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-[(4S)-2,2-
dimethyloxanyl]
[(4S)(4-fluoro-3,5-
dimethylphenyl)[3-[1-
(2-methoxyethyl)indazol-
SMD- 909
31 5-yl]oxoimidazolyl]- 1.48
TFA05-2 ([M+H] )
4-methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-[(4S)-2,2-
dimethyloxanyl]
[(4S)[3-(1,3-dimethyl-
2-oxobenzoimidazolyl)-
2-oxoimidazolyl](4-
fluoro-3,5- SMD- 895
32 1.39
dimethylphenyl)methyl- TFA05-1 ([M+H] )
6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-[(4S)-2,2-
dimethyloxanyl]
[(4S)(4-fluoro-3,5-
dimethylphenyl)[3-[1-
(2-methoxyethyl)
methyl
SMD- 939
33 oxobenzoimidazolyl] 1.41
TFA05-1 ([M+H] )
oxoimidazolyl]
methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-[(4S)-2,2-
dimethyloxanyl]
[(4S)(4-fluoro-3,5-
dimethylphenyl)[3-(1H-
indazolyl)
SMD- 851
34 oxoimidazolyl] 1.37
TFA05-1 ([M+H] )
methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-[(4S)-2,2-
dimethyloxanyl]
[(4S)(4-fluoro-3,5-
dimethylphenyl)[3-[4-
fluoro(2,2,2-
trifluoroethyl)indazol SMD- 951
1.51
yl]oxoimidazolyl] TFA05-1 ([M+H] )
methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-[(4S)-2,2-
dimethyloxanyl]
[(4S)(4-fluoro-3,5-
dimethylphenyl)[3-[4-
fluoro(2-
methoxyethyl)indazol SMD- 927
36 1.46
yl]oxoimidazolyl] TFA05-1 ([M+H] )
methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-[(4S)-2,2-
dimethyloxanyl]
[(4S)(4-fluoro-3,5-
dimethylphenyl)[3-[4-
fluoro[(3-methyloxetan-
3-yl)methyl]indazolyl]- SMD- 953
37 1.46
2-oxoimidazolyl] TFA05-1 ([M+H] )
methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-[(4S)-2,2-
dimethyloxanyl]
[(4S)(4-fluoro-3,5-
dimethylphenyl)[3-[4-
fluoro(2-hydroxy
methylpropyl)indazol SMD- 941
38 1.42
yl]oxoimidazolyl] TFA05-1 ([M+H] )
methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-[(4S)-2,2-
dimethyloxanyl]
[(4S)(4-fluoro-3,5-
dimethylphenyl)methyl-
3-[3-(2-methyloxo-1,4-
dihydroisoquinolinyl)- SMD- 894
39 1.33
2-oxoimidazolyl]-6,7- TFA05-1 ([M+H] )
dihydro-4H-pyrazolo[4,3-
c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-[(4S)-2,2-
dimethyloxanyl]
[(4S)(4-fluoro-3,5-
dimethylphenyl)[3-[4-
fluoro[(3S)-oxolan
yl]indazolyl] SMD- 939
40 1.46
oxoimidazolyl] TFA05-1 ([M+H] )
methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-
dimethylphenyl)[3-(4-
fluoromethylindazol
yl)oxoimidazolyl]
SMD- 869
41 methyl-6,7-dihydro-4H- 1.44
TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl][(2S,4S)
methyloxanyl]indol
yl]methylcyclopropyl]-
4H-1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
chloro-3,5-
dimethylphenyl)[3-[4-
fluoro(2,2,2-
trifluoroethyl)indazol
yl]oxoimidazolyl] SMD- 967
42 1.56
methyl-6,7-dihydro-4H- TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl][(4S)-2,2-
dimethyloxanyl]indol
yl]methylcyclopropyl]-
4H-1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
chloro-3,5-
dimethylphenyl)[3-[4-
fluoro(2-
methoxyethyl)indazol
yl]oxoimidazolyl] SMD- 943
43 1.53
methyl-6,7-dihydro-4H- TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl][(4S)-2,2-
dimethyloxanyl]indol
yl]methylcyclopropyl]-
4H-1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
chloro-3,5-
dimethylphenyl)[3-[4-
fluoro(2,2,2-
trifluoroethyl)indazol
yl]oxoimidazolyl] SMD- 939
44 1.50
methyl-6,7-dihydro-4H- TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
chloro-3,5-
dimethylphenyl)[3-[4-
fluoro(2-
methoxyethyl)indazol
yl]oxoimidazolyl] SMD- 915
45 1.46
methyl-6,7-dihydro-4H- TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoromethylphenyl)
[3-[4-fluoro(2,2,2-
trifluoroethyl)indazol
yl]oxoimidazolyl]
SMD- 909
46 methyl-6,7-dihydro-4H- 1.39
TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)[3-
[4-fluoro(2-
methoxyethyl)indazol
yl]oxoimidazolyl]
(4-fluoromethylphenyl)-
SMD- 885
47 4-methyl-6,7-dihydro-4H- 1.34
TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-[(4S)-2,2-
dimethyloxanyl]
[(4S)[3-[4-fluoro(2-
methoxyethyl)indazol
yl]oxoimidazolyl]
SMD- 913
48 (4-fluoromethylphenyl)- 1.41
TFA05-1 ([M+H] )
4-methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)[3-
(4-chloromethylindazol-
-yl)oxoimidazolyl]-
2-(4-fluoro
methylphenyl)methyl-
SMD- 885
49 6,7-dihydro-4H- 1.42
TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl][(4S)-2,2-
dimethyloxanyl]indol
yl]methylcyclopropyl]-
4H-1,2,4-oxadiazolone
3-[(1S,2S)[5-[(4S)-2,2-
dimethyloxanyl]
[(4S)(4-fluoro
methylphenyl)methyl
[3-(1-methylindazolyl)-
SMD- 851
50 2-oxoimidazolyl]-6,7- 1.37
TFA05-1 ([M+H] )
dihydro-4H-pyrazolo[4,3-
c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
The compounds in Table 2-1 have rotational isomers, and by way of example, the
H-NMR of Example 2 compound is shown below.
Rotational Isomer A
H-NMR (600 MHz, CDCl ) δ: 11.29 (1H, s), 8.40 (1H, d, J=5.2 Hz), 7.93 (1H, s),
7.74 (1H, d, J=1.5 Hz), 7.70 (1H, d, J=8.6 Hz), 7.56 (1H, s), 7.45 (1H, dd, J=9.0, 1.5 Hz),
7.38 (1H, d, J=9.0 Hz), 7.28 (1H, m), 7.14 (1H, d, J=5.2 Hz), 7.04 (2H, d, J =5.9 Hz), 6.82
(1H, s), 6.59 (1H, d, J=3.0 Hz), 6.08 (1H, d, J=3.0 Hz), 4.96 (1H, d, J=16.0 Hz), 4.92 (1H, d,
J=16.0 Hz), 4.69 (1H, ddd, J=13.1, 4.4, 4.4 Hz), 4.06 (3H, s), 3.75 (1H, ddd, J=13.1, 9.5, 5.0
Hz), 3.07 (2H, m), 2.97 (2H, q, J=7.6 Hz), 2.26 (3H, s), 2.25 (6H, s), 1.88 (1H, s), 1.51 (2H,
m), 1.37 (3H, t, J=7.6 Hz), 1.17 (3H, d, J=5.6 Hz).
Rotational Isomer B
H-NMR (600 MHz, CDCl ) δ: 11.29 (1H, s), 8.44 (1H, d, J=5.2 Hz), 8.04 (1H, s), 7.90 (1H,
d, J=1.4 Hz), 7.73 (1H, d, J=8.8 Hz), 7.63 (1H, dd, J=9.0, 1.4 Hz), 7.60 (1H, s), 7.51 (1H, d,
J=9.0 Hz), 7.30 (1H, m), 7.20 (1H, d, J=5.2 Hz), 7.11 (2H, d, J =6.0 Hz), 6.81 (1H, s), 6.71
(1H, d, J=3.0 Hz), 6.22 (1H, d, J=3.0 Hz), 5.24 (1H, d, J=16.3 Hz), 4.64 (1H, d, J=16.3 Hz),
4.45 (1H, ddd, J=13.5, 4.6, 4.0 Hz), 4.12 (3H, s), 3.87 (1H, ddd, J=13.5, 10.2, 3.8 Hz), 3.17
(1H, ddd, J=15.5, 10.2, 4.6 Hz), 3.02 (1H, m), 3.00 (2H, q, J=7.6 Hz), 2.30 (3H, s), 2.28 (6H,
s), 1.96 (1H, dd, J=6.0 Hz), 1.64 (1H, m), 1.58 (1H, dd, J=9.4, 6.0 Hz), 1.39 (3H, t, J=7.6
Hz), 1.19 (3H, d, J=6.1 Hz).
[Table 2-2]
Table 2-2. 2-Oxoimidazole compound that was used
LC/MS
LC/MS
mass
2-Oxoimidazole Analysis retention
Compound spectrome
compound Condition time
(min.)
(m/z)
3-[(1S,2S)[5-(2-ethyl
methylpyridinyl)[2-(4-
fluoro-3,5-dimethylphenyl)
(2-oxo-1H-imidazolyl)-6,7- SMD- 728
0.86
dihydro-4H-pyrazolo[4,3- FA05-3 ([M+H] )
c]pyridinecarbonyl]indol
yl]methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(4-fluoro-
3,5-dimethylphenyl)(2-oxo-
1H-imidazolyl)-6,7-
dihydro-4H-pyrazolo[4,3-
SMD- 730
c]pyridinecarbonyl](2- 1.33
FA05-2 ([M+H] )
methoxymethylpyridin
yl)indolyl]
methylcyclopropyl]-4H-1,2,4-
oxadiazolone
6 2-5 Example
(Compound 6i) (Compound 2g) No.
3-[(1S,2S)[5-(2,2-
dimethylmorpholinyl)[2-
(4-fluoro-3,5-
dimethylphenyl)(2-oxo-1H-
SMD- 722
imidazolyl)-6,7-dihydro- 1.22
FA05-3 ([M+H] )
4H-pyrazolo[4,3-c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-1,2,4-
oxadiazolone
3-[(1S,2S)[2-[2-(4-fluoro-
3,5-dimethylphenyl)(2-oxo-
1H-imidazolyl)-6,7-
dihydro-4H-pyrazolo[4,3- SMD- 693
1.19
c]pyridinecarbonyl] FA05-1 ([M+H] )
(oxanyl)indolyl]
methylcyclopropyl]-4H-1,2,4-
oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-dimethylphenyl)
methyl(2-oxo-1H-imidazol-
3-yl)-6,7-dihydro-4H-
SMD- 744
pyrazolo[4,3-c]pyridine 1.33
FA05-1 ([M+H] )
carbonyl](2-methoxy
methylpyridinyl)indol
yl]methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-dimethylphenyl)
methyl(2-oxo-1H-imidazol-
3-yl)-6,7-dihydro-4H-
SMD- 732
pyrazolo[4,3-c]pyridine 1.15
FA05-1 ([M+H] )
carbonyl](3-fluoro
methylpyridinyl)indol
yl]methylcyclopropyl]-4H-
1,2,4-oxadiazolone
11- 8-
14 7
13 10
(Compound 14d) (Compound 7c)
(Compound 11m) (Compound 8c)
3-[(1S,2S)[5-[2-
(dimethylamino)
methylpyridinyl][(4S)
(4-fluoro-3,5-
dimethylphenyl)methyl SQD- 757
0.67
(2-oxo-1H-imidazolyl)-6,7- FA05-1 ([M+H] )
dihydro-4H-pyrazolo[4,3-
c]pyridinecarbonyl]indol
yl]methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-dimethylphenyl)
methyl(2-oxo-1H-imidazol-
3-yl)-6,7-dihydro-4H- SMD- 707
1.21
pyrazolo[4,3-c]pyridine FA05-1 ([M+H] )
carbonyl](oxanyl)indol-
1-yl]methylcyclopropyl]-
4H-1,2,4-oxadiazolone
3-[(1S,2S)[5-[(4S)-2,2-
dimethyloxanyl][(4S)
(4-fluoro-3,5-
dimethylphenyl)methyl
SMD- 735
(2-oxo-1H-imidazolyl)-6,7- 1.29
FA05-1 ([M+H] )
dihydro-4H-pyrazolo[4,3-
c]pyridinecarbonyl]indol
yl]methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoro-3,5-dimethylphenyl)
methyl(2-oxo-1H-imidazol-
3-yl)-6,7-dihydro-4H-
SQD- 722
pyrazolo[4,3-c]pyridine 0.96
FA05-1 ([M+H] )
carbonyl][(2S,4S)
methyloxanyl]indolyl]-
2-methylcyclopropyl]-4H-
1,2,4-oxadiazolone
31- 16-
41 15
40 30
(Compound 41f) (Compound 15d)
(Compound 31l) (Compound 16a)
3-[(1S,2S)[2-[(4S)(4-
chloro-3,5-dimethylphenyl)
methyl(2-oxo-1H-imidazol-
3-yl)-6,7-dihydro-4H-
SMD- 751
pyrazolo[4,3-c]pyridine 1.34
FA05-1 ([M+H] )
carbonyl][(4S)-2,2-
dimethyloxanyl]indol
yl]methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
chloro-3,5-dimethylphenyl)
methyl(2-oxo-1H-imidazol-
3-yl)-6,7-dihydro-4H- SMD- 723
1.27
pyrazolo[4,3-c]pyridine FA05-1 ([M+H] )
carbonyl](oxanyl)indol-
1-yl]methylcyclopropyl]-
4H-1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)(4-
fluoromethylphenyl)
methyl(2-oxo-1H-imidazol-
3-yl)-6,7-dihydro-4H- SMD- 693
1.16
pyrazolo[4,3-c]pyridine FA05-1 ([M+H] )
carbonyl](oxanyl)indol-
1-yl]methylcyclopropyl]-
4H-1,2,4-oxadiazolone
3-[(1S,2S)[5-[(4S)-2,2-
dimethyloxanyl][(4S)
(4-fluoromethylphenyl)
methyl(2-oxo-1H-imidazol-
SMD- 721
3-yl)-6,7-dihydro-4H- 1.24
FA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-1,2,4-
oxadiazolone
[Table 2-3]
Table 2-3. Halogen compound that was used
48- 46- 44- 42-
50 47 45 43
(Compound 48a) (Compound 46f) (Compound 44a) (Compound 42g)
Halogen compound Halogen compound Halogen compound
12 3
18
6 11
13 16
8 9 10
17 19
21 41
24 25 26
27 42
Example
Example
Example
32 33
34 45 39
40 49
The 2-oxoimidazole compound (3-[(1S,2S)[5-(2-ethylmethylpyridinyl)
[2-(4-fluoro-3,5-dimethylphenyl)(2-oxo-1H-imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-
c]pyridinecarbonyl]indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazolone,
Compound 2g) used in the synthesis of Example Compounds 2 to 5 was synthesized by the
following process.
[Chemical Formula 19]
<Step 2-1>
4-Fluoro-3,5-dimethylaniline hydrochloride (Compound 2b)
4-Fluoro-3,5-dimethylaniline (Compound 2a, 3.97 g, 28.5 mmol) was added at room
temperature while concentrated hydrochloric acid (20 mL) and water (20 mL) were stirred.
The reaction mixture was stirred for 1 h. at that temperature, then the solid in the reaction
mixture was collected by filtration and dried. To the obtained solid was added
methoxycyclopentane (20 mL), and the mixture was stirred at 50ºC for 1 h., then at room
temperature for 1.5 h. The precipitated solid was collected by filtration and washed with
methoxycyclopentane (12 mL). The obtained solid was dried under reduced pressure to
obtain titled Compound 2b (4.88 g, yield 97%) as an off-white solid.
The compound was directly put to use in the next step, <Step 2-2>.
<Step 2-2>
(4-Fluoro-3,5-dimethylphenyl)hydrazine hydrochloride (Compound 2c)
To Compound 2b (1.00 g, 5.69 mmol) obtained in Step 2-1 was added concentrated
hydrochloric acid (10 mL), and an aqueous solution (2.4 mL of water) of sodium nitrite (511
mg, 7.40 mmol) was added over a period of 1 min. while the mixture was stirred vigourously
at 0ºC, then the mixture was stirred at 0ºC for 30 min. Then, an aqueous solution (2.4 mL
of water) of tin(II) chloride (2.27 g, 12.0 mmol) was added over a period of 2 min. Further,
water (7 mL) was added, and the mixture was stirred at room temperature for 1 h. The solid
in the reaction mixture was collected by filtration and washed with water (2 mL). Then, it
was dried to obtain the titled Compound 2c (1.75 g, yield 77%, content 48%) as a grey solid.
LC/MS mass spectrometry: m/z 155 ([M+H] ).
LC/MS retention time: 0.54 min. (Analysis Condition: SMD-FA05-1).
<Step 2-3>
tert-Butyl 3-amino(4-fluoro-3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-
c]pyridinecarboxylate (Compound 2d)
The titled compound was obtained from Compound 1b obtained in Step 1-1 and
Compound 2c obtained in Step 2-2 by performing an operation similar to Step 1-2 of
Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 361 ([M+H] ).
LC/MS retention time: 1.04 min. (Analysis Condition: SMD-FA05-3).
<Step 2-4>
tert-Butyl 3-(2,2-dimethoxyethylcarbamoylamino)(4-fluoro-3,5-dimethylphenyl)-
6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate (Compound 2e)
The titled compound was synthesized from Compound 2d obtained in Step 2-3 by
performing an operation similar to Step 1-3 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 492 ([M+H] ).
LC/MS retention time: 1.07 min. (Analysis Condition: SMD-FA05-3).
<Step 2-5>
3-[2-(4-Fluoro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinyl]-
1H-imidazolone hydrochloride (Compound 2f)
The titled compound was synthesized from Compound 2e obtained in Step 2-4 by
performing an operation similar to Step 1-4 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 328 ([M+H] ).
LC/MS retention time: 0.61 min. (Analysis Condition: SMD-FA05-3).
<Step 2-6>
3-[(1S,2S)[5-(2-Ethylmethylpyridinyl)[2-(4-fluoro-3,5-dimethylphenyl)
(2-oxo-1H-imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl]indolyl]
methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound 2g)
The titled compound was synthesized from Compound 2f obtained in Step 2-5 and
Compound 1o obtained in Step 1-9 by performing an operation similar to Step 1-10 of
Example 1 using an appropriate reagent.
The 2-oxoimidazole compound (3-[(1S,2S)[2-[2-(4-fluoro-3,5-dimethylphenyl)-
3-(2-oxo-1H-imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl](2-
methoxymethylpyridinyl)indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazolone,
Compound 6i) used in the synthesis of Example Compound 6 was synthesized by the
following process.
[Chemical Formula 20]
<Step 6-1>
-Bromo(cyanomethyl)-N-methyl-N-phenylindolecarboxamide (Compound 6c)
The titled compound was synthesized from 5-bromo(cyanomethyl)indole
carboxylic acid (Compound 6a) and N-methylaniline (Compound 6b) by performing an
operation similar to Step 1-10 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 368 ([M+H] ).
LC/MS retention time: 1.25 min. (Analysis Condition: SMD-FA05-3).
<Step 6-2>
-Bromo[(1S,2S)cyanomethylcyclopropyl]-N-methyl-N-phenylindole
carboxamide (Compound 6d)
The titled compound was synthesized from Compound 6c obtained in Step 6-1 by
performing an operation similar to Step 1-6 of Example 1 using an appropriate reagent.
LC/MS retention time: 1.37 min. (Analysis Condition: SMD-FA05-1).
H-NMR (400 MHz, DMSO-d ) δ: 7.69 (1H, s), 7.65-7.25 (7H, m), 6.02 (1H, brs),
3.44 (3H, s), 3.31 (3H, d, J=9.5 Hz), 2.04-1.74 (3H, m).
<Step 6-3>
-Bromo-N-methyl[(1S,2S)methyl (5-oxo-4H-1,2,4-oxadiazol
yl)cyclopropyl]-N-phenylindolecarboxamide (Compound 6e)
The titled compound was synthesized from Compound 6d obtained in Step 6-2 by
performing an operation similar to Step 1-8 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 467 ([M+H] ).
LC/MS retention time: 1.33 min. (Analysis Condition: SMD-FA05-01).
<Step 6-4>
-Bromo[(1S,2S)methyl(5-oxo-4H-1,2,4-oxadiazolyl)cyclopropyl]indole-
2-carboxylic acid (Compound 6f)
A mixture of Compound 6e (9.70 g, 20.8 mmol) obtained in Step 6-3, potassium
hydroxide (11.7 g, 208 mmol), and methoxyethanol (41.5 mL) was stirred at 100ºC for 4 h.
6N Hydrochloric acid (51.9 mL) was added under ice cold condition, and the suspension was
stirred at room temperature for 30 min. The solid was collected by filtration and washed
with water (29.1 mL), then dried under reduced pressure to obtain the titled Compound 6f
(7.42 g, yield 95%) as a light brown solid.
LC/MS mass spectrometry: m/z 376 ([M-H] ).
LC/MS retention time: 1.10 min. (Analysis Condition: SMD-FA05-2).
<Step 6-5>
-(2-Methoxymethylpyridinyl)[(1S,2S)methyl(5-oxo-4H-1,2,4-
oxadiazolyl)cyclopropyl]indolecarboxylic acid (Compound 6h)
The DMSO (34.7 mL) suspension of Compound 6f (3.00 g, 7.93 mmol) obtained in
Step 6-4, palladium(II) acetate (0.178 g, 0.793 mmol), dicyclohexyl (2’,4’,6’-triisopropyl-
[1,1’-biphenyl]yl)phosphane (0.756 g, 1.587 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-
bi(1,3,2-dioxaborolane) (3.02 g, 11.9 mmol), potassium phosphate (10.1 g, 47.6 mmol) was
deaerated at room temperature under reduced pressure, then, nitrogen was introduced in the
vessel. Under nitrogen atmosphere, the suspension was stirred at 100ºC for 0.5 h., then
cooled to room temperature. 4-Iodomethoxymethylpyridine (Compound 6g 、1.98 g,
7.93 mmol), water (4.96 mL) were added to the solution, and the solution was subjected to
deaeration under reduced pressure. Nitrogen was introduced in the vessel, and the solution
was stirred at 100ºC for 0.5 h. After cooling to room temperature, water (12.4 mL) and
formic acid (6 mL) were added to the solution. After filtration, the filtrate was directly
purified by reversed-phase chromatography (acetonitrile/water, 0.1% formic acid) to obtain
the titled Compound 6h (1.83 g, yield 55%).
LC/MS mass spectrometry: m/z 421 ([M+H] ).
LC/MS retention time: 1.10 min. (Analysis Condition: SMD-FA05-1).
<Step 6-6>
3-[(1S,2S)[2-[2-(4-Fluoro-3,5-dimethylphenyl) (2-oxo-1H-imidazolyl)-6,7-
dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl] (2-methoxymethylpyridinyl)indol-
1-yl]methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound 6i)
The titled compound was synthesized from Compound 2f obtained in Step 2-5 and
Compound 6h obtained in Step 6-5 by performing an operation similar to Step 1-10 of
Example 1 using an appropriate reagent.
The halogen compound (1- (5-bromoindazolyl)methylpropanol, Compound
6l) used in the synthesis of Example Compound 6 was synthesized by the following process.
<Step 6-7>
1-(5-Bromoindazolyl)methylpropanol (Compound 6k)
[Chemical Formula 21]
5-Bromoindazole (Compound 6j, 150 mg, 0.761 mmol) and 2,2-dimethyloxirane
(Compound 6k, 274 mg, 3.81 mmol) were dissolved in 1-methylpyrrolidinone (NMP)
(1.52 mL), to which potassium carbonate (526 mg, 3.81 mmol) was added. The solution
was stirred under microwave at 180ºC for 30 min. Water was added to the reaction mixture,
and extraction was performed using ethyl acetate. The organic layer was washed with
water, and the solvent was removed by evaporation under reduced pressure. The resulting
product was purified by silica gel column chromatography (ethyl acetate/hexane=1:1) to
obtain the titled Compound 6l (115 mg, yield 56%).
LC/MS mass spectrometry: m/z 269 ([M+H] ).
LC/MS retention time: 1.00 min. (Analysis Condition: SMD-FA05-2).
The 2-oxoimidazole reagent (3-[(1S,2S)[5- (2,2-dimethylmorpholinyl)[2-
(4-fluoro-3,5-dimethylphenyl) (2-oxo-1H-imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-
c]pyridinecarbonyl]indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazolone,
Compound 7c) used in the synthesis of Example Compound 7 was synthesized by the
following process.
[Chemical Formula 22]
<Step 7-1>
-(2,2-Dimethylmorpholinyl)[(1S,2S)methyl (5-oxo-4H-1,2,4-oxadiazol-
3-yl)cyclopropyl]indolecarboxylic acid (Compound 7b)
The NMP (44 mL) suspension of 2,2-dimethylmorpholine (Compound 7a, 1.98 g, 17.2
mmol), tris (dibenzylideneacetone)dipalladium(0) (0.121 g, 0.132 mmol), 2-
dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl (0.123 g, 0.264 mmol), sodium tert-
butoxide (5.08 g, 529 mmol) was deaerated at room temperature under reduced pressure,
then, nitrogen was introduced in the vessel. Under nitrogen atmosphere, Compound 6f (5.0
g, 13.2 mmol) obtained in Step 6-4 was added to the suspension, and the mixture was stirred
at 100ºC for 0.5 h. then cooled to room temperature. Formic acid was added to the mixture,
and the resulting product was directly purified by reversed-phase chromatography
(acetonitrile/water, 0.1% formic acid) to obtain the titled Compound 7b (5.26 g, yield 96%).
LC/MS mass spectrometry: m/z 413 ([M+H] ).
LC/MS retention time: 1.00 min. (Analysis Condition: SMD-FA05-1).
<Step 7-2>
3-[(1S,2S)[5-(2,2-Dimethylmorpholinyl)[2-(4-fluoro-3,5-dimethylphenyl)
(2-oxo-1H-imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl]indolyl]
methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound 7c)
The titled compound was synthesized from Compound 7b obtained in Step 7-1 by
performing an operation similar to Step 1-10 of Example 1 using an appropriate reagent.
The 2-oxoimidazole reagent (3-[(1S,2S)[2-[2-(4-fluoro-3,5-dimethylphenyl)
(2-oxo-1H-imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl](oxan
yl)indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazolone, Compound 8c) used in the
synthesis of Example Compounds 8 to 10 was synthesized by the following process.
[Chemical Formula 23]
<Step 8-1>
1-[(1S,2S)Methyl(5-oxo-4H-1,2,4-oxadiazolyl)cyclopropyl](oxan
yl)indolecarboxylic acid (Compound 8b)
The N,N-dimethylacetamide (DMA) (2.64 mL) suspension of Compound 6f (0.30 g,
0.793 mmol) obtained in Step 6-4, palladium(II) acetate (35.6 mg, 0.159 mmol), 2-
dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl (0.148 g, 0.317 mmol) was deaerated
under reduced pressure, then, nitrogen was introduced in the vessel and the suspension was
stirred at room temperature for 15 min. Under nitrogen atmosphere, a DMA solution (7.9
mL, 7.93 mmol) of 1M (tetrahydro-2H-pyranyl)zinc (II) iodide (Compound 8a) was
added, and the mixture was stirred at 80ºC for 15 min., and then the mixture was cooled to
room temperature. Formic acid was added to the mixture, and the resulting product was
directly purified by reversed-phase chromatography (methanol/water) to obtain the titled
Compound 8b (0.19 g, yield 61%).
LC/MS mass spectrometry: m/z 382 ([M-H] ).
LC/MS retention time: 1.00 min. (Analysis Condition: SMD-FA05-2).
<Step 8-2>
3-[(1S,2S)[2-[2-(4-Fluoro-3,5-dimethylphenyl)(2-oxo-1H-imidazolyl)-6,7-
dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl] (oxanyl)indolyl]
methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound 8c)
The titled compound was synthesized from Compound 8b obtained in Step 8-1 by
performing an operation similar to Step 1-10 of Example 1 using an appropriate reagent.
The halogen compound (5-bromo[(3R)-oxolanyl]indazole, Compound 8f) used
in the synthesis of Example Compound 8 was synthesized by the following process.
[Chemical Formula 24]
<Step 8-3>
4-Methylbenzenesulfonic acid [(3S)-oxolanyl] (Compound 8e)
To a dichloromethane solution (3.78 mL) of (3S)-oxolanol (Compound 8d, 500 mg,
.68 mmol) was added pyridine (1.28 mL, 15.9 mmol) and 4-methylbenzenesulfonyl chloride
(1.51 g, 7.95 mmol) at 0ºC. The solution was stirred at room temperature, then 15 h. later,
water and 1N hydrochloric acid were added to separate out the organic layer. The organic
layer was washed sequentially with saturated sodium hydrogen carbonate solution, and brine.
The solvent was removed by evaporation under reduced pressure to obtain the titled
Compound 8e (1.36 g, yield 99%).
LC/MS retention time: 0.96 min. (Analysis Condition: SMD-FA05-1).
H-NMR (400 MHz, CDCl ) δ: 7.79 (2H, d, J=8 Hz), 7.35 (2H, d, J=8 Hz), 5.12 (1H,
m), 3.93-3.76 (4H, m), 2.46 (3H, s), 2.13-2.05 (2H, m).
<Step 8-4>
-Bromo[(3R)-oxolanyl]indazole (Compound 8f)
To a DMF (3.8 mL) solution of 5-bromo-1H-indazole (Compound 6j, 300 mg, 1.52
mmol) was added cesium carbonate (992 mg, 3.05 mmol) and Compound 8e (369 mg, 1.52
mmol) obtained in Step 8-3, and the mixture was stirred at 100ºC for 2 h. After cooling to
room temperature, water was added to the reaction solution and extraction was performed
using ethyl acetate. The organic layer was washed with water, and the solvent was removed
by evaporation under reduced pressure. The resulting product was purified by silica gel
column chromatography (ethyl acetate/hexane=1:1) to obtain the titled Compound 8f (198
mg, yield 49%) as a colorless oil-like product.
LC/MS mass spectrometry: m/z 267 ([M+H] ).
LC/MS retention time: 1.07 min. (Analysis Condition: SMD-FA05-1).
The halogen compound (N-(4-bromomethoxyphenyl)-N-(3-methoxypropyl)
acetamide, Compound 9c) used in the synthesis of Example Compound 9 was synthesized by
the following process.
<Step 9-1>
[Chemical Formula 25]
To a DMF (0.8 mL) solution of N-(4-bromomethoxyphenyl)acetamide
(Compound 9a, 80 mg, 0.33 mmol) was sequentially added sodium hydride (50 wt% oil
dispersion) (18.9 mg, 0.39 mmol) and 1-bromomethoxypropane (75 mg, 0.49 mmol), and
the resulting mixture was stirred at room temperature for 12 h. Formic acid was added to
the reaction solution, and the resulting product was purified by reversed-phase silica gel
chromatography (acetonitrile/water, 0.1% formic acid) to obtain the titled Compound 9c (103
mg, yield 99%) as a colorless gum-like product.
LC/MS mass spectrometry: m/z 316 ([M+H] ).
LC/MS retention time: 1.02 min. (Analysis Condition: SMD-FA05-1).
The halogen compound (5-bromo (2,2,2-trifluoroethyl)indazole, Compound 10b)
used in the synthesis of Example Compound 10 was synthesized by the following process.
<Step 10-1>
[Chemical Formula 26]
The titled compound was synthesized from 2,2,2-trifluoroethyl
trifluoromethanesulfonate (Compound 10a) and 5-bromo-1H-indazole (Compound 6j) by
performing an operation similar to Step 8-4 of Example 8 using an appropriate reagent.
LC/MS mass spectrometry: m/z 279 ([M+H] ).
LC/MS retention time: 1.17 min. (Analysis Condition: SMD-FA05-1).
The 2-oxoimidazole reagent (3-[(1S,2S)[2-[(4S) (4-fluoro-3,5-
dimethylphenyl)methyl (2-oxo-1H-imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-
c]pyridinecarbonyl] (2-methoxymethylpyridinyl)indolyl]
methylcyclopropyl]-4H-1,2,4-oxadiazolone, Compound 11m) used in the synthesis of
Example Compounds 11 to 13 was synthesized by the following process.
[Chemical Formula 27]
<Step 11-1>
tert-Butyl N-(4-fluoro-3,5-dimethylphenyl)-N-[(2-methylpropan
yl)oxycarbonylamino]carbamate (Compound 11b)
-Bromofluoro-1,3-dimethylbenzene (Compund 11a, 4.66 g, 22.6 mmol) was
dissolved in THF (47.6 mL) and cooled under an external temperature of -70ºC. 1.55M n-
Butyl lithium (13.1 mL, 20.4 mmol) was added dropwise at a temperature of -70ºC or lower
and stirred for 1 h. A toluene solution (25.0 g, 21.7 mmol) of 20 wt% di-tert-butyl
azodicarboxylate was added dropwise at an internal temperature of -40ºC or lower, and the
mixture was stirred for 30 min. Then, the mixture was warmed to room temperature over a
period of 1 h., and heptane (23.8 mL) and 20% ammonium chloride solution (47.6 mL) were
added to perform extraction. The organic layer was concentrated and heptane (7.14 mL)
was added to the concentrated organic layer, and the mixture was heated to an external
temperature of 70ºC to promote dissolution. Then, the solution was cooled over a period of
1 h. to induce the precipitation of crystals. The crystals were collected by filtration and
washed with heptane (2.38 mL). The crystals were dried to obtain a crude product (3.53 g,
yield 44%) of the titled Compound 11b.
H-NMR (400 MHz, DMSO-D ) δ: 9.64-9.51 (0.8H, m), 9.24-9.07 (0.2H, m), 7.09-
6.91 (2H, m), 2.29-2.09 (6H, m), 1.53-1.32 (18H, m).
LC/MS retention time: 1.40 min. (Analysis Condition: SMD-FA05-3).
<Steps 11-2, 3, and 4>
tert-Butyl (2S)cyanomethyloxopiperidinecarboxylate (Compound 11g)
(3S)Aminobutanenitrile hydrochloride (Compound 11c, 10.0 g, 82.9 mmol) was
dissolved in ethanol (50.0 mL), and triethyl amine (13.9 mL, 99.5 mmol) and, to the mixture,
ethyl acrylate (10.8 mL, 99.5 mmol) were added at room temperature. The solution was
stirred at an external temperature of 70ºC for 3 h., then cooled to room temperature to obtain
a mixture containing ethyl 3-[[(2S)cyanopropanyl]amino]propanoate (Compound 11e).
To the reaction solution was added di-tert-butyl dicarbonate (21.7 mL, 99.5 mmol)
at room temperature. The solution was stirred at room temperature for 14 h., then N-
methylpiperazine (2.76 mL, 24.9 mmol) was added and the mixture was stirred for 4 h.
Then, 1N hydrochloric acid (50 mL) was added and extraction was performed using toluene
(50 mL). The organic layer was washed with 15% sodium chloride aqueous solution (50.0
mL). The organic layer was concentrated under reduced pressure to obtain a mixture
containing ethyl 3-[[(2S)cyanopropanyl]-[(2-methylpropan
yl)oxycarbonyl]amino]propanoate (Compound 11f).
To the mixture was added THF (50.0 mL), then potassium tert-butoxide (10.2 g,
91.2 mmol) was added at an internal temperature of 30ºC or lower. Then, the mixture was
stirred at room temperature for 1 h. At an internal temperature of 15ºC, 2N hydrochloric
acid (82.9 mL, 99.5 mmol) was added and extraction was performed using ethyl acetate.
The organic layer was concentrated after it was washed twice with 15% sodium chloride
aqueous solution (50.0 mL) to obtain the titled Compound 11g (15.8 g, yield 80%).
LC/MS mass spectrometry: m/z 237 ([M-H] ).
LC/MS retention time: 0.92 min. (Analysis Condition: SMD-FA05-1).
<Step 11-5>
tert-Butyl (4S)amino(4-fluoro-3,5-dimethylphenyl)methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridinecarboxylate (Compound 11h)
Compound 11b (2.13 g, 6.01 mmol) obtained in Step 11-1 was dissolved in NMP
(6.39 mL), to which methanesulfonic acid (1.30 g, 13.2 mmol) was added and the mixture
was stirred at an external temperature of 80ºC for 7 h. After the reaction solution was
cooled to room temperature, toluene (12.8 mL), potassium carbonate (0.914 g), and water
(12.8 g) were added to it, and the reaction solution was stirred at room temperature for 10
min. After removing the water layer, a toluene (6.3 mL) solution of Compound 11g (1.43 g,
6.01 mmol) obtained in Step 11-4, pyridine hydrochloride (71.0 mg, 0.60 mmol) and toluene
(4.2 mL) were added and the reaction solution was stirred at an external temperature of 90ºC
for 1 h. The reaction solution was cooled, then washed with 1M sodium hydroxide aqueous
solution (12.6 mL). The organic layer was concentrated under reduced pressure to
synthesize the titled Compound 11h (1.68 g, yield 75%).
LC/MS mass spectrometry: m/z 375 ([M+H] ).
LC/MS retention time: 1.08 min. (Analysis Condition: SMD-FA05-1).
<Step 11-6>
tert-Butyl (4S)(2,2-dimethoxyethylcarbamoylamino) (4-fluoro-3,5-
dimethylphenyl)methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate
(Compound 11j)
To a DMA (0.53 mL) solution of Compound 11h (106 mg, 0.283 mmol) obtained in
Step 11-5 was added N-(2,2-dimethoxyethyl)imidazolecarboxamide (Compound 11i, 62.0
mg, 0.311 mol), then potassium tert-butoxide (95.0 mg, 0.849mol) was added under a
nitrogen atmosphere, and the mixture was stirred at an external temperature of 25ºC for 4 h.
Water was added to the reaction solution and extraction was performed using ethyl acetate.
The organic layer was washed with water, and the solvent was removed by evaporation under
reduced pressure. The resulting product was purified by silica gel column chromatography
(ethyl acetate/hexane=3:2) to obtain the titled Compound 11j (105 mg, yield 73%).
LC/MS mass spectrometry: m/z 506 ([M+H] ).
LC/MS retention time: 1.09 min. (Analysis Condition: SMD-FA05-1).
<Step 11-7>
tert-Butyl (4S)(4-fluoro-3,5-dimethylphenyl)methyl (2-oxo-1H-imidazol
yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate (Compound 11k)
Compound 11j (4.45 g, 8.79 mmol) obtained in Step 11-6 was suspended by adding
THF (44.5 mL), then methylsulfonic acid (0.676 g, 7.03 mmol) was added, and the resulting
mixture was stirred at an external temperature of 60ºC for 2 h. After cooling to room
temperature, a solution of tripotassium phosphate (1.87 g, 8.79 mmol) in water (17.8 mL)
was added, di-tert-butyl dicarbonate (0.768 g, 3.52 mmol) was added, and the resulting
mixture was stirred at room temperature for 1 h. Water was added to the reaction solution
and extraction was performed using ethyl acetate. The organic layer was washed with a
saturated sodium chloride aqueous solution, then dried using magnesium sulfate. After
filtration, the organic layer was concentrated under reduced pressure, and purified by silica
gel column chromatography (ethyl acetate/hexane=3:7) to obtain the titled Compound 11k
(3.43 g, yield 88%).
LC/MS mass spectrometry: m/z 442 ([M+H] ).
LC/MS retention time: 1.09 min. (Analysis Condition: SMD-FA05-1).
<Step 11-8>
3-[(4S)(4-Fluoro-3,5-dimethylphenyl)methyl-4,5,6,7-tetrahydropyrazolo[4,3-
c]pyridinyl]-1H-imidazolone hydrochloride (Compound 11l)
To a dichloromethane (8.38 ml) solution of Compound 11k (1.85 g, 4.19 mmol)
obtained in Step 11-7 was added a 4M hydrogen chloride dioxane solution (10.5 mL, 41.9
mmol). The mixture was stirred at room temperature for 1h., and the reaction mixture was
concentrated under reduced pressure to obtain a crude product (1.63 g) containing the titled
Compound 11l as a brown solid.
LC/MS mass spectrometry: m/z 342 ([M+H] ).
LC/MS retention time: 0.63 min. (Analysis Condition: SMD-FA05-1).
<Step 11-9>
3-[(1S,2S)[2-[(4S)(4-Fluoro-3,5-dimethylphenyl)methyl(2-oxo-1H-
imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl](2-methoxy
methylpyridinyl)indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound
11m)
The titled compound was synthesized from Compound 11l obtained in Step 11-8 and
Compound 6h obtained in Step 6-5 by performing an operation similar to Step 1-10 of
Example 1 using an appropriate reagent.
The 2-oxoimidazole reagent (3-[(1S,2S)[2-[(4S) (4-fluoro-3,5-
dimethylphenyl)methyl(2-oxo-1H-imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-
c]pyridinecarbonyl](3-fluoromethylpyridinyl)indolyl]methylcyclopropyl]-
4H-1,2,4-oxadiazolone, Compound 14d) used in the synthesis of Example Compound 14
was synthesized by the following process.
[Chemical Formula 28]
<Step 14-1>
-(2-Chlorofluoropyridinyl)[(1S,2S)methyl(5-oxo-4H-1,2,4-oxadiazol-
3-yl)cyclopropyl]indolecarboxylic acid (Compound 14b)
The titled compound was synthesized from Compound 6f obtained in Step 6-4 and 2-
chlorofluoroiodopyridine (Compound 14a) by performing an operation similar to Step
6-5 of Example 6 using an appropriate reagent.
LC/MS mass spectrometry: m/z 429 ([M+H] ).
LC/MS retention time: 1.14 min. (Analysis Condition: SMD-TFA05-3).
<Step 14-2>
-(3-Fluoromethylpyridinyl)[(1S,2S)methyl (5-oxo-4H-1,2,4-
oxadiazolyl)cyclopropyl]indolecarboxylic acid (Compound 14c)
To a mixed suspension of DMSO/water at 7:1 (13.2 mL) containing Compound 14b
(810 mg, 1.32 mmol) obtained in Step 14-1, 1,1’-bis (diphenylphosphino)ferrocene-
palladium(II) dichloride (48 mg, 0.066 mmol), potassium carbonate (2.74 g, 19.8 mmol),
methylboronic acid (792 mg, 13.2 mmol) was deaerated under reduced pressure at room
temperature, then nitrogen was introduced in the vessel. Under a nitrogen atmosphere, the
mixture was stirred at 100ºC for 0.5 h, then cooled to room temperature. Formic acid was
added to the mixture, which was directly purified by reversed-phase chromatography
(acetonitrile/water, 0.1% formic acid) to obtain the titled Compound 14c (124 mg, yield 23%)
as a pale yellow solid.
LC/MS mass spectrometry: m/z 409 ([M+H] ).
LC/MS retention time: 0.85 min. (Analysis Condition: SMD-FA05-3).
<Step 14-3>
3-[(1S,2S)[2-[(4S) (4-fluoro-3,5-dimethylphenyl)methyl (2-oxo-1H-
imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl](3-fluoro
methylpyridinyl)indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound
14d)
The titled compound was synthesized from Compound 11l obtained in Step 11-8 and
Compound 14c obtained in Step 14-2 by performing an operation similar to Step 1-10 of
Example 1 using an appropriate reagent.
The 2-oxoimidazole reagent (3-[(1S,2S)[5-[2- (dimethylamino)methylpyridin-
4-yl][(4S)(4-fluoro-3,5-dimethylphenyl)methyl (2-oxo-1H-imidazolyl)-6,7-
dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl]indolyl]methylcyclopropyl]-4H-1,2,4-
oxadiazolone, Compound 15d) used in the synthesis of Example Compound 15 was
synthesized by the following process.
[Chemical Formula 29]
<Step 15-1>
4-Iodo-N,N,3-trimethylpyridineamine (Compound 15b)
A DMF (7.9 mL) solution of 2-chloroiodomethylpyridine (Compound 15a, 500
mg, 1.97 mmol), N-ethyl-N-propanylpropaneamine (0.515 mL, 2.96 mmol), and a THF
solution (2.96 mL, 5.92 mmol) of 2M dimethylamine was stirred at 130ºC for 17 h., then the
solution was cooled to room temperature and formic acid (0.4 mL) was added. The solution
was purified by reversed-phase chromatography (acetonitrile/water, 0.1% formic acid) to
obtain the titled Compound 15b (258 mg, yield 50%) as a light brown solution.
LC/MS mass spectrometry: m/z 263 ([M+H] ).
LC/MS retention time: 0.52 min. (Analysis Condition: SQD-FA05-1).
<Step 15-2>
-[2-(Dimethylamino)methylpyridinyl][(1S,2S)methyl(5-oxo-4H-1,2,4-
oxadiazolyl)cyclopropyl]indolecarboxylic acid (Compound 15c)
The titled compound was obtained from Compound 6f obtained in Step 6-4 and
Compound 15b obtained in Step 15-1 by performing an operation similar to Step 6-5 of
Example 6 using an appropriate reagent.
LC/MS mass spectrometry: m/z 432 ([M-H] ).
LC/MS retention time: 0.51 min. (Analysis Condition: SQD-FA05-1).
<Step 15-3>
3-[(1S,2S)[5-[2-(Dimethylamino)methylpyridinyl][(4S)(4-fluoro-3,5-
dimethylphenyl)methyl (2-oxo-1H-imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-
c]pyridinecarbonyl]indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazolone
(Compound 15d)
The titled compound was synthesized from Compound 15c obtained in Step 15-2 and
Compound 11l obtained in Step 11-8 by performing an operation similar to Step 1-10 of
Example 1 using an appropriate reagent.
The 2-oxoimidazole reagent (3-[(1S,2S)[2-[(4S) (4-fluoro-3,5-
dimethylphenyl)- 4-methyl(2-oxo-1H-imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-
c]pyridinecarbonyl](oxanyl)indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazol
one, Compound 16a) used in the synthesis of Example Compounds 16 to 30 was synthesized
by the following process.
[Chemical Formula 30]
<Step 16-1>
3-[(1S,2S)[2-[(4S)(4-Fluoro-3,5-dimethylphenyl)methyl (2-oxo-1H-
imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl](oxanyl)indol
yl]methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound 16a)
The titled compound was obtained from Compound 11l obtained in Step 11-8 and
Compound 8b obtained in Step 8-1 by performing an operation similar to Step 1-10 of
Example 1 using an appropriate reagent.
The halogen compound (5-bromo[(3-methyloxetanyl)methyl]indazole,
Compound 17b) used in the synthesis of Example Compound 17 was synthesized by the
following process.
<Step 17-1>
[Chemical Formula 31]
The titled compound was synthesized from 3-methyl[(4-
methylphenyl)sulfonylmethyl]oxetane (Compound 17a) and 5-bromo-1H-indazole
(Compound 6j) by performing an operation similar to Step 9-1 of Example 9 using an
appropriate reagent.
LC/MS mass spectrometry: m/z 281 ([M+H] ).
LC/MS retention time: 1.10 min. (Analysis Condition: SMD-FA05-2).
The halogen compound (2-(4-bromomethoxyphenoxy)methylpropanol,
Compound 20b) used in the synthesis of Example Compound 20 was synthesized by the
following process.
<Step 20-1>
2-(4-Bromomethoxyphenoxy)methylpropanol (Compound 20b)
[Chemical Formula 32]
Under a nitrogen atmosphere, a THF solution (0.95M, 4.37 mL, 4.15 mmol) of
borane was added dropwise at 0ºC to a THF solution (1.38 mL) of 2-(4-bromo
methoxyphenoxy)methylpropane carboxylic acid (Compound 20a, 400 mg, 1.38 mmol)
and the resulting mixture was stirred for 24 h. After 1M sodium hydroxide aqueous solution
was added to the mixture and the mixture was stirred, 1N hydrochloric acid was added for
neutralization. Then, ethyl acetate was added to perform extraction. The organic layer
was washed with water and the solvent was removed by evaporation under reduced pressure
to obtain the titled Compound 20b (339 mg, yield 89%).
LC/MS retention time: 1.04 min. (Analysis Condition: SMD-FA05-3).
H-NMR (400 MHz, CDCl ) δ: 7.04-7.01 (2H, m), 6.90-6.86 (1H, m), 3.85 (3H, s),
3.44 (2H, m), 3.34 (1H, m), 1.28 (6H, s).
The halogen compound (5-bromo[(3S)-oxolanyl]indazole, Compound 22c)
used in the synthesis of Example Compound 22 was synthesized by the following process.
[Chemical Formula 33]
<Step 22-1>
(3R)-Oxolanyl 4-methylbenzenesulfonate (Compound 22b)
The titled compound was synthesized by performing an operation similar to Step 8-3
of Example 8 using (3R)-oxolanol and an appropriate reagent.
LC/MS retention time: 0.95 min. (Analysis Condition: SMD-FA05-3).
<Step 22-2>
-Bromo[(3S)-oxolanyl]indazole (Compound 22c)
The titled compound was synthesized from Compound 22b obtained in Step 22-1 and
-bromo-1H-indazole by performing an operation similar to Step 8-4 of Example 8 using an
appropriate reagent.
LC/MS mass spectrometry: m/z 267 ([M+H] ).
LC/MS retention time: 1.06 min. (Analysis Condition: SMD-FA05-3).
The halogen compound (6-bromo-1,1-dimethyl-3,4-dihydroisochromene,
Compound 24d) used in the synthesis of Example Compound 24 was synthesized by the
following process.
[Chemical Formula 34]
<Step 24-1>
(1,1-Dimethyl-3,4-dihydroisochromenyl) trifluoromethanesulfonate (Compound
24b)
The titled compound was synthesized from 1,1-dimethyl-3,4-dihydroisochromenol
(Compound 24a) and trifluoromethylsulfonyl trifluoromethanesulfonate (triflate anhydride)
by performing an operation similar to Step 8-3 of Example 8 using an appropriate reagent.
LC/MS retention time: 0.96 min. (Analysis Condition: SQD-FA05-01).
<Step 24-2>
2-(1,1-Dimethyl-3,4-dihydroisochromenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (Compound 24c)
After the 1,4-dioxane (2.58 mL) solution of Compound 24b (120 mg, 0.387 mmol)
obtained in Step 24-1, 4,4,5,5-tetramethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-
1,3,2-dioxaborolane (147 mg, 0.580 mmol), triethyl amine (0.162 mL, 1.16 mmol), [1,1’-bis
(diphenylphosphino)ferrocene]dichloropalladium(II) (14.2 mg, 0.019 mmol) was deaerated
under reduced pressure, nitrogen was introduced in the vessel and the solution was stirred at
100ºC for 14 h. The solution was cooled to room temperature, then formic acid was added
and the resulting product was purified by reversed-phase chromatography (acetonitrile/water,
0.1% formic acid) to obtain a mixture (134 mg) containing the titled Compound 24c as a light
brown liquid.
LC/MS mass spectrometry: m/z 289 ([M+H] ).
LC/MS retention time: 1.03 min. (Analysis Condition: SQD-FA05-1).
<Step 24-3>
6-Bromo-1,1-dimethyl-3,4-dihydroisochromene (Compound 24d)
To a methanol (1.9 mL) solution of Compound 24c (111 mg, 0.385 mmol) obtained in
Step 24-2, an aqueous solution (1.9 mL) of copper(II) bromide (258 mg, 1.16 mmol) was
added and the mixture was stirred at 60ºC for 6 h. After the mixture was cooled to room
temperature, a saturated ammonium chloride solution was added, then extraction using
dichloromethane was performed twice, and then the organic layer was dried with magnesium
sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue
was purified by silica gel column chromatography (ethyl acetate/hexane=1:4) to obtain the
titled Compound 24d (47.7 mg, yield 51%) as a colorless liquid.
H-NMR (400 MHz, CDCl ) δ: 7.29 (1H, dd, J=2.0, 8.4 Hz), 7.24-7.22 (1H, m), 6.97
(1H, d, J=8.4 Hz), 3.92 (2H, t, J=5.6 Hz), 2.80 (2H, t, J=5.6 Hz), 1.50 (6H, s).
LC/MS retention time: 0.96 min. (Analysis Condition: SQD-FA05-1).
The halogen compound (6-(4-bromomethylphenyl)-N,N-dimethylpyrimidine
amine, Compound 25b) used in the synthesis of Example Compound 25 was synthesized by
the following process.
[Chemical Formula 35]
<Step 25-1>
6-(4-Bromomethylphenyl)-N,N-dimethylpyrimidineamine (Compound 25b)
To a methanol (0.2 mL) solution of 4-(4-bromomethylphenyl)chloropyrimidine
(Compound 25a, 12.9 mg, 0.045 mmol) was added 2M dimethylamine THF solution (0.227
mL, 0.455 mmol), and the mixture was stirred at room temperature for 3 h. The reaction
mixture was purified by the reversed-phase silica gel column chromatography
(acetonitrile/water, 0.1% formic acid) to synthesize the titled Compound 25b (9.2 mg, yield
69%) as an off-white solid.
LC/MS mass spectrometry: m/z 292 ([M+H] ).
LC/MS retention time: 0.67 min. (Analysis Condition: SMD-FA05-3).
The halogen compound (5-bromofluoro (2,2,2-trifluoroethyl)indazole,
Compound 28b) used in the synthesis of Example Compound 28 was synthesized by the
following process.
[Chemical Formula 36]
<Step 28-1>
-Bromofluoro(2,2,2-trifluoroethyl)indazole (Compound 28b)
The titled compound was synthesized from 2,2,2-trifluoroethyl
trifluoromethanesulfonate (Compound 10a) and 5-bromofluoro-1H-indazole (Compound
28a) by performing an operation similar to Step 8-4 of Example 8 using an appropriate
reagent.
LC/MS mass spectrometry: m/z 297 ([M+H] ).
LC/MS retention time: 1.20 min. (Analysis Condition: SMD-FA05-1).
The halogen compound (5-bromofluoro[(3-methyloxetan
yl)methyl]indazole, Compound 29a) used in the synthesis of Example Compound 29 was
synthesized by the following process.
[Chemical Formula 37]
<Step 29-1>
-Bromofluoro[(3-methyloxetanyl)methyl]indazole (Compound 29a)
The titled compound was synthesized from 3-methyl[(4-
methylphenyl)sulfonylmethyl]oxetane (Compound 17a) and 5-bromofluoro-1H-indazole
(Compound 28a) by performing an operation similar to Step 8-4 of Example 8 using an
appropriate reagent.
LC/MS mass spectrometry: m/z 299 ([M+H] ).
LC/MS retention time: 1.11 min. (Analysis Condition: SMD-FA05-1).
The halogen compound (1-(5-bromofluoroindazolyl)methylpropanol,
Compound 30a) used in the synthesis of Example Compound 30 was synthesized by the
following process.
[Chemical Formula 38]
<Step 30-1>
1-(5-Bromofluoroindazolyl)methylpropanol (Compound 30a)
The titled compound was synthesized from 5-bromofluoro-1H-indazole
(Compound 28a) and 2,2-dimethyloxirane (Compound 6k) by performing an operation
similar to Step 6-7 of Example 6 using an appropriate reagent.
LC/MS mass spectrometry: m/z 287 ([M+H] ).
LC/MS retention time: 1.01 min. (Analysis Condition: SMD-FA05-1).
The 2-oxoimidazole reagent (3-[(1S,2S)[5-[(4S)-2,2-dimethyloxanyl][(4S)-
2-(4-fluoro-3,5-dimethylphenyl)methyl(2-oxo-1H-imidazolyl)-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridinecarbonyl]indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazol
one, Compound 31l) used in the synthesis of Example Compounds 31 to 40 was synthesized
by the following process.
[Chemical Formula 39]
<Step 31-1>
Ethyl 5-(2,2-dimethyloxanyl)-1H-indolecarboxylate (Compound 31c)
Zinc powder (1.95 g, 29.8 mmol) was suspended in DMF (6 mL), and the suspension
was subjected to nitrogen substitution. Chlorotrimethylsilane (0.417 mL, 3.28 mmol), and
1,2-dibromoethane (0.284 mL, 3.28 mmol) were added and the resulting mixture was stirred
at room temperature for 5 min. A DMF (9 mL) solution of 4-iodo-2,2-
dimethyltetrahydropyran (5.37 g, 22.4 mmol)was added dropwise to the mixture, and the
mixture was stirred at room temperature for 20 min. To this solution were added
palladium(II) acetate (0.084 g, 0.373 mmol), and 4-(N,N-dimethylamino)phenyl]di-tert-
butylphosphine (0.198 g, 0.746mol), ethyl 5-bromoindolecarboxylate (2.0 g, 7.46 mmol),
and nitrogen was introduced in the vessel. The mixture was stirred at an external
temperature of 50ºC for 1 h., then the external temperature was cooled to 0ºC, and 5N
hydrochloric acid (6 mL) was added for neutralization. A 30% sodium chloride aqueous
solution (50 mL) and ethyl acetate (100 mL) were added and the non-dissolved matters were
removed with cerite. The filtrate was subjected to extraction using ethyl acetate and the
organic layer was washed with 30% sodium chloride aqueous solution. Then, it was dried
with magnesium sulfate and run through a filter, and the solvent was removed by evaporation
under reduced pressure. The residue was purified by silica gel column chromatography
(ethyl acetate/hexane) to synthesize the titled Compound 31c (1.86 g, yield 83%) as a pale
pink solid.
LC/MS mass spectrometry: m/z 302 ([M+H] ).
LC/MS retention time: 0.90 min. (Analysis Condition: SQD-FA05-4).
<Step 31-2>
Ethyl 5-[(4S)-2,2-dimethyloxanyl]-1H-indolecarboxylate (Compound 31d)
The stereoisomers included in Compound 31c (900 mg) obtained by Step 31-1 were
separated by supercritical-fluid chromatography to obtain the titled Compound 31d (423 mg,
yield 47%).
Separation condition
Device: SFC15 (Waters)
Column: CHIRALPAK-IE/SFC, 10×250 mm, 5 μm (Daicel)
Column temperature: 40ºC
Solvent: Super-critical carbon dioxide/methanol: ethyl acetate (1:1)=60/40
(Homogenous system)
Flow rate: 15 mL/min., 140 bar
Analysis Condition
Device: Nexera (Shimadzu)
Column: CHIRALPAK-IE, 4.6×250 mm, 5 μm (Daicel)
Column Temperature: 25ºC
Solvent: hexane/ethanol=30/70 (homogenous system)
Flow rate: 1 mL/min., room temperature
Titled Compound retention time: 9.98 min., isomer retention time: 6.86 min.
Note that the titled compound was determined to be the S-isomer by X-ray
crystallography of Compound 31j.
<Step 31-3>
-[(4S)-2,2-Dimethyloxanyl]-1H-indolecarboxylic acid (Compound 31e)
Compound 31d (993 mg, 3.29 mmol) obtained in Step 31-2 was dissolved in methanol
(14.9 mL), and a 2M sodium hydroxide aqueous solution (3.62 mL, 7.25 mmol) was added
dropwise into the mixture and the mixture was stirred at an external temperature of 65ºC for
1 h. The reaction solution was cooled at an external temperature of 15ºC, and 5N
hydrochloric acid (1.52 mL, 7.58 mmol) was added dropwise into the reaction solution.
Water (7.45 mL) was added dropwise, and the precipitated solid was collected by filtration.
The obtained solid was washed with water (5.0 mL) and dried under reduced pressure to
obtain the titled Compound 31e (827 mg, yield 96%).
LC/MS mass spectrometry: m/z 274 ([M+H] ).
LC/MS retention time: 0.65 min. (Analysis Condition: SQD-FA05-4).
<Step 31-4>
-[(4S)-2,2-Dimethyloxanyl]-N-methyl-N-phenyl-1H-indolecarboxamide
(Compound 31f)
Compound 31e (805 mg, 2.95 mmol) obtained in Step 31-3 was dissolved in DMA
(8.0 mL), and thionyl chloride (0.256 mL, 3.53 mmol) was added dropwise into the solution
at an internal temperature of 10ºC or lower. After the solution was stirred for an hour, N-
methylaniline (0.384 mL, 3.53 mmol) and triethyl amine (0.985 mL, 7.07 mmol) were added
dropwise at 10ºC or lower, and the solution was stirred at room temperature for 1 h. Water
(4.0 mL) was added dropwise into the solution, and the precipitated solid was collected by
filtration. The obtained solid was washed with water (8.0 mL) and dried under reduced
pressure to obtain the titled Compound 31f (995 mg, yield 93%).
LC/MS mass spectrometry: m/z 363 ([M+H] ).
LC/MS retention time: 1.20 min. (Analysis Condition: SMD-FA05-1).
<Step 31-5>
1-(Cyanomethyl)[(4S)-2,2-dimethyloxanyl]-N-methyl-N-phenylindole
carboxamide (Compound 31h)
Compound 31f (101 mg, 0.276 mmol) obtained in Step 31-4 was dissolved in 1,3-
dimethylimidazolidinone (DMI) (1.0 mL) at room temperature, and 8M potassium
hydroxide aqueous solution (0.103 mL, 0.828 mmol) and water (0.10 mL) were added to the
solution. To the obtained solution was added 2-chloroacetonitrile (0.026 mL, 0.414 mmol)
at an external temperature of 10ºC, and the solution was stirred for 2.5 h. 5N Hydrochloric
acid (0.193 mL), water (0.10 mL), and cyclopentylmethyl ether (1.0 mL) were added to the
reaction solution to perform extraction, and the aqueous layer was subjected to a second
extraction using cyclopentylmethyl ether (1.0 mL). The combined organic layer was
washed with 15% sodium chloride solution (1.0 mL), then, the titled Compound 31h was
obtained as a light brown oil-like product by concentration under a reduced pressure at an
external temperature of 40ºC and was put to use in the subsequent Step 31-6 without being
purified.
LC/MS mass spectrometry: m/z 402 ([M+H] ).
LC/MS retention time: 0.93 min. (Analysis Condition: SMD-FA05-1).
<Step 31-6>
1-[(1S,2S)Cyanomethylcyclopropyl][(4S)-2,2-dimethyloxanyl]-N-methyl-
N-phenylindolecarboxamide (Compound 31i)
The titled compound was synthesized from Compound 31h obtained in Step 31-5 by
performing an operation similar to Step 1-6 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 442 ([M+H] ).
LC/MS retention time: 0.95 min. (Analysis Condition: SQD-FA05-1).
<Step 31-7>
-[(4S)-2,2-Dimethyloxanyl]-N-methyl[(1S,2S)methyl(5-oxo-4H-1,2,4-
oxadiazolyl)cyclopropyl]-N-phenylindolecarboxamide (Compound 31j)
The titled compound was synthesized from Compound 31i obtained in Step 31-6 by
performing an operation similar to Step 1-6 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 501 ([M+H] ).
LC/MS retention time: 0.99 min. (Analysis Condition: SQD-FA05-1).
<Step 31-8>
-[(4S)-2,2-Dimethyloxanyl][(1S,2S)methyl(5-oxo-4H-1,2,4-oxadiazol
yl)cyclopropyl]indolecarboxylic acid (Compound 31k)
The titled compound was synthesized from Compound 31j obtained in Step 31-7 by
performing an operation similar to Step 6-4 of Example 6 using an appropriate reagent.
LC/MS mass spectrometry: m/z 401 ([M-H] ).
LC/MS retention time: 1.05 min. (Analysis Condition: SMD-FA05-1).
<Step 31-9>
3-[(1S,2S)[5-[(4S)-2,2-Dimethyloxanyl][(4S)(4-fluoro-3,5-
dimethylphenyl)methyl(2-oxo-1H-imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-
c]pyridinecarbonyl]indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazolone
(Compound 31l)
The titled compound was synthesized from Compound 11l obtained in Step 11-8 and
Compound 31k obtained in Step 31-8 by performing an operation similar to Step 1-10 of
Example 1 using an appropriate reagent.
The halogen compound 5-bromo(2-methoxyethyl)methylbenzoimidazolone
(Compound 33b) used in the synthesis of Example Compound 33 was synthesized by the
following process.
<Step 33-1>
[Chemical Formula 40]
The titled compound was synthesized from 5-bromomethyl-1H-benzoimidazol
one (Compound 33a) by performing an operation similar to Step 8-4 of Example 8 using an
appropriate reagent.
LC/MS mass spectrometry: m/z 285 ([M+H] ).
LC/MS retention time: 0.95 min. (Analysis Condition: SMD-FA05-1).
The halogen compound (5-bromofluoro (2-methoxyethyl)indazole, Compound
36a) used in the synthesis of Example Compound 36 was synthesized by the following
process.
<Step 36-1>
[Chemical Formula 41]
The titled compound was synthesized from 5-bromofluoro-1H-indazole
(Compound 28a) by performing an operation similar to Step 8-4 of Example 8 using an
appropriate reagent.
LC/MS mass spectrometry: m/z 273 ([M+H] ).
LC/MS retention time: 1.10 min. (Analysis Condition: SMD-FA05-1).
The halogen compound (5-bromofluoro[(3S)-oxolanyl]indazole, Compound
40a) used in the synthesis of Example Compound 40 was synthesized by the following
process.
<Step 40-1>
[Chemical Formula 42]
The titled compound was synthesized from 5-bromofluoro-1H-indazole
(Compound 28a) and (3R)-oxolanyl 4-methylbenzenesulfonate (Compound 22b) by
performing an operation similar to Step 8-4 of Example 8 using an appropriate reagent.
LC/MS mass spectrometry: m/z 285 ([M+H] ).
LC/MS retention time: 1.10 min. (Analysis Condition: SMD-FA05-1).
The 2-oxoimidazole reagent (3-[(1S,2S)[2-[(4S)(4-fluoro-3,5-
dimethylphenyl)methyl(2-oxo-1H-imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-
c]pyridinecarbonyl][(2S,4S)methyloxanyl]indolyl]methylcyclopropyl]-4H-
1,2,4-oxadiazolone, Compound 41f) used in the synthesis of Example Compound 41 was
synthesized by the following process.
[Chemical Formula 43]
<Steps 41-1 and 2>
1-[(1S,2S)Cyanomethylcyclopropyl]-N-methyl[(2S,4S)methyloxanyl]-
N-phenylindolecarboxamide (Compound 41c)
After a DMA (0.12 mL) suspension of zinc (29 mg, 0.44 mmol) was deaerated under
at room temperature at room temperature, nitrogen was introduced in the vessel. Under a
nitrogen atmosphere, a 7:5 mixed solution of chlorotrimethylsilane/1,2-dibromoethane
(0.0083 mL, 0.039 mmol of chlorotrimethylsilane) was added, and the mixture was stirred for
min., then (2S)iodomethyltetrahydro-2H-pyran (80 mg, 0.35 mmol) was added
dropwise at room temperature and the mixture was stirred for 30 min. to obtain a mixture
containing iodo-[(2S)methyloxanyl]zinc (Compound 41b). Palladium(II) acetate (6.4
mg, 0.028 mmol), 2-dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl (26 mg, 0.057
mmol), 5-bromo[(1S,2S)cyanomethylcyclopropyl]-N-methyl-N-phenylindole
carboxamide (58 mg, 0.14 mmol), and DMA (0.123 mL) were added, and the mixture was
deaerated under reduced pressure, then nitrogen was introduced in the vessel and the mixture
was stirred for an hour at 80ºC. The mixture was cooled to room temperature, to which
ethyl acetate and 1N hydrochloric acid were added, and the mixture was filtered. Then, the
filtrate was subjected to extraction using ethyl acetate. The organic layer was washed once
with brine and concentrated under reduced pressure, then, the residue was purified by silica
gel column chromatography (ethyl acetate/hexane=1:1) to obtain the titled Compound 41c
(31 mg, yield 51%).
LC/MS mass spectrometry: m/z 428 ([M+H] ).
LC/MS retention time: 1.01 min. (Analysis Condition: SQD-AA05-1).
<Step 41-3>
N-Methyl[(2S,4S)methyloxanyl][(1S,2S)methyl (5-oxo-4H-1,2,4-
oxadiazolyl)cyclopropyl]-N-phenylindolecarboxamide (Compound 41d)
The titled compound was synthesized from Compound 41c obtained in Step 41-2 by
performing an operation similar to Step1-8 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 487 ([M+H] ).
LC/MS retention time: 1.30 min. (Analysis Condition: SMD-FA05-1).
<Step 41-4>
-[(2S,4S)Methyloxanyl][(1S,2S)methyl(5-oxo-4H-1,2,4-oxadiazol
yl)cyclopropyl]indolecarboxylic acid (Compound 41e)
The titled compound was synthesized from Compound 41d obtained in Step 41-3 by
performing an operation similar to Step 6-4 of Example 6 using an appropriate reagent.
LC/MS mass spectrometry: m/z 396 ([M-H] ).
LC/MS retention time: 1.02 min. (Analysis Condition: SMD-FA05-1).
<Step 41-5>
3-[(1S,2S)[2-[(4S)(4-Fluoro-3,5-dimethylphenyl)methyl(2-oxo-1H-
imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl][(2S,4S)
methyloxanyl]indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound
41f)
The titled compound was synthesized from Compound 41e obtained in Step 41-4 by
performing an operation similar to Step 1-10 of Example 1 using an appropriate reagent.
The 2-oxoimidazole reagent (3-[(1S,2S)[2-[(4S)(4-chloro-3,5-
dimethylphenyl)methyl(2-oxo-1H-imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-
c]pyridinecarbonyl][(4S)-2,2-dimethyloxanyl]indolyl]methylcyclopropyl]-4H-
1,2,4-oxadiazolone, Compound 42g) used in the synthesis of Example Compounds 42 and
43 were synthesized by the following process.
[Chemical Formula 44]
<Steps 42-1, 2>
tert-Butyl (4S)amino(4-chloro-3,5-dimethylphenyl)methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridinecarboxylate (Compound 42c)
After (4-chloro-3,5-dimethylphenyl)hydrazine hydrochloride (Compound 42b) was
obtained from 4-chloro-3,5-dimethylaniline (Compound 42a) by performing an operation
similar to Step 2-2 of Example 2 using an appropriate reagent, Compound 11g obtained in
Step 11-4 and an appropriate reagent were used to synthesize Compound 42c by an operation
similar to Step 1-2 of Example 1.
LC/MS mass spectrometry: m/z 391 ([M+H] ).
LC/MS retention time: 1.22 min. (Analysis Condition: SMD-FA10-4).
<Step 42-3>
tert-Butyl (4S)(4-chloro-3,5-dimethylphenyl)(2,2-
dimethoxyethylcarbamoylamino)methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine
carboxylate (Compound 42d)
The titled compound was synthesized from Compound 42c obtained in Step 42-2 by
performing an operation similar to Step 1-3 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 522 ([M+H] ).
LC/MS retention time: 1.55 min. (Analysis Condition: SMD-TFA05-5).
<Step 42-4>
tert-Butyl (4S)(4-chloro-3,5-dimethylphenyl)methyl (2-oxo-1H-imidazol
yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate (Compound 42e)
The titled compound was synthesized from Compound 42d obtained in Step 42-3 by
performing an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 458 ([M+H] ).
LC/MS retention time: 1.16 min. (Analysis Condition: SMD-FA05-1).
<Step 42-5>
3-[(4S)(4-Chloro-3,5-dimethylphenyl)methyl-4,5,6,7-tetrahydropyrazolo[4,3-
c]pyridinyl]-1H-imidazolone hydrochloride (Compound 42f)
The titled compound was synthesized from Compound 42e obtained in Step 42-4 by
performing an operation similar to Step 111-8 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 358 ([M+H] ).
LC/MS retention time: 0.69 min. (Analysis Condition: SMD-FA05-1).
<Step 42-6>
3-[(1S,2S)[2-[(4S)(4-chloro-3,5-dimethylphenyl)methyl(2-oxo-1H-
imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl][(4S)-2,2-
dimethyloxanyl]indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound
42g)
The titled compound was synthesized from Compound 42f obtained in Step 42-5 and
Compound 31k obtained in Step 31-8 by performing an operation similar to Step 1-10 of
Example 1 using an appropriate reagent.
The 2-oxoimidazole reagent (3-[(1S,2S)[2-[(4S) (4-chloro-3,5-
dimethylphenyl)methyl(2-oxo-1H-imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-
c]pyridinecarbonyl](oxanyl)indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazol
one, Compound 44a) used in the synthesis of Example Compounds 44 and 45 were
synthesized by the following process.
[Chemical Formula 45]
<Step 44-1>
3-[(1S,2S)[2-[(4S) (4-Chloro-3,5-dimethylphenyl)methyl(2-oxo-1H-
imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl] (oxanyl)indol
yl]methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound 44a)
The titled compound was synthesized from Compound 42f obtained in Step 42-5 and
Compound 8b obtained in Step 8-1 by performing an operation similar to Step 1-10 of
Example 1 using an appropriate reagent.
The 2-oxoimidazole reagent (3-[(1S,2S)[2-[(4S)(4-fluoromethylphenyl)
methyl (2-oxo-1H-imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl]
(oxanyl)indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazolone, Compound 46f)
used in the synthesis of Example Compounds 46 and 47 was synthesized by the following
process.
[Chemical Formula 46]
<Step 46-1>
tert-Butyl (4S)amino(4-fluoromethylphenyl)methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridinecarboxylate (Compound 46b)
The titled compound was synthesized from (4-fluoromethylphenyl)hydrazine
hydrochloride (Compound 46a) and Compound 11g obtained in Step 11-4 by performing an
operation similar to Step 1-2 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 361 ([M+H] ).
LC/MS retention time: 1.02 min. (Analysis Condition: SMD-FA05-1).
<Step 46-2>
tert-Butyl (4S)(2,2-dimethoxyethylcarbamoylamino)(4-fluoromethylphenyl)-
4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate (Compound 46c)
The titled compound was synthesized from Compound 46b obtained in Step 46-1 by
performing an operation similar to Step 1-3 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 492 ([M+H] ).
LC/MS retention time: 1.03 min. (Analysis Condition: SMD-FA05-1).
<Step 46-3>
tert-Butyl (4S)(4-fluoromethylphenyl)methyl(2-oxo-1H-imidazolyl)-
6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate (Compound 46d)
The titled compound was synthesized from Compound 46c obtained in Step 46-2 by
performing an operation similar to Step 11-7 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 428 ([M+H] ).
LC/MS retention time: 2.11 min. (Analysis Condition: SMD-FA05-long).
<Step 46-4>
3-[(4S)(4-Fluoromethylphenyl)methyl-4,5,6,7-tetrahydropyrazolo[4,3-
c]pyridinyl]-1H-imidazolone hydrochloride (Compound 46e)
The titled compound was synthesized from Compound 46d obtained in Step 46-3 by
performing an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 328 ([M+H] ).
LC/MS retention time: 0.59 min. (Analysis Condition: SMD-FA05-3).
<Step 46-5>
3-[(1S,2S)[2-[(4S)(4-fluoromethylphenyl)methyl(2-oxo-1H-imidazol
yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl] (oxanyl)indolyl]
methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound 46f)
The titled compound was synthesized from Compound 46e obtained in Step 46-4 and
Compound 8b obtained in Step 8-1 by performing an operation similar to Step 1-10 of
Example 1 using an appropriate reagent.
The 2-oxoimidazole reagent (3-[(1S,2S)[5-[(4S)-2,2-dimethyloxanyl][(4S)-
2-(4-fluoromethylphenyl)methyl(2-oxo-1H-imidazolyl)-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridinecarbonyl]indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazol
one, Compound 48a) used in the synthesis of Example Compounds 48 to 50 was synthesized
by the following process.
[Chemical Formula 47]
<Step 48-1>
3-[(1S,2S)[5-[(4S)-2,2-dimethyloxanyl][(4S) (4-fluoromethylphenyl)
methyl(2-oxo-1H-imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine
carbonyl]indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound 48a)
The titled compound was synthesized from Compound 46e obtained in Step 46-5 and
Compound 31k obtained in Step 31-8 by performing an operation similar to Step 1-10 of
Example 1 using an appropriate reagent.
<Examples 51 to 53>
An operation similar to Step 7-1 of Example 7 was performed using 3-[(1S,2S)[5-
bromo[2-(4-fluoro-3,5-dimethylphenyl)[3-(1-methylindazolyl)oxoimidazolyl]-
6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl]indolyl]methylcyclopropyl]-4H-
1,2,4-oxadiazolone (Compound 51d), substituted morpholine and an appropriate reagent to
obtain Example Compounds 51 to 53 shown in Table 2-4 by the following reaction.
[Chemical Formula 48]
[Table 2-4]
Table 2-4.The Obtained Example Compounds 51 to 53
LC/MS LC/MS
Analysis retention mass
Structure Compound
Condition time spectrometry
(min.) (m/z)
3-[(1S,2S)[2-[2-(4-
fluoro-3,5-dimethylphenyl)-
3-[3-(1-methylindazolyl)-
2-oxoimidazolyl]-6,7-
dihydro-4H-pyrazolo[4,3- SMD- 864
51 1.31
c]pyridinecarbonyl](5- TFA05-3 ([M+H] )
oxaazaspiro[3.5]nonan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(4-
fluoro-3,5-dimethylphenyl)-
3-[3-(1-methylindazolyl)-
2-oxoimidazolyl]-6,7-
dihydro-4H-pyrazolo[4,3- SMD- 850
52 1.16
c]pyridinecarbonyl](4- TFA05-3 ([M+H] )
oxaazaspiro[2.5]octan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-[(2S)
ethylmorpholinyl][2-
(4-fluoro-3,5-
dimethylphenyl)[3-(1-
methylindazolyl) SMD- 852
53 1.21
oxoimidazolyl]-6,7- TFA05-3 ([M+H] )
dihydro-4H-pyrazolo[4,3-
c]pyridinecarbonyl]indol-
1-yl]methylcyclopropyl]-
4H-1,2,4-oxadiazolone
Compound 51d was synthesized as follows.
[Chemical Formula 49]
Example
<Step 51-1>
tert-Butyl 2-(4-fluoro-3,5-dimethylphenyl)(2-oxo-1H-imidazolyl)-6,7-dihydro-
4H-pyrazolo[4,3-c]pyridinecarboxylate (Compound 51a)
To a dichloromethane (16.8 mL) suspension of Compound 2f (0.611 g, 1.68 mmol)
obtained in Step 2-5 was added triethyl amine (0.936 mL, 6.72 mmol), di-tert-butyl
dicarbonate (0.425 mL, 1.85 mmol), and the suspension was stirred at room temperature for 2
h. Water (20.0 mL) and 5% potassium hydrogen sulfate aqueous solution (20.0 mL) were
added to the reaction solution, then extraction was performed using dichloromethane, and the
resulting product was dried using magnesium sulfate. After filtration, the filtrate was
concentrated under reduced pressure and the residue was purified by silica gel column
chromatography (ethyl acetate/hexane=0:1 to 1:0) to obtain the titled Compound 51a (0.360
g, yield 50%).
LC/MS mass spectrometry: m/z 428 ([M+H] ).
LC/MS retention time: 1.06 min. (Analysis Condition: SMD-FA05-3).
<Step 51-2>
tert-Butyl 2-(4-fluoro-3,5-dimethylphenyl)[3-(1-methylindazolyl)
oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate (Compound 51b)
The titled compound was synthesized from Compound 51a obtained in Step 51-1 and
-bromomethylindazole by performing an operation similar to Step 1-11 of Example 1
using an appropriate reagent.
LC/MS mass spectrometry: m/z 558 ([M+H] ).
LC/MS retention time: 1.25 min. (Analysis Condition: SMD-FA05-1).
<Step 51-3>
1-[2-(4-Fluoro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinyl]
(1-methylindazolyl)imidazolone hydrochloride (Compound 51c)
The titled compound was synthesized from Compound 51b obtained in Step 51-2 by
performing an operation similar to Step 11-9 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 458 ([M+H] ).
LC/MS retention time: 0.78 min. (Analysis Condition: SMD-FA05-1).
<Step 51-4>
3-[(1S,2S)[5-Bromo[2-(4-fluoro-3,5-dimethylphenyl)[3-(1-methylindazol
yl)oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl]indolyl]
methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound 51d)
The titled compound was synthesized from Compound 51c obtained in Step 51-3 and
Compound 6f obtained in Step 6-4 by performing an operation similar to Step 1-10 of
Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 817 ([M+H] ).
LC/MS retention time: 1.41 min. (Analysis Condition: SMD-FA05-1).
<Examples 54 to 73>
An operation similar to Step 1-10 of Example 1 was performed using an amine
derivative and a carboxylic acid derivative to obtain Example Compounds 54 to 72 shown in
Table 2-5 and Example Compound 73 by the following reaction.
[Chemical Formula 50]
[Table 2-5]
Table 2-5. The Obtained Example Compounds 54 to 72
LC/MS LC/MS
Analysis retention mass
Structure Compound
Condition time spectrometry
(min.) (m/z)
3-[(1S,2S)[2-[2-(4-
fluoro-3,5-
dimethylphenyl)[3-
(1-methylindazolyl)-
2-oxoimidazolyl]-
SMD-
54 6,7-dihydro-4H- 1.41 823
TFA05-3
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(4-
chloro-3,5-
dimethylphenyl)[3-
(1-methylindazolyl)-
2-oxoimidazolyl]-
SMD-
55 6,7-dihydro-4H- 1.43 839
TFA05-2
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
Example
3-[(1S,2S)[2-[2- (4-
fluoro-3,5-
dimethylphenyl)[3-
[1-(2-
methoxyethyl)indazol-
-yl]oxoimidazol
SMD-
56 yl]-6,7-dihydro-4H- 1.23 868
TFA05-2
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)pyrrolo[2,3-
b]pyridinyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
N-[4-[3-[(4S)(4-
fluoro-3,5-
dimethylphenyl)
methyl[1-[(1S,2S)
methyl(5-oxo-4H-
1,2,4-oxadiazol
yl)cyclopropyl] SMD-
57 1.34 924
(oxanyl)indole TFA05-1
carbonyl]-6,7-dihydro-
4H-pyrazolo[4,3-
c]pyridinyl]
oxoimidazol
yl]cubanyl]-N-(2-
methoxyethyl)acetamide
3-[(1S,2S)[5-(2,2-
dimethylmorpholin
yl)[2-(4-fluoro
methylphenyl)[3-[1-
methoxyethyl)indazol-
SMD-
58 5-yl]oxoimidazol 1.29 883
TFA05-3
yl]-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl]indolyl]-
2-methylcyclopropyl]-
4H-1,2,4-oxadiazol
3-[(1S,2S)[5-[(4S)-
2,2-dimethyloxanyl]-
2-[2-(4-fluoro-3,5-
dimethylphenyl)[3-
(1-methylindazolyl)-
2-oxoimidazolyl]- SMD-
59 1.44 851
6,7-dihydro-4H- TFA05-2
pyrazolo[4,3-c]pyridine-
-carbonyl]indolyl]-
2-methylcyclopropyl]-
4H-1,2,4-oxadiazol
3-[(1S,2S)[5-[(4S)-
2,2-dimethyloxanyl]-
2-[2-(3,5-
dimethylphenyl)[3-
(1-methylindazolyl)-
2-oxoimidazolyl]- SMD-
60 1.41 833
6,7-dihydro-4H- TFA05-1
pyrazolo[4,3-c]pyridine-
-carbonyl]indolyl]-
2-methylcyclopropyl]-
4H-1,2,4-oxadiazol
3-[(1S,2S)[2-[(4S)
(4-fluoro-3,5-
dimethylphenyl)
methyl[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7-
SMD-
61 dihydro-4H- 1.45 851
TFA05-1
pyrazolo[4,3-c]pyridine-
-carbonyl][(2S,4S)-
2-methyloxan
yl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)
(4-fluoro-3,5-
dimethylphenyl)[3-
[1-(2-
methoxyethyl)indazol-
-yl]oxoimidazol
yl]methyl-6,7- SMD-
62 1.45 895
dihydro-4H- TFA05-1
pyrazolo[4,3-c]pyridine-
-carbonyl][(2S,4S)-
2-methyloxan
yl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[7-fluoro-
2-[(4S)(4-fluoro-3,5-
dimethylphenyl)[3-
[1-(2-
methoxyethyl)indazol-
-yl]oxoimidazol
SMD-
63 yl]methyl-6,7- 1.38 899
TFA05-1
dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[7-fluoro-
2-[(4S)(4-fluoro-3,5-
dimethylphenyl)
methyl[2-oxo[1-
[(3R)-oxolan
yl]indazol
SMD-
64 yl]imidazolyl]-6,7- 1.38 911
TFA05-1
dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)
(4-chloro-3,5-
dimethylphenyl)[3-
(4-fluoro
methylindazolyl)
oxoimidazolyl]
SMD-
65 methyl-6,7-dihydro-4H- 1.53 899
TFA05-1
pyrazolo[4,3-c]pyridine-
-carbonyl][(4S)-2,2-
dimethyloxan
yl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-[(4S)-
2,2-dimethyloxanyl]-
2-[(4S)(4-fluoro-3,5-
dimethylphenyl)
methyl[3-(1-
methylindazolyl)
SMD-
66 oxoimidazolyl]-6,7- 1.47 866
TFA05-2
dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl]indolyl]-
2-methylcyclopropyl]-
4H-1,2,4-oxadiazol
3-[(1S,2S)[5-[(4S)-
2,2-dimethyloxanyl]-
2-[(4S)(4-fluoro-3,5-
dimethylphenyl)[3-
(4-fluoro
methylindazolyl)
SMD-
67 oxoimidazolyl] 1.46 883
TFA05-1
methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl]indolyl]-
2-methylcyclopropyl]-
4H-1,2,4-oxadiazol
3-[(1S,2S)[2-[(4S)
[3-(4-chloro
methylindazolyl)
oxoimidazolyl](4-
fluoro-3,5-
dimethylphenyl)
SMD-
68 methyl-6,7-dihydro-4H- 1.47 899
TFA05-1
pyrazolo[4,3-c]pyridine-
-carbonyl][(4S)-2,2-
dimethyloxan
yl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-[(4S)-
2,2-dimethyloxanyl]-
2-[(4S)[3-(4-fluoro-
1-methylindazolyl)-
2-oxoimidazolyl]
(4-fluoro
SMD-
69 methylphenyl) 1.40 869
TFA05-1
methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl]indolyl]-
2-methylcyclopropyl]-
4H-1,2,4-oxadiazol
3-[(1S,2S)[5-[(4S)-
2,2-dimethyloxanyl]-
2-[(4S)(4-fluoro-3,5-
dimethylphenyl)[3-
(6-fluoro
methylindazolyl)
SMD-
70 oxoimidazolyl] 1.43 883
TFA05-1
methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl]indolyl]-
2-methylcyclopropyl]-
4H-1,2,4-oxadiazol
3-[(1S,2S)[5-[(4S)-
2,2-dimethyloxanyl]-
2-[(4S)(4-fluoro-3,5-
dimethylphenyl)[3-
[6-fluoro(2-
methoxyethyl)indazol-
-yl]oxoimidazol SMD-
71 1.44 927
yl]methyl-6,7- TFA05-1
dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl]indolyl]-
2-methylcyclopropyl]-
4H-1,2,4-oxadiazol
3-[(1S,2S)[2-[(4S)
[3-(4-chloro
methylindazolyl)
oxoimidazolyl](4-
fluoro-3,5-
dimethylphenyl) SMD-
72 1.40 871
methyl-6,7-dihydro-4H- TFA05-1
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
Note that the compounds in Table 2-5 have rotational isomers, and by way of
example, the H-NMR of Example Compounds 66 and 67 are shown below.
<Example Compound 66>
Main rotational isomer
H-NMR (600MHz, CDCl ) δ: 11.32 (1H, s), 8.04 (1H, d, J=0.4 Hz), 7.86 (1H, d,
J=1.4 Hz), 7.61 (1H, m), 7.59 (1H, m), 7.52 (1H, s), 7.50 (H, d, J=9.0 Hz), 7.27 (1H, m), 7.15
(2H, d, J =6.0 Hz), 6.74 (1H, d, J=3.1 Hz), 6.70 (1H, s), 6.32 (1H, d, J=3.1 Hz), 5.79 (1H, q,
J=6.6 Hz), 4.47 (1H, dd, J=13.6, 5.0 Hz), 4.12 (3H, s), 3.89-3.81 (2H, m), 3.60 (1H, ddd,
J=13.6, 13.1, 3.6 Hz), 3.15 (1H, ddd, J=16.0, 13.1, 5.0 Hz), 3.09-2.98 (2H, m), 2.27 (6H, d,
J =1.4 Hz), 1.91 (1H, dd, J=6.0 Hz), 1.82-1.60 (4H, m), 1.60-1.50 (2H, m), 1.55 (3H, d,
J=6.6 Hz), 1.34 (3H, s), 1.28 (3H, s), 1.19 (3H, d, J=5.9 Hz).
Secondary rotational isomer
H-NMR (600 MHz, CDCl ) δ: 11.26 (1H, s), 7.93 (1H, s), 7.65 (1H, s), 7.57 (1H, d,
J=8.6 Hz), 7.49 (1H, m), 7.34 (2H, s), 7.25 (1H, m), 7.05 (2H, d, J =6.0 Hz), 6.69 (1H, s),
6.59 (1H, d, J=3.1 Hz), 6.09 (1H, d, J=3.1 Hz), 5.26 (1H, q, J=6.6 Hz), 4.87 (1H, dd, J=12.8,
.1 Hz), 4.07 (3H, s), 3.90-3.78 (2H, m), 3.40 (1H, ddd, J=12.8, 12.6, 4.5 Hz), 3.10-2.98 (3H,
m), 2.23 (6H, s), 1.82-1.37 (10H, m), 1.33 (3H, s), 1.25 (3H, s), 1.06 (3H, d, J=6.2 Hz).
<Example Compound 67>
Main rotational isomer
H-NMR (600 MHz, CDCl ) δ: 11.32 (1H, s), 8.13 (1H, d, J =0.7 Hz), 7.59 (1H, d,
3 HF
J=8.6 Hz), 7.52 (1H, s), 7.48 (1H, dd, J=8.9 Hz, J =6.9 Hz), 7.28 (1H, d, J=8.9 Hz), 7.26
(1H, dd, J=8.6, 1.7 Hz), 7.16 (2H, d, J =6.1 Hz), 6.70 (1H, s), 6.61 (1H, dd, J=3.0 Hz,
J =1.1 Hz), 6.31 (1H, d, J=3.0 Hz), 5.79 (1H, q, J=6.7 Hz), 4.47 (1H, dd, J=13.5, 5.2 Hz),
4.12 (3H, s), 3.88 (1H, m), 3.83 (1H, m), 3.60 (1H, ddd, J=13.5, 12.9, 3.6 Hz), 3.15 (1H, ddd,
J=15.8, 12.9, 5.2 Hz), 3.04 (1H, m), 3.00 (1H, m), 2.29 (6H, d, J =1.1 Hz), 1.91 (1H, dd,
J=6.1, 5.8 Hz), 1.79-1.76 (2H, m), 1.74 (1H, m), 1.65 (1H, m), 1.57 (3H, d, J=6.7 Hz), 1.60-
1.55 (1H, m), 1.52 (1H, dd, J=9.5, 5.8 Hz), 1.34 (3H, s), 1.28 (3H, s), 1.20 (3H, d, J=6.0 Hz).
Secondary rotational isomer
H-NMR (600 MHz, CDCl ) δ: 11.27 (1H, s), 8.04 (1H, s), 7.55 (1H, d, J=8.7 Hz),
7.52 (1H, s), 7.25-7.22 (2H, m), 7.12 (1H, d, J=8.8 Hz), 7.06 (2H, d, J =6.0 Hz), 6.71 (1H,
s), 6.47 (1H, m), 6.08 (1H, d, J=3.0 Hz), 5.26 (1H, q, J=6.6 Hz), 4.87 (1H, dd, J=13.1, 4.8
Hz), 4.07 (3H, s), 3.90-3.80 (2H, m), 3.39 (1H, ddd, J=13.1, 12.2, 4.6 Hz), 3.08-2.97 (3H, m),
2.25 (6H, s), 1.79-1.73 (3H, m), 1.67 (3H, d, J=6.6 Hz), 1.64 (1H, m), 1.45-1.37 (2H, m),
1.34 (3H, s), 1.28 (3H, s), 1.06 (3H, d, J=6.0 Hz).
Compound 55e used in the synthesis of Example Compound 55 was synthesized as
follows.
[Chemical Formula 51]
<Step 55-1>
tert-Butyl 3-amino (4-chloro-3,5-dimethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-
c]pyridinecarboxylate (Compound 55a)
The titled compound was synthesized from Compound 42a obtained in Step 42-1 and
Compound 1b obtained in Step 1-1 by performing an operation similar to Step 1-2 of
Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 377 ([M+H] ).
LC/MS retention time: 0.87 min. (Analysis Condition: SQD-FA05-1).
<Step 55-2>
tert-Butyl 2-(4-chloro-3,5-dimethylphenyl) (2,2-dimethoxyethylcarbamoylamino)-
6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate (Compound 55b)
The titled compound was synthesized from Compound 55a obtained in Step 55-1 by
performing an operation similar to Step 1-3 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 508 ([M+H] ).
LC/MS retention time: 0.83 min. (Analysis Condition: SQD-FA05-1).
<Step 55-3>
tert-Butyl 2-(4-chloro-3,5-dimethylphenyl)(2-oxo-1H-imidazolyl)-6,7-dihydro-
4H-pyrazolo[4,3-c]pyridinecarboxylate (Compound 55c)
The DMF (7.11 mL) suspension of Compound 55b (903 mg, 1.78 mmol) obtained in
Step 55-2 and p-toluenesulfonic acid monohydrate (338 mg, 1.78 mmol) was stirred at 80ºC
for 1 h. After the suspension was cooled to room temperature, potassium phosphate (377
mg, 1.78 mmol), water (3.5 mL), and di-tert-butyl dicarbonate (388 mg, 1.78 mmol) were
added and the resulting mixture was stirred at room temperature for 1 h. Water was added
to the reaction mixture, and extraction was perfomed using ethyl acetate, then the organic
layer was washed with brine and the resulting product was dried with magnesium sulfate
anhydride. After filtration, the filtrate was concentrated under reduced pressure and the
residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:4 to 1:0)
to obtain the titled Compound 55c (799 mg, yield 100%) as a pale yellow foam.
LC/MS mass spectrometry: m/z 444 ([M+H] ).
LC/MS retention time: 0.82 min. (Analysis Condition: SQD-FA05-1).
<Step 55-4>
tert-Butyl 2-(4-chloro-3,5-dimethylphenyl)[3- (1-methylindazolyl)
oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate (Compound 55d)
The titled compound was synthesized from Compound 55c obtained in Step 55-3 and
-bromomethylindazole (Compound 1q) by performing an operation similar to Step 1-11
of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 574 ([M+H] ).
LC/MS retention time: 1.34 min. (Analysis Condition: SMD-FA05-1).
<Step 55-5>
1-[2-(4-Chloro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinyl]
(1-methylindazolyl)imidazolone hydrochloride (Compound 55e)
The titled compound was synthesized from Compound 55d obtained in Step 55-4 by
performing an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 474 ([M+H] ).
LC/MS retention time: 0.81 min. (Analysis Condition: SMD-FA05-1).
Compound 56c used in the synthesis of Example Compound 56 was synthesized as
follows.
[Chemical Formula 52]
<Step 56-1>
tert-Butyl 2-(4-fluoro-3,5-dimethylphenyl)[3-[1- (2-methoxyethyl)indazolyl]
oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate (Compound 56b)
The titled compound was synthesized from Compound 51a obtained in Step 51-1 and
-bromo (2-methoxyethyl)indazole (Compound 56a) by performing an operation similar
to Step 1-11 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 602 ([M+H] ).
LC/MS retention time: 1.30 min. (Analysis Condition: SMD-FA05-2).
<Step 56-2>
1-[2-(4-Fluoro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinyl]
[1-(2-methoxyethyl)indazolyl]imidazolone hydrochloride (Compound 56c)
The titled compound was synthesized from Compound 56b obtained in Step 56-1 by
performing an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 502 ([M+H] ).
LC/MS retention time: 0.54 min. (Analysis Condition: SQD-FA05-1).
The amine derivative (Compound 57j) used in the synthesis of Example Compound
57 was synthesized as follows.
[Chemical Formula 53]
<Step 57-1>
tert-Butyl N-(4-isocyanatocubanyl) carbamate (Compound 57b)
To a toluene (2.1 mL) solution of 4-[(2-methylpropan
yl)oxycarbonylamino]cubanecarboxylic acid (Compound 57a, 111 mg, 0.423 mmol) was
added at room temperature triethyl amine (0.0676 mL, 0.487 mmol) and diphenylphosphoryl
azide (0.10 mL, 0.465 mmol), and the resulting mixture was stirred at room temperature for
100 min., then at 85ºC for 3.5 h. The solvent in the reaction mixture was removed by
evaporation under reduced pressure, and the titled Compound 57b was obtained as a crude
product.
H-NMR (400 MHz, CDCl ) δ: 12.3 (1H, brs), 3.95 (6H, brs), 1.45 (9H, s).
<Step 57-2>
tert-Butyl (4S)(4-fluoro-3,5-dimethylphenyl)methyl[[4-[(2-methylpropan
yl)oxycarbonylamino]cubanyl]carbamoylamino]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-
-carboxylate (Compound 57c)
The titled compound was synthesized from Compound 57b obtained in Step 57-1 and
Compound 11h obtained by Step 11-5 by performing an operation similar to Step 1-3 of
Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 636 ([M+H] ).
LC/MS retention time: 0.93 min. (Analysis Condition: SQD-FA05-1).
<Step 57-3>
tert-Butyl (4S)(4-fluoro-3,5-dimethylphenyl)[5-hydroxy3-[4-[(2-methylpropan-
2-yl)oxycarbonylamino]cubanyl]oxoimidazolidinyl]methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridinecarboxylate (Compound 57d)
To a DMA (0.25 mL) suspension of Compound 57c (31.6 mg, 0.050 mmol) obtained
in Step 57-2 and cesium carbonate (82.8 mg, 0.254 mmol) were added at room temperature
1,2-dichloroethoxyethane (0.0155 mL, 0.127 mmol), and the mixture was stirred at room
temperature for 170 min. Cesium carbonate (104 mg, 0.32 mmol) followed by 1,2-dichloro-
1-ethoxyethane (0.0184 mL, 0.162 mmol) were added to the reaction mixture at room
temperature, and the resulting mixture was stirred at room temperature for 16 h. The
reaction mixture was diluted with ethyl acetate and water, then 1N hydrochloric acid (0.54
mL) was added to adjust the pH to 7, and then extraction was performed using ethyl acetate.
The organic layer was dried using magnesium sulfate, then the solvent was removed by
evaporation under reduced pressure, and then toluene was added and the solvent was
removerd by evaporation under reduced pressure to obtain the titled Compound 57d as a
crude product.
LC/MS mass spectrometry: m/z 678 ([M+H] ).
LC/MS retention time: 0.98 min. (Analysis Condition: SQD-FA05-1).
<Step 57-4>
tert-Butyl (4S)(4-fluoro-3,5-dimethylphenyl)methyl[3-[4-[(2-methylpropan-
2-yl)oxycarbonylamino]cubanyl]oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-
c]pyridinecarboxylate (Compound 57e)
To a THF (1.1 mL) solution of Compound 57d (115 mg, 0.17 mmol) obtained in Step
57-3 was added at room temperature methylsulfonic acid (0.011 mL, 0.17 mmol), then the
mixture was stirred at 60ºC for 90 min. Potassium phosphate (36.5 mg, 0.172 mmol), water
(0.45 mL) and (2-methylpropanyl)oxycarbonyl tert-butyl carbonate (0.012 mL, 0.052
mmol) were added to the reaction mixture, and the resulting mixture was stirred for 1 h.
Then, after the reaction mixture was diluted with dichloromethane, it was washed with water.
The organic layer was dried using magnesium sulfate, and the solvent was removed by
evaporation under reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane=1:2 to 1:1) to obtain the titled Compound 57e (48.5
mg, yield 43%).
LC/MS mass spectrometry: m/z 660 ([M+H] ).
LC/MS retention time: 1.04 min. (Analysis Condition: SQD-FA05-1).
<Step 57-5>
tert-Butyl (4S)[3-[4-[acetyl-[(2-methylpropanyl)oxycarbonyl]amino]cuban
yl]oxoimidazolyl] (4-fluoro-3,5-dimethylphenyl)methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridinecarboxylate (Compound 57f)
To a THF (0.22 mL) solution of Compound 57e (16.1 mg, 0.024 mmol) obtained in
Step 57-4 was added at -26ºC, a 1.7M potassium pentoxide toluene solution (0.024 mL, 0.041
mmol), and the mixture was stirred at -30ºC for 3 min. Acetic anhydride (8 μL, 0.085
mmol) was added to the reaction mixture at -30ºC, and the mixture was stirred at a
temperature of -30ºC to -25ºC for 5 min. and at a temperature of -25ºC to room temperature
for 3 min. After water (0.5 mL) was added to the reaction mixture, the mixture was diluted
using ethyl acetate, and more water was added and extraction was performed using ethyl
acetate. The organic layer was dried using magnesium sulfate, and the solvent was removed
by distiallation under reduced pressure, then the resulting product was purified by silica gel
column chromatography (ethyl acetate/hexane=1:3 to 2:3) to obtain the titled Compound 57f
(9.2 mg, yield 54%).
LC/MS mass spectrometry: m/z 701 ([M+H] ).
LC/MS retention time: 1.12 min. (Analysis Condition: SQD-FA05-1).
<Step 57-6>
N-[4-[3-[(4S)(4-Fluoro-3,5-dimethylphenyl)methyl-4,5,6,7-
tetrahydropyrazolo[4,3-c]pyridinyl]oxoimidazolyl]cubanyl]acetamide 2,2,2-
trifluoroacetate (Compound 57g)
To a dichloromethane (0.097 mL) solution of Compound 57f (8.5 mg, 0.012 mmol)
obtained in Step 57-5 was added TFA (0.019 mL) at room temperature, and the resulting
mixture was stirred at room temperature for 3 h. After the solvent in the reaction mixture
was removed by evaporation under reduced pressure, toluene was added and the solvent was
removed by evaporation, and hexane-dichloromethane was added and the solvent was
removed by evaporation to obtain the titled Compound 57g (9.4 mg) as a crude product.
LC/MS mass spectrometry: m/z 501 ([M+H] ).
LC/MS retention time: 0.49 min. (Analysis Condition: SQD-FA05-1).
<Step 57-7>
tert-Butyl (4S)[3-(4-acetamidecubanyl)oxoimidazolyl](4-fluoro-3,5-
dimethylphenyl)methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate
(Compound 57h)
The titled compound was synthesized from Compound 57g obtained in Step 57-6 by
performing an operation similar to Step 51-1 of Example 51 using an appropriate reagent.
LC/MS mass spectrometry: m/z 602 ([M+H] ).
LC/MS retention time: 0.85 min. (Analysis Condition: SQD-FA05-1).
<Step 57-8>
tert-Butyl (4S)[3-[4-[acetyl(2-methoxyethyl)amino]cubanyl]oxoimidazol
yl](4-fluoro-3,5-dimethylphenyl)methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine
carboxylate (Compound 57i)
The titled compound was synthesized from Compound 57h obtained in Step 57-7 by
performing an operation similar to Step 57-5 of Example 57 using an appropriate reagent.
LC/MS mass spectrometry: m/z 660 ([M+H] ).
LC/MS retention time: 0.93 min. (Analysis Condition: SQD-FA05-1).
<Step 57-9>
N-[4-[3-[(4S)(4-Fluoro-3,5-dimethylphenyl)methyl-4,5,6,7-
tetrahydropyrazolo[4,3-c]pyridinyl]oxoimidazolyl]cubanyl]-N- (2-
methoxyethyl)acetamide; hydrochloride (Compound 57j)
The titled compound was synthesized from Compound 57i obtained in Step 57-8 by
performing an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 560 ([M+H] ).
LC/MS retention time: 0.53 min. (Analysis Condition: SQD-FA05-1).
Compound 58e used in the synthesis of Example Compound 58 was synthesized as
follows.
[Chemical Formula 54]
<Step 58-1>
tert-Butyl 3-amino (4-fluoromethylphenyl)-6,7-dihydro-4H-pyrazolo[4,3-
c]pyridinecarboxylate (Compound 58a)
The titled compound was synthesized from Compound 1b obtained in Step 1-1 and
Compound 46a obtained in Step 46-1 by performing an operation similar to Step 1-2 of
Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 347 ([M+H] ).
LC/MS retention time: 0.98 min. (Analysis Condition: SMD-FA05-3).
<Step 58-2>
tert-Butyl 3-(2,2-dimethoxyethylcarbamoylamino)(4-fluoromethylphenyl)-6,7-
dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate (Compound 58b)
The titled compound was synthesized from Compound 58a obtained in Step 58-1 by
performing an operation similar to Step 1-3 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 478 ([M+H] ).
LC/MS retention time: 1.03 min. (Analysis Condition: SMD-FA05-3).
<Step 58-3>
tert-Butyl 2-(4-fluoromethylphenyl)(2-oxo-1H-imidazolyl)-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridinecarboxylate (Compound 58c)
The titled compound was synthesized from Compound 58b obtained in Step 58-2 by
performing an operation similar to Step 11-7 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 414 ([M+H] ).
LC/MS retention time: 0.72 min. (Analysis Condition: SQD-FA05-1).
<Step 58-4>
tert-Butyl 2-(4-fluoromethylphenyl)[3-[1-(2-methoxyethyl)indazolyl]
oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate (Compound 58d)
The titled compound was synthesized from Compound 58c obtained in Step 58-3 and
-bromo(2-methoxyethyl)indazole (Compound 56a) by performing an operation similar to
Step 1-11 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 588 ([M+H] ).
LC/MS retention time: 0.88 min. (Analysis Condition: SQD-FA05-1).
<Step 58-5>
1-[2-(4-Fluoromethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinyl][1-
(2-methoxyethyl)indazolyl]imidazolone hydrochloride (Compound 58e)
The titled compound was synthesized from Compound 58d obtained in Step 58-4 by
performing an operation similar to Step 11-9 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 488 ([M+H] ).
LC/MS retention time: 0.50 min. (Analysis Condition: SQD-FA05-1).
Compound 60c used in the synthesis of Example Compound 60 was synthesized by
the following process.
[Chemical Formula 55]
<Step 60-1>
tert-Butyl 2-(3,5-dimethylphenyl)(2-oxo-1H-imidazolyl)-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridinecarboxylate (Compound 60a)
The titled compound was synthesized from Compound 1g obtained in Step 1-4 by
performing an operation similar to Step 51-1 of Example 51 using an appropriate reagent.
LC/MS mass spectrometry: m/z 410 ([M+H] ).
LC/MS retention time: 0.77 min. (Analysis Condition: SQD-FA05-1).
<Step 60-2>
tert-Butyl 2-(3,5-dimethylphenyl)[3-(1-methylindazolyl)oxoimidazolyl]-
6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate (Compound 60b)
The titled compound was synthesized from Compound 60a obtained in Step 60-1 and
-bromomethylindazole (Compound 1q) by performing an operation similar to Step 1-11
of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 540 ([M+H] ).
LC/MS retention time: 1.24 min. (Analysis Condition: SMD-FA05-3).
<Step 60-3>
1-[2-(3,5-Dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinyl](1-
methylindazolyl)imidazolone hydrochloride (Compound 60c)
The titled compound was synthesized from Compound 60b obtained in Step 60-2 by
performing an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 440 ([M+H] ).
LC/MS retention time: 0.74 min. (Analysis Condition: SMD-FA05-2).
Compound 61b used in the synthesis of Example Compound 61 was synthesized by
the following process.
[Chemical Formula 56]
<Step 61-1>
tert-Butyl (4S)(4-fluoro-3,5-dimethylphenyl)methyl[3- (1-methylindazol
yl)oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate (Compound
61a)
The titled compound was synthesized from Compound 11k obtained in Step 11-7 and
-bromomethylindazole (Compound 1q) by performing an operation similar to Step 1-11
of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 572 ([M+H] ).
LC/MS retention time: 1.30 min. (Analysis Condition: SMD-FA05-1).
<Step 61-2>
1-[(4S)(4-Fluoro-3,5-dimethylphenyl)methyl-4,5,6,7-tetrahydropyrazolo[4,3-
c]pyridinyl] (1-methylindazolyl)imidazolone hydrochloride (Compound 61b)
The titled compound was synthesized from Compound 61a obtained in Step 61-1 by
performing an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 472 ([M+H] ).
LC/MS retention time: 0.79 min. (Analysis Condition: SMD-FA05-1).
Compound 62b used in the synthesis of Example Compound 62 was synthesized by
the following process.
[Chemical Formula 57]
<Step 62-1>
tert-Butyl (4S)(4-fluoro-3,5-dimethylphenyl)[3-[1- (2-methoxyethyl)indazol
yl]oxoimidazolyl]methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate
(Compound 62a)
The titled compound was synthesized from Compound 11k obtained in Step 11-7 and
-bromo (2-methoxyethyl)indazole (Compound 56a) by performing an operation similar
to Step 1-11 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 616 ([M+H] ).
LC/MS retention time: 1.29 min. (Analysis Condition: SMD-FA05-1).
<Step 62-2>
1-[(4S)(4-Fluoro-3,5-dimethylphenyl)methyl-4,5,6,7-tetrahydropyrazolo[4,3-
c]pyridinyl][1-(2-methoxyethyl)indazolyl]imidazolone hydrochloride (Compound
62b)
The titled compound was synthesized from Compound 62a obtained in Step 62-1 by
performing an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 516 ([M+H] ).
LC/MS retention time: 0.76 min. (Analysis Condition: SMD-FA05-1).
Compound 63g used in the synthesis of Example Compound 63 was synthesized by
the following process.
[Chemical Formula 58]
<Step 63-1>
-Bromofluoro-N-methyl-N-phenyl-1H-indolecarboxamide (Compound 63b)
The titled compound was synthesized from 5-bromofluoro-1H-indolecarboxylic
acid (Compound 63a) by performing an operation similar to Step 1-10 of Example 1 using an
appropriate reagent.
<Step 63-2>
-Bromo(cyanomethyl)fluoro-N-methyl-N-phenylindolecarboxamide
(Compound 63c)
The titled compound was synthesized from Compound 63b obtained in Step 63-1 by
performing an operation similar to Step 9-1 of Example 9 using an appropriate reagent.
LC/MS mass spectrometry: m/z 386 ([M+H] ).
LC/MS retention time: 3.17 min. (Analysis Condition: SMD-FA10-long).
<Step 63-3>
-Bromo[(1S,2S)cyanomethylcyclopropyl]fluoro-N-methyl-N-
phenylindolecarboxamide (Compound 63d)
The titled compound was synthesized from Compound 63c obtained in Step 63-2 by
performing an operation similar to Step 1-6 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 426 ([M+H] ).
LC/MS retention time: 1.36 min. (Analysis Condition: SMD-FA05-1).
H-NMR (300 MHz, CDCl ) δ: 7.75 (1H, s), 7.43-7.30 (6H, m), 6.08 (1H, brs), 3.44 (3H, s),
2.11-1.69 (3H, m), 1.40-1.35 (3H, m).
<Step 63-4>
1-[(1S,2S)Cyanomethylcyclopropyl]fluoro-N-methyl (oxanyl)-N-
phenylindolecarboxamide (Compound 63e)
The titled compound was synthesized from Compound 63d obtained in Step 63-3 and
(tetrahydro-2H- pyranyl)zinc (II) iodide (Compound 8a) by performing an operation
similar to Step 8-1 of Example 8 using an appropriate reagent.
LC/MS mass spectrometry: m/z 432 ([M+H] ).
LC/MS retention time: 1.22 min. (Analysis Condition: SMD-FA05-1).
<Step 63-5>
7-Fluoro-N-methyl[(1S,2S)methyl (5-oxo-4H-1,2,4-oxadiazol
yl)cyclopropyl] (oxanyl)-N-phenylindolecarboxamide (Compound 63f)
The titled compound was synthesized from Compound 63e obtained in Step 63-4 by
performing an operation similar to Step 1-8 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 491 ([M+H] ).
LC/MS retention time: 1.21 min. (Analysis Condition: SQD-FA05-01).
<Step 63-6>
7-Fluoro[(1S,2S)methyl(5-oxo-4H-1,2,4-oxadiazolyl)cyclopropyl]
(oxanyl)indolecarboxylic acid (Compound 63g)
The titled compound was synthesized from Compound 63f obtained in Step 63-5 by
performing an operation similar to Step 6-4 of Example 6 using an appropriate reagent.
LC/MS mass spectrometry: m/z 402 ([M+H] ).
LC/MS retention time: 0.97 min. (Analysis Condition: SMD-FA05-1).
Compound 64b used in the synthesis of Example Compound 64 was synthesized by
the following process.
[Chemical Formula 59]
<Step 64-1>
tert-Butyl (4S)(4-fluoro-3,5-dimethylphenyl)methyl[2-oxo[1-[(3R)-
oxolanyl]indazolyl]imidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine
carboxylate (Compound 64a)
The titled compound was synthesized from Compound 11k obtained in Step 11-7 and
Compound 8f obtained in Step 8-4 by performing an operation similar to Step 1-11 of
Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 628 ([M+H] ).
LC/MS retention time: 1.32 min. (Analysis Condition: SMD-FA05-1).
<Step 64-2>
1-[(4S)(4-Fluoro-3,5-dimethylphenyl)methyl-4,5,6,7-tetrahydropyrazolo[4,3-
c]pyridinyl][1-[(3R)-oxolanyl]indazolyl]imidazolone hydrochloride
(Compound 64b)
The titled compound was synthesized from Compound 64a obtained in Step 64-1 by
performing an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 528 ([M+H] ).
LC/MS retention time: 0.78 min. (Analysis Condition: SMD-FA05-1).
Compound 65c used in the synthesis of Example Compound 65 was synthesized by
the following process.
[Chemical Formula 60]
<Step 65-1>
tert-Butyl (4S)(4-chloro-3,5-dimethylphenyl)[3-(4-fluoromethylindazolyl)-
2-oxoimidazolyl]methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate
(Compound 65b)
The titled compound was synthesized from Compound 42e obtained in Step 42-4 and
-bromofluoromethylindazole (Compound 65a) by performing an operation similar to
Step 1-11 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 606 ([M+H] ).
LC/MS retention time: 1.38 min. (Analysis Condition: SMD-FA05-1).
<Step 65-2>
1-[(4S)(4-Chloro-3,5-dimethylphenyl)methyl-4,5,6,7-tetrahydropyrazolo[4,3-
c]pyridinyl](4-fluoromethylindazolyl)imidazolone hydrochloride (Compound
65c)
The titled compound was synthesized from Compound 65b obtained in Step 65-1 by
performing an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 506 ([M+H] ).
LC/MS retention time: 0.86 min. (Analysis Condition: SMD-FA05-1).
Compound 67b used in the synthesis of Example Compound 67 was synthesized by
the following process.
[Chemical Formula 61]
<Step 67-1>
tert-Butyl (4S)(4-fluoro-3,5-dimethylphenyl)[3-(4-fluoromethylindazolyl)-
2-oxoimidazolyl]methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate
(Compound 67a)
The titled compound was synthesized from Compound 11k obtained in Step 11-7 and
-bromofluoromethylindazole (Compound 65a) by performing an operation similar to
Step 1-11 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 590 ([M+H] ).
LC/MS retention time: 1.31 min. (Analysis Condition: SMD-FA05-1).
<Step 67-2>
1-[(4S)(4-Fluoro-3,5-dimethylphenyl)methyl-4,5,6,7-tetrahydropyrazolo[4,3-
c]pyridinyl](4-fluoromethylindazolyl)imidazolone hydrochloride (Compound
67b)
The titled compound was synthesized from Compound 67a obtained in Step 67-1 by
performing an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 490 ([M+H] ).
LC/MS retention time: 0.80 min. (Analysis Condition: SQD-FA05-1).
Compound 68c used in the synthesis of Example Compound 68 was synthesized by
the following process.
[Chemical Formula 62]
<Step 68-1>
tert-Butyl (4S)[3-(4-chloromethylindazolyl)oxoimidazolyl] (4-
fluoro-3,5-dimethylphenyl)methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate
(Compound 68b)
The titled compound was synthesized from Compound 11k obtained in Step 11-7 and
-bromochloromethylindazole (Compound 68a) by performing an operation similar to
Step 1-11 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 606 ([M+H] ).
LC/MS retention time: 1.34 min. (Analysis Condition: SMD-FA05-1).
<Step 68-2>
1-(4-Chloromethylindazolyl)[(4S)(4-fluoro-3,5-dimethylphenyl)
methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinyl]imidazolone hydrochloride
(Compound 68c)
The titled compound was synthesized from Compound 68b obtained in Step 68-1 by
performing an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 506 ([M+H] ).
LC/MS retention time: 0.83 min. (Analysis Condition: SMD-FA05-1).
Compound 69b used in the synthesis of Example Compound 69 was synthesized by
the following process.
[Chemical Formula 63]
<Step 69-1>
tert-Butyl (4S)[3-(4-fluoromethylindazolyl)oxoimidazolyl] (4-
fluoromethylphenyl)methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate
(Compound 69a)
The titled compound was synthesized from Compound 46d obtained in Step 46-3 and
-bromofluoromethylindazole (Compound 65a) by performing an operation similar to
Step 1-11 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 576 ([M+H] ).
LC/MS retention time: 1.25 min. (Analysis Condition: SMD-FA05-1).
<Step 69-2>
1-(4-Fluoromethylindazolyl)[(4S)(4-fluoromethylphenyl)methyl-
4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinyl]imidazolone hydrochloride (Compound
69b)
The titled compound was synthesized from Compound 69a obtained in Step 69-1 by
performing an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 476 ([M+H] ).
LC/MS retention time: 0.77 min. (Analysis Condition: SMD-FA05-1).
Compound 70c used in the synthesis of Example Compound 70 was synthesized by
the following process.
[Chemical Formula 64]
<Step 70-1>
tert-Butyl (4S)(4-fluoro-3,5-dimethylphenyl)[3-(6-fluoromethylindazolyl)-
2-oxoimidazolyl]methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarboxylate
(Compound 70b)
The titled compound was synthesized from Compound 11k obtained in Step 11-7 and
-bromofluoromethylindazole (Compound 70a) by performing an operation similar to
Step 1-11 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 590 ([M+H] ).
LC/MS retention time: 1.28 min. (Analysis Condition: SMD-FA05-1).
<Step 70-2>
1-[(4S)(4-Fluoro-3,5-dimethylphenyl)methyl-4,5,6,7-tetrahydropyrazolo[4,3-
c]pyridinyl](6-fluoromethylindazolyl)imidazolone hydrochloride (Compound
70c)
The titled compound was synthesized from Compound 70b obtained in Step 70-1 by
performing an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 490 ([M+H] ).
LC/MS retention time: 0.81 min. (Analysis Condition: SMD-FA05-1).
Compound 71b used in the synthesis of Example Compound 71 was synthesized by
the following process.
[Chemical Formula 65]
<Step 71-1>
-Bromofluoro(2-methoxyethyl)indazole (Compound 71b)
The titled compound was synthesized from 5-bromofluoro-1H-indazole
(Compound 71a) by performing an operation similar to Step 8-4 of Example 8 using an
appropriate reagent.
LC/MS mass spectrometry: m/z 273 ([M+H] ).
LC/MS retention time: 1.06 min. (Analysis Condition: SMD-FA05-1).
<Step 71-2>
tert-Butyl (4S)(4-fluoro-3,5-dimethylphenyl)[3-[6-fluoro(2-
methoxyethyl)indazolyl]oxoimidazolyl]methyl-6,7-dihydro-4H-pyrazolo[4,3-
c]pyridinecarboxylate (Compound 71c)
The titled compound was synthesized from Compound 11k obtained in Step 11-7 and
Compound 71b obtained in Step 71-1 by performing an operation similar to Step 1-11 of
Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 634 ([M+H] ).
LC/MS retention time: 1.30 min. (Analysis Condition: SMD-FA05-1).
<Step 71-3>
1-[(4S)(4-Fluoro-3,5-dimethylphenyl)methyl-4,5,6,7-tetrahydropyrazolo[4,3-
c]pyridinyl][6-fluoro(2-methoxyethyl)indazolyl]imidazolone hydrochloride
(Compound 71d)
The titled compound was synthesized from Compound 71c obtained in Step 71-2 by
performing an operation similar to Step 11-8 of Example 11 using an appropriate reagent.
LC/MS mass spectrometry: m/z 534 ([M+H] ).
LC/MS retention time: 0.83 min. (Analysis Condition: SMD-FA05-1).
<Example 73> Synthesis of 3-[(1S,2S)[5-(2-ethylmethylpyridinyl)
[(4S)(4-fluoro-3,5-dimethylphenyl)methyl[3-(1-methylindazolyl)oxoimidazol-
1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl]indolyl]methylcyclopropyl]-
4H-1,2,4-oxadiazolone (Compound 73)
<Step 73-1>
[Chemical Formula 66]
To a DMF (1.5 mL) solution of a racemic form (Compound 73a, 29.6 mg, 0.058
mmol) synthesized by a method similar to the compound obtained in Step 61-2 and
Compound 1o (26.8 mg, 0.064 mmol) obtained in Step 1-9 were added HATU (26.6 mg,
0.070 mmol) and N,N-diisopropylethylamine (18.1 mg, 0.14 mmol), and the mixture was
stirred at room temperature for an hour. The reaction solution was diluted by ethyl acetate,
and washed with distilled water. The organic layer was concentrated under reduced
pressure to obtain a residue which is a mixture of stereoisomers. The stereoisomers were
separated by reversed-phase HPLC to obtain Entity A (14.5 mg, yield 29%) and Entity B
(15.5 mg, yield 31%), which is a white, solid, titled Compound 73.
Separation Condition
Column: YMC Actus ODS-A, 20×100 mm, 5 μm
Solvent: 0.1% formic acid aqueous solution/0.1% formic acid acetonitrile
solution=40/60 (homogenous system)
Flow rate: 20 mL/min., room temperature
Entity A
LC/MS mass spectrometry: m/z 872 ([M+H] ).
LC/MS retention time: 0.99 min. (Analysis Condition: SMD-FA05-3).
Entity B (Compound 73)
LC/MS mass spectrometry: m/z 872 ([M+H] ).
LC/MS retention time: 1.01 min. (Analysis Condition: SMD-FA05-3).
<Example 74> Synthesis of 3-[(1S,2S)[6-Fluoro[(4S)(4-fluoro-3,5-
dimethylphenyl)methyl[3-(1-methylindazolyl)oxoimidazolyl]-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridinecarbonyl](2-methoxymethylpyridinyl)indolyl]
methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound 74)
[Chemical Formula 67]
<Step 74-1>
-Bromofluoro-N-methyl-N-phenyl-1H-indolecarboxamide (Compound 74b)
The titled compound was synthesized from 5-bromofluoro-1H-indolecarboxylic
acid (Compound 74a) by performing an operation similar to Step 1-10 of Example 1 using an
appropriate reagent.
LC/MS mass spectrometry: m/z 347 ([M+H] ).
LC/MS retention time: 1.06 min. (Analysis Condition: SMD-TFA05-4).
<Step 74-2>
-Bromo (cyanomethyl)fluoro-N-methyl-N-phenylindolecarboxamide
(Compound 74c)
The titled compound was synthesized from Compound 74b obtained in Step 74-1 by
performing an operation similar to Step 9-1 of Example 9 using an appropriate reagent.
LC/MS mass spectrometry: m/z 386 ([M+H] ).
LC/MS retention time: 1.06 min. (Analysis Condition: SMD-TFA50-4).
<Step 74-3>
-Bromo[(1S,2S)cyanomethylcyclopropyl]fluoro-N-methyl-N-
phenylindolecarboxamide (Compound 74d)
The titled compound was synthesized from Compound 74c obtained in Step 74-2 and
(4R)methyl-1,3,2-dioxathiolane 2,2-dioxide (Compound 1k) by performing an operation
similar to Step 1-6 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 426 ([M+H] ).
LC/MS retention time: 1.04 min. (Analysis Condition: SMD-FA10-5).
<Step 74-4>
-Bromofluoro-N-methyl[(1S,2S)methyl(5-oxo-4H-1,2,4-oxadiazol
yl)cyclopropyl]-N-phenylindolecarboxamide (Compound 74e)
The titled compound was synthesized from Compound 74d obtained in Step 74-3 by
performing an operation similar to Step 1-8 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 485 ([M+H] ).
LC/MS retention time: 1.33 min. (Analysis Condition: SMD-FA05-1).
<Step 74-5>
-Bromofluoro[(1S,2S)methyl(5-oxo-4H-1,2,4-oxadiazol
yl)cyclopropyl]indolecarboxylic acid (Compound 74f)
The titled compound was synthesized from Compound 74e obtained in Step 74-4 by
performing an operation similar to Step 6-4 of Example 6 using an appropriate reagent.
LC/MS mass spectrometry: m/z 396 ([M+H] ).
LC/MS retention time: 0.80 min. (Analysis Condition: SQD-FA05-1).
<Step 74-6>
3-[(1S,2S)[5-Bromofluoro[(4S)(4-fluoro-3,5-dimethylphenyl)methyl
[3- (1-methylindazolyl)oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine
carbonyl]indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound 74g)
The titled compound was synthesized from Compound 74f obtained in Step 74-5 and
Compound 61b obtained in Step 61-2 by performing an operation similar to Step 1-10 of
Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 849 ([M+H] ).
LC/MS retention time: 1.42 min. (Analysis Condition: SMD-FA05-1).
<Step 74-7>
3-[(1S,2S)[6-Fluoro[(4S) (4-fluoro-3,5-dimethylphenyl)methyl[3- (1-
methylindazolyl)oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine
carbonyl] (2-methoxymethylpyridinyl)indolyl]methylcyclopropyl]-4H-1,2,4-
oxadiazolone (Compound 74)
The titled compound was synthesized by performing an operation similar to Step 6-5
of Example 6 using Compound 74g obtained in Step 74-6 and 4-iodomethoxy3-
methylpyridine (Compound 6g), and an appropriate reagent.
LC/MS mass spectrometry: m/z 892 ([M+H] ).
LC/MS retention time: 1.48 min. (Analysis Condition: SMD-TFA05-1).
<Examples 75-77>
An operation similar to Step 8-1 of Example 8 was performed using an indole bromide
compound and an iodo (oxanyl) zinc derivative, and an appropriate reagent to obtain
Example Compounds 75 to 77 shown in Table 2-6 by the following reaction.
[Chemical Formula 68]
[Table 2-6]
Table 2-6. The Obtained Example Compounds 75 to 77
LC/MS
LC/MS
Analysis mass
retention
Structure Compound Condi- spectro-
time
tion metry
(min.)
(m/z)
3-[(1S,2S)[2-[2-(4-
fluoro-3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7-
SMD- 878
75 dihydro-4H-pyrazolo[4,3- 1.57
TFA05-2 ([M+H] )
c]pyridinecarbonyl]
(6-oxaspiro[4.5]decan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-(2,2-
dimethyloxanyl)[2-
(4-fluoro-3,5-
dimethylphenyl)[3-[1-
(2-methoxyethyl)indazol-
SMD- 895
76 5-yl]oxoimidazolyl]- 1.44
TFA05-2 ([M+H] )
6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
Example
3-[(1S,2S)[5-[(2S,4S)-
(2-ethyloxanyl)[2-(4-
fluoro-3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
SMD- 851
77 oxoimidazolyl]-6,7- 1.51
TFA05-2 ([M+H] )
dihydro-4H-pyrazolo[4,3-
c]pyridine
carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
Compound 75b used in the synthesis of Example Compound 75 was synthesized by
the following process.
<Step 75-1>
Iodo(6-oxaspiro[4.5]decanyl) zinc (Compound 75b)
[Chemical Formula 69]
The titled compound was synthesized from 9-iodooxaspiro[4.5]decane
(Compound 75a) by performing an operation similar to Step 41-1 of Example 41 using an
appropriate reagent.
The compound was directly put to use in the next step.
Compound 76a used in the synthesis of Example Compound 76 was synthesized by
the following process.
[Chemical Formula 70]
<Step 76-1>
3-[(1S,2S)[5-Bromo[2-(4-fluoro-3,5-dimethylphenyl)[3-[1-(2-
methoxyethyl)indazolyl]oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine
carbonyl]indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound 76a)
The titled compound was synthesized from Compound 56b obtained in Step 56-1 and
Compound 6f obtained in Step 6-4 by performing an operation similar to Step 1-10 of
Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 861 ([M+H] ).
LC/MS retention time: 1.45 min. (Analysis Condition: SMD-FA05-2).
<Example 77>
[Chemical Formula 71]
<Step 77-1>
2-Ethyliodooxane (Compound 77b)
To an acetic acid (2.48 mL) solution of butenol (0.588 mL, 6.93 mmol) was
sequentially added propionaldehyde (0.650 mL, 9.01 mmol) and lithium iodide (2.78 g, 20.8
mmol), and the mixture was stirred at 60ºC for 1 h. Water was added to the reaction
mixture, and extraction was performed using dichloromethane. The organic layer was
washed with 10% sodium thiosulfate aqueous solution and saturated sodium acid carbonate
aqueous solution, then dried with magnesium sulfate. After filtration, the filtrate was
concentrated under reduced pressure (lower limit being 150 hpa), and the residue was
purified by silica gel chromatography (ethyl acetate/hexane=0:1 to 1:9) to obtain the titled
Compound 77b as a pale yellow oil-like diastereomer mixture (1.12 g, yield 67%,
syn:anti=1.00:0.45).
H-NMR (400 MHz,CDCl ):
syn δ: 4.31-4.23 (1H, m), 3.90-3.82 (1H, m), 3.44-3.37 (1H, m), 3.21-3.15 (1H, m),
2.37-1.38 (6H, m), 0.92 (3H, t, J=7.4 Hz).
anti δ: 4.87-4.84 (1H, m), 3.90-3.82 (2H, m), 3.70-3.64 (1H, m), 2.37-1.38 (6H, m),
0.94 (3H, t, J=7.6 Hz).
<Step 77-2>
(2-Ethyloxanyl)-iodozinc (Compound 77c)
To a DMA (0.25 mL) solution of zinc (102 mg, 1.56 mmol) was slowly added
dropwise a mixture of chloro(trimethyl)silane (0.017 mL, 0.137 mmol) and 1,2-
dibromoethane (0.012 mL, 0.137 mmol) under a nitrogen atmosphere while maintaining a
temperature of 65ºC or lower, and the mixture was stirred at room temperature for 15 min.
Then, the DMA (0.625 mL) solution of Compound 77b (300 mg, 1.25 mmol) obtained in
Step 77-1 was added dropwise slowly into the mixture while maintaining a temperature of
65ºC or lower, and the mixture was stirred under a nitrogen atmosphere at room temperature
for 30 min. to obtain a DMA solution (0.86M) of a diastereomer mixture of the titled
Compound 77c.
<Step 77-3>
3-[(1S,2S)[5-(2-Ethyloxanyl)[2-(4-fluoro-3,5-dimethylphenyl)[3-(1-
methylindazolyl)oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine
carbonyl]indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound 77)
To a DMA (0.163 mL) solution of Compound 51d (40.0 mg, 0.049 mmol) obtained in
Step 51-4 were added palladium(II) acetate (2.20 mg, 0.00978mmol), and 2- (2-
dicyclohexylphosphanylphenyl)N,1-N,3-N,3-N-tetramethylbenzene-1,3-diamine (8.54 mg,
0.020 mmol), and the mixture was deaerated under reduced pressure, then nitrogen was
introduced in the vessel and the mixture was stirred at room temperature for 5 min. Then, a
DMA (0.86 M, 0.398 mL, 0.342 mmol) solution of Compound 77c obtained in Step 77-2 was
added and the mixture was stirred at room temperature for 1.5 h. Formic acid was added to
the reaction mixture, and the reaction mixture was purified by reversed-phase silica gel
chromatography (acetonitrile/water, 0.1% formic acid) to obtain the syn-type diastereomer
mixture. The syn-type diastereomer mixture was separated into stereoisomers by the
reversed-phase HPLC to obtain a white, amorphous Entity A (17.4 mg, yield 41%) and a
white, amorphous Entity B (14.9 mg, yield 37%), which is the titled Compound 77.
Separation Condition
Column: CHIRALCEL OD-RH 5 μm, 4.6 mm×150 mm (Daicel)
Solvent: 0.1% formic acid aqueous solution/0.1% formic acid acetonitrile
solution=20/80 (homogenous system)
Flow rate: 1.0 mL/min., room temperature
Entity A
LC/MS mass spectrometry: m/z 851 ([M+H] ).
HPLC retention time: 4.99 min. (Separation condition).
LC/MS retention time: 1.46 min. (Analysis Condition: SMD-FA05-1).
Entity B (Compound 77)
LC/MS mass spectrometry: m/z 851 ([M+H] ).
HPLC retention time: 6.64 min. (Separation condition).
LC/MS retention time: 1.46 min. (Analysis Condition: SMD-FA05-1).
<Example 78> Synthesis of 3-[(1S,2S)Ethyl[2-[2-(4-fluoro-3,5-
dimethylphenyl)[3-(1-methylindazolyl)oxoimidazolyl]-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridinecarbonyl](oxanyl)indolyl]cyclopropyl]-4H-1,2,4-
oxadiazolone (Compound 78)
[Chemical Formula 72]
<Step 78-1>
2-[5-Bromo[2-(4-fluoro-3,5-dimethylphenyl)[3-(1-methylindazolyl)
oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl]indolyl]acetonitrile
(Compound 78a)
The titled compound was synthesized from Compound 51c obtained in Step 51-3 and
-bromo(cyanomethyl)indolecarboxylic acid (Compound 6a) by performing an
operation similar to Step 1-10 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 718 ([M+H] ).
LC/MS retention time: 1.30 min. (Analysis Condition: SMD-FA05-1).
<Step 78-2>
2-[2-[2-(4-Fluoro-3,5-dimethylphenyl)[3-(1-methylindazolyl)oxoimidazol
yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl](oxanyl)indolyl]acetonitrile
(Compound 78b)
The titled compound was synthesized from Compound 78a obtained in Step 78-1 and
(tetrahydro-2H-pyranyl)zinc (II) iodide (Compound 8a) by performing an operation
similar to Step 8-1 of Example 8 using an appropriate reagent.
LC/MS mass spectrometry: m/z 724 ([M+H] ).
LC/MS retention time: 1.21 min. (Analysis Condition: SMD-FA05-1).
<Step 78-3>
(1S,2S)Ethyl[2-[2-(4-fluoro-3,5-dimethylphenyl)[3-(1-methylindazolyl)-
2-oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl](oxan
yl)indolyl]cyclopropanecarbonitrile (Compound 78d)
The titled compound was synthesized from Compound 78b obtained in Step 78-2 by
performing an operation similar to Step 1-6 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 778 ([M+H] ).
LC/MS retention time: 1.27 min. (Analysis Condition: SMD-FA05-RP).
<Step 78-4>
3-[(1S,2S)Ethyl[2-[2-(4-fluoro-3,5-dimethylphenyl)[3-(1-methylindazol
yl)oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl] (oxan
yl)indolyl]cyclopropyl]-4H-1,2,4-oxadiazolone (Compound 78)
The titled compound was synthesized from Compound 78d obtained in Step 78-2 by
performing an operation similar to Step 1-8 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 837 ([M+H] ).
LC/MS retention time: 1.39 min. (Analysis Condition: SMD-TFA05-2).
<Example 79> Synthesis of 3-[(1S,2S)[2-[2-(4-fluoro-3,5-dimethylphenyl)
[3-(1-methylindazolyl)oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine
carbonyl](oxanyl)indolyl](hydroxymethyl)cyclopropyl]-4H-1,2,4-oxadiazol
one (Compound 79)
[Chemical Formula 73]
<Step 79-1>
-Bromo[(1S,2S)cyano(phenylmethoxymethyl)cyclopropyl]-N-methyl-N-
phenylindolecarboxamide (Compound 79b)
The titled compound was synthesized from Compound 6c obtained in Step 6-1 and
(4R) (phenylmethoxymethyl)-1,3,2-dioxathiolane 2,2-dioxide (Compound 79a) by
performing an operation similar to Step 1-6 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 514 ([M+H] ).
LC/MS retention time: 1.48 min. (Analysis Condition: SMD-FA05-1).
<Step 79-2>
1-[(1S,2S)Cyano(phenylmethoxymethyl)cyclopropyl]-N-methyl(oxanyl)-
N-phenylindolecarboxamide (Compound 79c)
The titled compound was synthesized from Compound 79b obtained in Step 79-1 and
(tetrahydro-2H-pyranyl)zinc (II) iodide (Compound 8a) by performing an operation
similar to Step 8-1 of Example 8 using an appropriate reagent.
LC/MS mass spectrometry: m/z 520 ([M+H] ).
LC/MS retention time: 1.37 min. (Analysis Condition: SMD-FA05-1).
<Step 79-3>
N-Methyl(oxanyl)[(1S,2S)(5-oxo-4H-1,2,4-oxadiazolyl)
(phenylmethoxymethyl)cyclopropyl]-N-phenylindolecarboxamide (Compound 79d)
The titled compound was synthesized from Compound 79c obtained in Step 79-2 by
performing an operation similar to Step 1-8 of Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 579 ([M+H] ).
LC/MS retention time: 1.37 min. (Analysis Condition: SMD-FA05-1).
<Step 79-4>
-(Oxanyl)[(1S,2S)(5-oxo-4H-1,2,4-oxadiazolyl)
(phenylmethoxymethyl)cyclopropyl]indolecarboxylic acid (Compound 79e)
The titled compound was synthesized from Compound 79d obtained in Step 79-3 by
performing an operation similar to Step 6-4 of Example 6 using an appropriate reagent.
LC/MS mass spectrometry: m/z 490 ([M+H] ).
LC/MS retention time: 1.12 min. (Analysis Condition: SMD-FA05-1).
<Step 79-5>
3-[(1S,2S)[2-[2-(4-Fluoro-3,5-dimethylphenyl)[3-(1-methylindazolyl)
oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl](oxanyl)indol-
1-yl](phenylmethoxymethyl)cyclopropyl]-4H-1,2,4-oxadiazolone (Compound 79f)
The titled compound was synthesized from Compound 79e obtained in Step 79-4 and
Compound 51c obtained in Step 51-3 by performing an operation similar to Step 1-10 of
Example 1 using an appropriate reagent.
LC/MS mass spectrometry: m/z 929 ([M+H] ).
LC/MS retention time: 1.41 min. (Analysis Condition: SMD-FA05-1).
<Step 79-6>
3-[(1S,2S)[2-[2-(4-Fluoro-3,5-dimethylphenyl)[3-(1-methylindazolyl)
oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl] (oxanyl)indol-
1-yl](hydroxymethyl)cyclopropyl]-4H-1,2,4-oxadiazolone (Compound 79)
The dichloromethane (0.762 mL) solution of Compound 79f (35.4 mg, 0.0381mmol)
obtained in Step 79-5 was cooled to 0ºC, and a hexane solution (0.191 mL, 0.191 mmol) of
1M boron trichloride was slowly added. The reaction solution was warmed to room
temperature and stirred for 105 min., and thena saturated sodium acid carbonate solution was
added to the reaction solution and the water layer was subjected to extraction using
dichloromethane. The organic layer was washed with brine and dried with sodium sulfate.
After filtration, the filtrate was concentrated under reduced pressure and the residue was
purified by reversed-phase column chromatography (acetonitrile/water, 0.1% formic acid) to
obtain the titled compound (18.5 mg, yield 50%).
LC/MS mass spectrometry: m/z 839 ([M+H] ).
LC/MS retention time: 1.20 min. (Analysis Condition: SMD-TFA05-1).
<Example 80> Synthesis of 3-[(1S,2S)[2-[(4S,6R)(4-fluoro-3,5-
dimethylphenyl)-4,6-dimethyl[3-(1-methylindazolyl)oxoimidazolyl]-6,7-dihydro-
4H-pyrazolo[4,3-c]pyridinecarbonyl](oxanyl)indolyl]methylcyclopropyl]-4H-
1,2,4-oxadiazolone (Compound 80)
[Chemical Formula 74]
<Step 80-1>
Ethyl (E)[[(2S)Cyanopropanyl]amino]butenoate (Compound 80c)
To an acetonitrile (50 mL) solution of (3S)aminobutanenitrile (Compound 80b, 7.0
g, 83.2 mmol) and iodine (2.12 g, 8.35 mmol) was added ethyl 3-oxobutanoate (Compound
80a, 13 g, 99.9 mmol), and the mixture was stirred at room temperature for 4 h. The
reaction solution was concentrated under reduced pressure and the solvent was removed by
evaporation, and then the residue was purified by silica gel column chromatography
(petroleum ether/ethyl acetate=1:0 to 3:2) to obtain the titled Compound 80c (9.5 g, yield
58%) as a yellow oil-like material.
LC/MS mass spectrometry: m/z 197 ([M+H] ).
LC/MS retention time: 0.86 min. (Analysis Condition: SMD-FA10-1).
<Step 80-2>
Ethyl 3-[[(2S)Cyanopropanyl]amino]butanoate (Compound 80d)
To a dichloromethane (200 mL) solution of Compound 80c (10g, 51.0 mmol) obtained
in Step 80-1 and sodium triacetoxyborohydride (43.3 g, 204 mmol) was added acetic acid (3
mL), and the mixture was stirred at room temperature for 16 h. Water and acetic acid were
added to the reaction solution, and the pH was adjusted to 5, and then the water layer was
subjected to extraction using ethyl acetate. The organic layer was washed with brine and
dried using sodium sulfate. After filtration, the filtrate was concentrated under reduced
pressure, and the residue was purified by silica gel column chromatography (petroleum
ether/ethyl acetate=1:0 to 1:4) to obtain the titled Compound 80d (5.5 g, yield 54%) as a
yellow oil-like material.
LC/MS retention time: 0.83 min. (Analysis Condition: SMD-FA10-4).
<Step 80-3>
(6S)Formylhydroxy-2,6-dimethyl-3,6-dihydro-2H-pyridinecarbonitrile
(Compound 80e)
A toluene (5 mL) solution of Compound 80d (1.0 g, 5.04 mmol) obtained in Step 80-2
was added dropwise slowly at 80ºC to a toluene (10 mL) solution of potassium tert-butoxide
(680 mg, 6.06 mmol). After the solution was stirred at 80ºC for 1h., the solution was cooled
to room temperature to obtain a toluene solution of (6S)hydroxy-2,6-dimethyl-1,2,3,6-
tetrahydropyridinecarbonitrile.
A toluene (5 mL) solution of acetic anhydride (12.1 g, 118 mmol) was added
dropwise slowly into formic acid (7.26 g) at 0ºC and stirred at 0ºC for 30 min., and then the
toluene solution of (6S)hydroxy-2,6-dimethyl-1,2,3,6-tetrahydropyridinecarbonitrile
that had been prepared was added dropwise slowly. After the reaction solution was stirred
at 110ºC for 16 h., it was cooled to room temperature and concentrated under reduced
pressure to remove the solvent by evaporation, and a mixture (1.3 g) containing the titled
Compound 80e was obtained as an oil-like material.
<Step 80-4>
(4S)Amino(4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridinecarbaldehyde (Compound 80f)
The ethanol (30 mL) solution of Compound 80e (1.30 g, 7.21 mmol) obtained in Step
80-3 and (4-fluoro-3,5-dimethylphenyl)hydrazine hydrochloride (Compound 2c, 690 mg,
3.62 mmol) was heated to 75ºC and was stirred for 16 h. The reaction solution was cooled
to room temperature and concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (dichloromethane /methanol=1:0 to 9:1), and the titled
Compound 80f (2 steps from Step 80-3, 800 mg, yield 35%) was obtained as a yellow solid.
LC/MS mass spectrometry: m/z 317 ([M+H] ).
LC/MS retention time: 0.79 min. (Analysis Condition: SMD-FA10-3).
<Step 80-5>
1-(2,2-Dimethoxyethyl)[(4S) (4-fluoro-3,5-dimethylphenyl)formyl-4,6-
dimethyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinyl]urea (Compound 80g)
2,2-Dimethoxyethaneamine (1.14 g, 10.8 mmol) was added at 0ºC to a DMA (50
mL) solution of N,N’-carbodiimidazole (1.63 g, 10.1 mmol), and the mixture was stirred for
min. To the solution was added sequentially potassium tert-butoxide (5.62 g, 50.1
mmol) and Compound 80f (2.64 g, 8.34 mmol) obtained in Step 80-4. After the mixture
was stirred at room temperature for 6 h., water was added, and the water layer was subjected
to extraction using ethyl acetate. After the organic layer was washed with brine, it was
dried with sodium sulfate. After filtration, the filtrate was concentrated under reduced
pressure to obtain the titled Compound 80g (2.80 g, yield 75%) as a brown oil-like material.
LC/MS mass spectrometry: m/z 448 ([M+H] ).
LC/MS retention time: 0.84 min. (Analysis Condition: SMD-FA10-2).
<Step 80-6>
(4S,6R)(4-Fluoro-3,5-dimethylphenyl)-4,6-dimethyl(2-oxo-1H-imidazolyl)-
6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbaldehyde (Compound 80h)
A DMF (30 mL) solution of Compound 80g (2.50 g, 5.59 mmol) obtained in Step 80-
and 4-methylbenzenesulfonic acid (1.06 g, 6.16 mmol) was heated to 80ºC and stirred for 2
h. After the solution was cooled to room temperature, water was added and the water layer
was subjected to extraction using ethyl acetate. The organic layer was washed with brine,
and dried with sodium sulfate. After filtration, the filtrate was concentrated under reduced
pressure. The obtained residue was purified by silica gel column chromatography
(petroleum ether/ethyl acetate=1:0 to 3:1), to obtain the diastereomer mixture (480 mg)
containing the titled compound (Compound 80h) as a white solid.
LC/MS mass spectrometry: m/z 384 ([M+H] ).
LC/MS retention time: 1.64 min. (Analysis Condition: SMD-TFA05-6).
The diaseteromer mixture (480 mg, 5.59 mmol) containing the titled compound
(Compound 80h: (4S,6R) (4-fluoro-3,5-dimethylphenyl)-4,6-dimethyl (2-oxo-1H-
imidazolyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbaldehyde) was separated to
stereoisomers by SFC to obtain Entity A (155 mg, yield 7.0%) which is the titled Compound
80h and Entity B (270 mg, yield 12%).
SFC Separation condition
Column: CHIRALPAK AD-H, 50×500 mm, 3 μm (Daicel)
Solvent: supercritical carbon dioxide/ethanol=70:30 (homogenous system)
Flow rate: 150 mL/min., 35ºC
Detected wavelength: 254 nm
Entity A (Compound 80h)
SFC retention time: 4.07 min.
LC/MS mass spectrometry: m/z 384 ([M+H] ).
LC/MS retention time: 2.15 min. (Analysis Condition: SMD-FA1060-1).
H-NMR (300 MHz, DMSO-D ) δ: 10.35 (1H, s), 8.24 (1H, s), 7.11 (2H, d, J=6.3
Hz), 6.60-6.58 (2H, m), 5.21-5.14 (1H, m), 4.46-4.21 (1H, m), 2.96-2.89 (1H, m), 2.74-2.68
(1H, m), 2.20 (6H, s), 1.27-1.13 (6H, m).
Note that the Compound 80h was determined to be the R-isomer from the result
obtained by 2D-NOESY that the steric configuration thereof is a cis configuration.
Entity B
SFC retention time: 5.60 min.
LC/MS mass spectrometry: m/z 384 ([M+H] ).
LC/MS retention time: 2.16 min. (Analysis Condition: SMD-FA1060-1).
H-NMR (300 MHz, DMSO-D ) δ: 10.35 (1H, s), 8.31 (1H, s), 7.08 (2H, d, J=6.3
Hz), 6.61-6.54 (2H, m), 5.39 (1H, q, J=6.9 Hz), 3.89-3.84 (1H, m), 2.90 (1H, dd, J=3.3, 15.6
Hz), 2.59-2.51 (1H, m), 2.20 (6H, d, J=2.1 Hz), 1.55 (3H, d, J=6.6 Hz), 1.18 (3H, d, J=6.6
Hz).
<Step 80-7>
3-[(4S,6R)(4-Fluoro-3,5-dimethylphenyl)-4,6-dimethyl-4,5,6,7-
tetrahydropyrazolo[4,3-c]pyridinyl]-1H-imidazolone (Compound 80i)
5M Sodium hydroxide solution (0.261 mL) was added to an ethanol (1.0 mL) solution
of Compound 80h (100 mg, 0.261 mmol) obtained in Step 80-6, and the mixture was stirred
at 80ºC for 10 h. After the mixture was cooled to room temperature and stirred for 60 h.,
saturated ammonium chloride aqueous solution was added and the mixture was subjected to
extraction using ethyl acetate to synthesize the titled Compound 80i (79%, 73 mg) as a white
solid.
LC/MS mass spectrometry: m/z 356 ([M+H] ).
LC/MS retention time: 0.44 min. (Analysis Condition: SQD-FA05-2).
<Step 80-8>
1-[(4S,6R)(4-Fluoro-3,5-dimethylphenyl)-4,6-dimethyl-4,5,6,7-
tetrahydropyrazolo[4,3-c]pyridinyl](1-methylindazolyl)imidazolone (Compound
80j)
Copper iodide (I) (4.02 mg, 0.021 mmol) was added at a room temperature to a N-
methylpiperazine (0.188 mL) suspension of Compound 80i (15 mg, 0.042 mmol) obtained in
Step 80-7, 5-bromomethylindazole (Compound 1q, 10.7 mg, 0.051 mmol), (1S,2S)N,2-
N-dimethylcyclohexane-1,2-diamine (6.00 mg, 0.042 mmol), and potassium carbonate (17.5
mg, 0.127 mmol), and the mixture was stirred under a nitrogen atmosphere at 130ºC for 90
min. The reaction mixture was purified by reversed-phase silica gel chromatography
(acetonitrile/water, 0.1% formic acid) and concentrated under a reduced pressure. A
saturated sodium acid carbonate aqueous solution was added to the residue, and extraction
was performed using ethyl acetate, and then the organic layer was concentrated under
reduced pressure to obtain the titled Compound 80j (17.4 mg, yield 85%).
LC/MS mass spectrometry: m/z 486 ([M+H] ).
LC/MS retention time: 0.51 min. (Analysis Condition: SQD-FA05-2).
<Step 80-9>
2-Trimethylsilylethoxymethyl 5-(oxanyl)[(1S,2S)[5-oxo (2-
trimethylsilylethoxymethyl)-1,2,4-oxadiazolyl]methylcyclopropyl]indolecarboxylate
(Compound 80k)
To a DMF (2.6 mL) solution of Compound 8b (100 mg, 0.261 mmol) obtained in Step
8-1 was added 55 wt% sodium hydride (34.1 mg, 0.782 mmol) and 2-
(trimethylsilyl)ethoxymethylchloride (0.116 mL, 0.652 mmol), and the mixture was stirred
under room temperature for 1 h. A saturated ammonium chloride solution was added, and
extraction was performed using ethyl acetate. Then, the residue obtained after concentration
was purified by normal phase column chromatography (ethyl acetate/hexane) to obtain the
titled Compound 80k (147 mg, yield 88%) as a yellow gum-like material.
LC/MS retention time: 1.21 min. (Analysis Condition: SQD-FA05-2).
<Step 80-10>
-(Oxanyl)[(1S,2S)[5-oxo(2-trimethylsilylethoxymethyl)-1,2,4-oxadiazol-
3-yl]methylcyclopropyl]indolecarboxylic acid (80l)
To a dichloromethane (2.3 mL) solution of Compound 80k (147 mg, 0.228 mmol)
obtained in Step 80-9 was added a magnesium bromide/diethyl ether complex (295 mg, 1.14
mmol), and the mixture was stirred at 0ºC for 6.5 h. The mixture was warmed to room
temperature and stirred for 30 min., and then a saturated ammonium chloride aqueous
solultion was added. Then, extraction was performed using ethyl acetate, and the resulting
product was concentrated, and then the residue was diluted with DMSO and water and
purified by reversed-phase chromatography (acetonitrile/water, 0.1% formic acid) to
synthesize the titled Compound 80l (60 mg, yield 51%).
LC/MS mass spectrometry: m/z 512 ([M-H] ).
LC/MS retention time: 1.03 min. (Analysis Condition: SQD-FA05-2).
<Step 80-11>
-(Oxanyl)[(1S,2S)[5-oxo (2-trimethylsilylethoxymethyl)-1,2,4-oxadiazol-
3-yl]methylcyclopropyl]indolecarbonylchloride (Compound 80m)
To an acetonitrile (0.36 mL) solution of Compound 80l (18 mg, 0.036 mmol) obtained
in Step 80-10 was added 1-chloro-N,N,2-trimethylpropenamine (0.0057 mg, 0.043
mmol), and the mixture was stirred at room temperauter for 2 h., and then it was concentrated
to obtain a crude product of the titled Compound 80m. This compound was directly put to
use in the next step.
<Step 80-12>
3-[(1S,2S)[2-[(4S,6R)(4-Fluoro-3,5-dimethylphenyl)-4,6-dimethyl[3-(1-
methylindazolyl)oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine
carbonyl](oxanyl)indolyl]methylcyclopropyl](2-trimethylsilylethoxymethyl)-
1,2,4-oxadiazolone (Compound 80n)
Compound 80m obtained in Step 80-11 was dissolved in THF (0.717 mL), and
Compound 80j (19.1 mg, 0.036 mmol) obtained in Step 80-8 and N,N-diisopropylethylamine
(0.0188 mL, 0.108 mmol) were added to the solution, then the mixture was stirred at room
temperature for 22 h., and then methanol and formic acid were added. The mixture was
concentrated, and the residue was diluted with DMSO and water and purified by reversed-
phase column chromatography (acetonitrile/water, 0.1% formic acid) to synthesize the titled
Compound 80n (32 mg, yield 91%).
LC/MS mass spectrometry: m/z 982 ([M+H] ).
LC/MS retention time: 1.12 min. (Analysis Condition: SQD-FA50-1).
<Step 80-13>
3-[(1S,2S)[2-[(4S,6R)(4-Fluoro-3,5-dimethylphenyl)-4,6-dimethyl[3-(1-
methylindazolyl)oxoimidazolyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine
carbonyl](oxanyl)indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazolone
(Compound 80)
To a THF (0.326 mL) solution of Compound 80n (32 mg, 0.033 mmol) obtained in
Step 80-12 was added acetic acid (0.0019 mL, 0.033 mmol) and a THF solution (0.065 mL,
0.065 mmol) of 1M tetrabutylammonium fluoride, and the mixture was stirred at 80ºC for 66
h. Acetic acid (0.0019 mL, 0.033 mmol) and a THF solution (0.065 mL, 0.065 mmol) of
1M tetrabutylammonium fluoride were added, and the mixture was stirred for 23.5 h.
Further, a THF solution (0.065 mL, 0.065 mmol) of 1M tetrabutylammonium fluoride was
added, then the mixture was stirred for 7 h., and then formic acid was added. After
concentration, the mixture was diluted with DMSO and water and purified by reversed-phase
column chromatography (acetonitrile/water, 0.1% formic acid) to synthesize the titled
Compound 80 (18 mg, yield 65%).
LC/MS mass spectrometry: m/z 851 ([M+H] ).
LC/MS retention time: 1.42 min. (Analysis Condition: SMD-TFA05-1).
Example Compounds 101 to 159 shown in Table 2-7 below was obtained similarly
to Examples 1 to 80.
[Table 2-7]
Table 2-7. The Obtained Example Compounds 101 to 159
LC/M
S LC/MS
retenti mass
Analysis
Structure Compound on spectrom
Condition
time etry
(m/z)
(min.)
3-[(1S,2S)[5-(2-ethyl-
3-methylpyridinyl)
[2-(4-fluoro-3,5-
dimethylphenyl)[3-[1-
(2-methoxyethyl)indazol-
SMD- 902
101 5-yl]oxoimidazol 1.16
TFA05-3 ([M+H] )
yl]-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-(2-ethyl-
3-methylpyridinyl)
[2-(4-fluoro-3,5-
dimethylphenyl)[3-[4-
(1-hydroxy
methylpropanyl)oxy-
SMD- 922
102 3-methoxyphenyl] 1.17
TFA05-3 ([M+H] )
oxoimidazolyl]-6,7-
dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-(2-ethyl-
3-methylpyridinyl)
[2-(3-fluoro
methylphenyl)(3-
isoquinolinyl
SMD- 841
103 oxoimidazolyl)-6,7- 0.96
TFA05-3 ([M+H] )
dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(4-
chloro-3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7-
dihydro-4H- SMD- 875
1.20
104 +
pyrazolo[4,3-c]pyridine- TFA05-3 ([M+H] )
-carbonyl](2-ethyl
methylpyridinyl)indol-
1-yl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
Example No.
3-[(1S,2S)[2-[3-[3-
(1,3-dimethyl
oxoquinolinyl)
oxoimidazolyl](3-
methylphenyl)-6,7-
dihydro-4H- SMD- 867
1.16
pyrazolo[4,3-c]pyridine- TFA05-3 ([M+H] )
-carbonyl](2-ethyl
methylpyridinyl)indol-
1-yl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(2,6-
dimethylpyridinyl)
[3-(1-methylindazol
yl)oxoimidazolyl]-
6,7-dihydro-4H-
SMD- 841
pyrazolo[4,3-c]pyridine- 0.86
TFA05-3 ([M+H] )
-carbonyl](2-ethyl
methylpyridinyl)indol-
1-yl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-(2,3-
dimethylpyridinyl)
[2-(4-fluoro-3,5-
dimethylphenyl)[3-(1-
methyloxoquinolin
SMD- 871
yl)oxoimidazolyl]- 1.09
TFA05-3 ([M+H] )
6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(2-
fluoromethylphenyl)-
3-[3-[1-(2-
methoxyethyl)indazol
yl]oxoimidazolyl]-
6,7-dihydro-4H-
SMD- 890
pyrazolo[4,3-c]pyridine- 1.38
TFA05-3 ([M+H] )
-carbonyl](2-
methoxy
methylpyridinyl)indol-
1-yl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(4-
fluoro-3,5-
dimethylphenyl)[3-(4-
fluoromethylindazol-
-yl)oxoimidazol
SMD- 841
yl]-6,7-dihydro-4H- 1.34
TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(4-
fluoro-3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7-
dihydro-4H- SMD- 820
1.30
pyrazolo[4,3-c]pyridine- TFA05-3 ([M+H] )
-carbonyl](2-
methylpyrazol
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-(3-
chloromethylpyridin-
4-yl)[2-(4-fluoro-3,5-
dimethylphenyl)[3-[1-
(2-methoxyethyl)indazol-
SMD- 908
111 5-yl]oxoimidazol 1.24
TFA05-3 ([M+H] )
yl]-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7-
dihydro-4H-
SMD- 826
112 pyrazolo[4,3-c]pyridine- 0.95
FA05-3 ([M+H] )
-carbonyl](2-
ethylpyridinyl)indol
yl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(4-
fluoro-3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7-
dihydro-4H- SMD- 863
1.47
pyrazolo[4,3-c]pyridine- TFA05-2 ([M+H] )
-carbonyl](5-
oxaspiro[3.5]nonan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(3,5-
dimethylphenyl)[3-
(oxanyl)
oxoimidazolyl]-6,7-
dihydro-4H-
SMD- 795
pyrazolo[4,3-c]pyridine- 1.07
TFA05-3 ([M+H] )
-carbonyl](2-ethyl
methylpyridinyl)indol-
1-yl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(3,5-
dimethylphenyl)
methyl[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7-
dihydro-4H- SMD- 854
1.17
115 +
pyrazolo[4,3-c]pyridine- TFA05-3 ([M+H] )
-carbonyl](2-ethyl
methylpyridinyl)indol-
1-yl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)
(4-fluoro-3,5-
dimethylphenyl)
methyl[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7- SMD- 837
116 1.39
dihydro-4H- TFA05-2 ([M+H] )
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)
(4-fluoro-3,5-
dimethylphenyl)[3-[1-
(2-hydroxyethyl)indazol-
-yl]oxoimidazol
yl]methyl-6,7- SMD- 867
1.27
dihydro-4H- TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)
(4-fluoro-3,5-
dimethylphenyl)
methyl[3-[4-(oxan
yl)phenyl]
oxoimidazolyl]-6,7- SMD- 867
1.49
118 +
dihydro-4H- TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)
[3-[1-[(3S)
acetylpyrrolidin
yl]indazolyl]
oxoimidazolyl](4-
fluoro-3,5-
SMD- 934
119 dimethylphenyl) 1.29
TFA05-1 ([M+H] )
methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)
(4-fluoro-3,5-
dimethylphenyl)
methyl[3-[1-[2-[4-
(oxetanyl)piperazin
yl]ethyl]indazolyl]
SMD- 992
oxoimidazolyl]-6,7- 1.08
TFA05-1 ([M+H] )
dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)
(4-fluoro-3,5-
dimethylphenyl)
methyl[3-[3-methyl
[6-(4-methylpiperazin
yl)pyrimidin
yl]phenyl] SMD- 973
0.96
oxoimidazolyl]-6,7- TFA05-1 ([M+H] )
dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)
(4-fluoro-3,5-
dimethylphenyl)
methyl[2-oxo[1-
(2,2,2-
trifluoroethyl)indazol
SMD- 905
yl]imidazolyl]-6,7- 1.45
122 +
TFA05-1 ([M+H] )
dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)
(4-fluoro-3,5-
dimethylphenyl)
methyl[3-(3-
methylimidazo[1,5-
a]pyridinyl)
SMD- 837
123 oxoimidazolyl]-6,7- 1.07
TFA05-1 ([M+H] )
dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)
(4-fluoro-3,5-
dimethylphenyl)
methyl[3-(3-
methylimidazo[1,5-
a]pyridinyl)
SMD- 837
oxoimidazolyl]-6,7- 1.07
TFA05-1 ([M+H] )
dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)
[3-(1,4-dimethylindazol-
-yl)oxoimidazol
yl](4-fluoro-3,5-
dimethylphenyl)
SMD- 851
125 methyl-6,7-dihydro-4H- 1.37
TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)
[3-[1-[2-
(dimethylamino)ethyl]ind
azolyl]
oxoimidazolyl](4-
fluoro-3,5-
dimethylphenyl) SMD- 922
126 1.15
methyl-6,7-dihydro-4H- TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine-
-carbonyl][(4S)-2,2-
dimethyloxanyl]indol-
1-yl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[(4S)
[3-(1,4-dimethylindazol-
-yl)oxoimidazol
yl](4-fluoro-3,5-
dimethylphenyl)
methyl-6,7-dihydro-4H- SMD- 879
1.44
pyrazolo[4,3-c]pyridine- TFA05-1 ([M+H] )
-carbonyl][(4S)-2,2-
dimethyloxanyl]indol-
1-yl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-(2,2-
dimethylmorpholinyl)-
2-[(4S)(4-fluoro-3,5-
dimethylphenyl)[3-(4-
fluoromethylindazol-
-yl)oxoimidazol SMD- 884
128 1.30
yl]methyl-6,7- TFA05-1 ([M+H] )
dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[6-fluoro
[(4S)(4-fluoro-3,5-
dimethylphenyl)
methyl[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7- SMD- 855
1.38
dihydro-4H- TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[3-fluoro
[(4S)(4-fluoro-3,5-
dimethylphenyl)
methyl[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7- SMD- 855
1.40
130 +
dihydro-4H- TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[4-fluoro
[(4S)(4-fluoro-3,5-
dimethylphenyl)
methyl[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7- SMD- 855
131 1.38
dihydro-4H- TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[1-[2-[2-(4-fluoro-3,5-
dimethylphenyl)[3-[1-
(2-methoxyethyl)indazol-
-yl]oxoimidazol
yl]-6,7-dihydro-4H- SMD- 853
132 1.28
pyrazolo[4,3-c]pyridine- TFA05-2 ([M+H] )
-carbonyl](oxan
yl)indol
yl]cyclopropyl]-4H-
1,2,4-oxadiazolone
3-[1-[2-[2-(4-fluoro-3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7-
dihydro-4H- SMD- 809
1.26
pyrazolo[4,3-c]pyridine- TFA05-2 ([M+H] )
-carbonyl](oxan
yl)indol
yl]cyclopropyl]-4H-
1,2,4-oxadiazolone
3-[[2-[2-(4-fluoro-3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7-
SMD- 783
dihydro-4H- 1.18
TFA05-2 ([M+H] )
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]methyl]-
4H-1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(4-
fluoro-3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7-
dihydro-4H- SMD- 853
1.30
135 +
pyrazolo[4,3-c]pyridine- TFA05-2 ([M+H] )
-carbonyl](oxan
yl)indolyl]
(methoxymethyl)cyclopr
opyl]-4H-1,2,4-
oxadiazolone
3-[(1S,2R)[2-[2-(4-
fluoro-3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7-
dihydro-4H-
SMD- 908
pyrazolo[4,3-c]pyridine- 1.04
136 +
TFA05-1 ([M+H] )
-carbonyl](oxan
yl)indolyl]
(morpholin
ylmethyl)cyclopropyl]-
4H-1,2,4-oxadiazol
one; formic acid
3-[(2S,3R)[2-[2-(4-
fluoro-3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7-
SMD- 837
137 dihydro-4H- 1.39
TFA05-2 ([M+H] )
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]-2,3-
dimethylcyclopropyl]-
4H-1,2,4-oxadiazolone
3-[(1R,2S)[2-[[2-(4-
fluoro-3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7-
SMD- 859
138 dihydro-4H- 1.28
TFA05-1 ([M+H] )
pyrazolo[4,3-c]pyridin
yl]sulfonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1R)[2-[2-(4-
fluoro-3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7- SMD- 797
139 1.28
dihydro-4H- TFA05-2 ([M+H] )
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]ethyl]-4H-
1,2,4-oxadiazolone
4-[2-[2-(3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7-
dihydro-4H- SMD- 816
0.90
140 +
pyrazolo[4,3-c]pyridine- FA05-3 ([M+H] )
-carbonyl](2-ethyl
methylpyridinyl)indol-
1-yl]-2,2-
dimethylbutanoic acid
3-[2-[2-(3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7-
SMD- 774
141 dihydro-4H- 1.02
TFA05-3 ([M+H] )
pyrazolo[4,3-c]pyridine-
-carbonyl](2-ethyl
methylpyridinyl)indol-
1-yl]propanoic acid
2-[2-[2-(4-fluoro-3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7- SMD- 743
142 1.21
dihydro-4H- TFA05-2 ([M+H] )
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]acetic acid
(1S,2S)[2-[2-(3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7-
dihydro-4H-
SMD- 800
pyrazolo[4,3-c]pyridine- 1.08
143 +
TFA05-3 ([M+H] )
-carbonyl](2-ethyl
methylpyridinyl)indol-
1-yl]
methylcyclopropane
carboxylic acid
1-[2-(4-fluoro-3,5-
dimethylphenyl)[5-
(oxanyl)(1H-1,2,4-
triazol
ylmethyl)indole SMD- 766
144 1.10
carbonyl]-6,7-dihydro- TFA05-1 ([M+H] )
4H-pyrazolo[4,3-
c]pyridinyl](1-
methylindazol
yl)imidazolone
1-[2-(4-fluoro-3,5-
dimethylphenyl)[1-
[(1S,2S)methyl(5-
sulfanylidene-4H-1,2,4-
oxadiazol
SMD- 839
yl)cyclopropyl](oxan- 1.45
TFA05-2 ([M+H] )
4-yl)indolecarbonyl]-
6,7-dihydro-4H-
pyrazolo[4,3-c]pyridin
yl](1-methylindazol
yl)imidazolone
3-[(1S,2S)[2-[2-(4-
fluoro-3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7-
SMD- 839
146 dihydro-4H- 1.46
TFA05-2 ([M+H] )
pyrazolo[4,3-c]pyridine-
-carbonyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-thiadiazolone
1-[2-(4-fluoro-3,5-
dimethylphenyl)[1-
[(1S,2S)methyl(1H-
tetrazol
yl)cyclopropyl](oxan- SMD- 807
147 1.26
4-yl)indolecarbonyl]- TFA05-2 ([M+H] )
6,7-dihydro-4H-
pyrazolo[4,3-c]pyridin
yl](1-methylindazol
yl)imidazolone
(1S,2S)[2-[2-(4-
fluoro-3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7-
dihydro-4H- SMD- 860
1.31
148 +
pyrazolo[4,3-c]pyridine- TFA05-1 ([M+H] )
-carbonyl](oxan
yl)indolyl]methyl-
methylsulfonylcycloprop
anecarboxamide
3-[(1S,2S)[2-[[(4S)
(4-fluoro-3,5-
dimethylphenyl)
methyl[3-(1-
methylindazolyl)
oxoimidazolyl]-6,7- SMD- 823
149 1.17
dihydro-4H- TFA05-2 ([M+H] )
pyrazolo[4,3-c]pyridin
yl]methyl](oxan
yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
2-[2-[3-[3-
(cyclohexylmethyl)
oxoimidazolidinyl]
phenyl-6,7-dihydro-4H-
SMD- 714
pyrazolo[4,3-c]pyridine- 1.13
TFA05-3 ([M+H] )
-carbonyl](2,3-
dimethylpyridin
yl)indolyl]
methylpropanoic acid
3-[2-[2-[3-[3-
(cyclohexylmethyl)
oxoimidazolidinyl]
phenyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine- SMD- 755
151 1.10
-carbonyl](2,3- TFA05-3 ([M+H] )
dimethylpyridin
yl)indolyl]propan
yl]-4H-1,2,4-oxadiazol
3-[(1S,2S)[2-[3-[3-
(2,2-dimethylpropyl)
oxoimidazolidinyl]
phenyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine- SMD- 754
1.11
-carbonyl](2-ethyl TFA05-3 ([M+H] )
methylpyridinyl)indol-
1-yl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-(2-ethyl-
3-methylpyridinyl)
[2-(4-fluoro-3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
SMD- 860
153 oxoimidazolidinyl]- 1.15
TFA05-3 ([M+H] )
6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(3,5-
dimethylphenyl)[3-(4-
imidazolylphenyl)
oxoimidazolidinyl]-
6,7-dihydro-4H-
SMD- 854
pyrazolo[4,3-c]pyridine- 0.86
TFA05-1 ([M+H] )
-carbonyl](2-ethyl
methylpyridinyl)indol-
1-yl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(3,5-
dimethylphenyl)[3-(1-
methylindazolyl)
oxoimidazolidinyl]-
6,7-dihydro-4H-
SMD- 842
pyrazolo[4,3-c]pyridine- 1.14
TFA05-3 ([M+H] )
-carbonyl](2-ethyl
methylpyridinyl)indol-
1-yl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(3,5-
dimethylphenyl)(5-
imidazolyloxo-1H-
isoindolyl)-6,7-
dihydro-4H-
SMD- 825
pyrazolo[4,3-c]pyridine- 0.79
FA05-3 ([M+H] )
-carbonyl](2-ethyl
methylpyridinyl)indol-
1-yl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[2-[2-(3,5-
dimethylphenyl)[N,3-
dimethyl(3-propan
yl-1,2,4-triazol
yl)anilino]-6,7-dihydro-
SMD- 856
4H-pyrazolo[4,3- 1.10
TFA05-3 ([M+H] )
c]pyridinecarbonyl]
(2-ethylmethylpyridin-
4-yl)indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-(2-ethyl-
3-methylpyridinyl)
[2-(4-fluoro-3,5-
dimethylphenyl)[N-
methyl(2-propan
SMD- 859
ylimidazolyl)anilino]- 1.05
TFA05-3 ([M+H] )
6,7-dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
3-[(1S,2S)[5-(2-ethyl-
3-methylpyridinyl)
[2-(4-fluoro-3,5-
dimethylphenyl)[4-(3-
propanyl-1,2,4-triazol-
SMD- 846
4-yl)anilino]-6,7- 0.91
FA05-3 ([M+H] )
dihydro-4H-
pyrazolo[4,3-c]pyridine-
-carbonyl]indolyl]
methylcyclopropyl]-4H-
1,2,4-oxadiazolone
<Example 160> Preparation of Monosodium Salt Hydrate Crystal of Compound 1
Acetonitrile (3.02 mL) was added to 3-[(1S,2S)[5-[(4S)-2,2-dimethyloxanyl]-
2-[(4S)(4-fluoro-3,5-dimethylphenyl)[3-(4-fluoromethylindazolyl)
oxoimidazolyl]methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridinecarbonyl]indolyl]-
2-methylcyclopropyl]-4H-1,2,4-oxadiazolone (Compound 1, 1005.5 mg) obtained in
Example 1 to dissolve the compound at room temperature. 5M Sodium hydroxide aqueous
solution (0.495 mL) and seed crystals of sodium salt hydrate of Compound 1 were added to
the solution, and the mixture was stirred at room temperature for 2 h. Tert-Butylmethyl
ether (3.02 mL) was also added, and the mixture was stirred at room temperature for 1 h., and
then tert-butylmethyl ether (9.05 mL) was added and the mixture was stirred at room
temperature for 2 h. to obtain sodium salt hydrate crystals of the titled compound (1007.0
mg) as powder crystals (Sample 160a). Note that seed crystals were obtained by the
following method.
DMSO (0.244 mL) and 2M sodium hydroxide aqueous solution (0.032 mL) were
added to Compound 1 (26.9 mg). This solution (0.030 mL) was freeze-dried at -20ºC for 2
days. Acetonitrile (0.015 mL) was added to the obtained, freeze-dried product, and the
mixture was stirred by shaking at room temperature for 2 days, and then tert-butylmethyl
ether (0.015 mL) was added, and the mixture was stirred by shaking at toom temperature for
12 days to obtain sodium salt hydrate crystals of Compound 1 as powder crystals (Sample
160b).
<Example 161> Preparation of Crystal of Example Compound 66
3-[(1S,2S)[5-[(4S)-2,2-Dimethyloxanyl][(4S)(4-fluoro-3,5-
dimethylphenyl)methyl[3-(1-methylindazolyl)oxoimidazolyl]-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridinecarbonyl]indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazol
one (Example Compound 66, 400.3 mg) was suspended in ethanol (8.00 mL), to which seed
crytstals of Example Compound 66 were added, and the mixture was stirred at 70ºC for 5
min. After the suspension was stirred at 50ºC for 1 h., it was stirred at room temperature for
17 h. to obtain crystals (381.1 mg) of Example Compound 66 as powder crystals (Sample
161a). Note that seed crystals were obtained by the following method.
Example Compound 66 (31.8 mg) was suspended in ethanol (0.636 mL), and stirred
at 80ºC. After the suspension was stirred at 40ºC for 1 h., it was stirred at room temperature
for 22 h. to obtain crystals (24.2 mg) of Example Compound 66 as powder crystals (Sample
161b).
<Example 162> Preparation of Hemicalcium Salt Hydrate Crystal of Example
Compound 67
Ethanol (5.60 mL) and 2M sodium hydroxide aqueous solution (0.75 mL) were added
to 3-[(1S,2S)[5-[(4S)-2,2-dimethyloxanyl][(4S)(4-fluoro-3,5-dimethylphenyl)
[3-(4-fluoromethylindazolyl)oxoimidazolyl]methyl-6,7-dihydro-4H-
pyrazolo[4,3-c]pyridinecarbonyl]indolyl]methylcyclopropyl]-4H-1,2,4-oxadiazol
one (Example Compound 67, 1120 mg) and the compound was dissolved at room
temperature. 1.26 M calcium acetate aqueous solution (0.68 mL), seed crystals of the
calcium salt hydrate of Example Compound 67 and water (0.68 mL) were added to the
solution, and the mixture was stirred at room temperature for 3 h. Futher, water (1.2 mL)
was added and the mixture was stirred at room temperature for 1 h., and then water (2.3 mL)
was added and the mixture was stirred at room temperature for 1 h. to obtain calcium salt
hydrate crystals (973.0 mg) of Example Compound 67 as powder crystals (Sample 162a).
Note that seed crystals were obtained by the following method.
Example Compound 67 (69.0 mg) was dissolved in DMSO (0.229 mL), and 1.06M
calcium methoxyethoxide (0.147 mL) was added. This solution (0.015 mL) was freeze-
dried at -20ºC for 2 days. Water-acetonitrile mixture (3:1, 0.015 mL) was added to the
obtained, freeze-dried product, and the mixture was stirred by shaking at room temperature
for 7 days to obtain calcium salt hydrate crystals of Example Compound 67 as powder
crystals (Sample 162b).
<Example 163> Powder X-ray diffractometry
The sodium salt hydrate crystals (Samples 160a and 160b) of Compound 1 obtained in
Example 160, the crystals (Samples 161a and 161b) of Example Compound 66 obtained in
Example 161, the calcium salt hydrate crystals (Samples 162a and 162b) of Example
Compound 67 obtained in Example 162 were each subjected to powder X-ray diffractometry
by the following measurement method. The results are shown in Fig. 1 to Fig. 6.
Measurement Device: D8 Discover with GADDS CS diffractometer (Bruker AXS)
Anode: Cu
Voltage: 40 kV
Current: 40 mA
Scan Range: 5-25.3°
Step Width: 0.02°
<Example 164> Thermogravimetry/Differential thermal analysis
The sodium salt hydrate crystal of Compound 1 (Sample 160a) and the calcium salt
hydrate crystal of Example Compound 67 (Sample 162a) were each subjected to
thermogravimetry/differential thermal analysis by the following measurement method. The
results are shown in Fig. 7 and Fig. 8. Note that Sample 160a was dehydrated by
approximately 110ºC and showed no clear melting point. Also, Sample 162a was
dehydrated by approximately 240ºC and showed no clear melting point.
Measurement Device: EXSTAR TG/DTA6200R (Seiko Instruments Inc. (Current
Company Name: Hitachi High-Tech Science Corporation))
Measurement Range: 30-350ºC
Heat rate: 10ºC/min.
Atmosphere: Nitrogen
<Example 165> Karl Fischer Water Measurement
The rate of water content in the sodium salt hydrate crystal of Compound 1 (Sample
160a) and the calcium salt hydrate crystal (Sample 162a) of Example Compound 67 were
measured using the coulometric Karl Fischer moisture meter (Metrohm, 756 KF
Coulometer). The result was 7.4% for Sample 160a and 6.2% for Sample 162a.
From the results of Example 164 and Example 165, it was confirmed that the waters
contained in the sodium salt hydrate crystal of Compound 1 and the calcium salt hydrate
crystal of Example Compound 67 were mainly crystalline water.
<Test Example 1> Measurement of in vitro cAMP Signal Activation of a Compound
in Human GLP1R
<Peptide>
The human GLP-1 (7-37) was obtained from PEPTIDE INSTITUTE, INC., and it was
dissolved in phosphate buffered saline to 200 μM, then stored in a freezer of -80ºC.
<Cell Culture>
A human GLP1R stably-expressing cell line (hGLP1R-HEK293) was used in the
experiment. The cells were cultured in a Dulbecco's modified Eagle's medium (DMEM)
containing 10% fetal bovine serum (Sigma-Aldrich), 100 units/mL penicillin G and 100 μg /
mL streptomycin sulfate (Gibco), and 500 μg/mL Geneticin (Gibco), under a moist
atmosphere containing 5% CO , at 37ºC.
<cAMP Assay>
hGLP1R-HEK293 was seeded in 96 well plates at 2.0×10 cells per well and cultured
over night. The medium for culturing the cells was changed to 50 μL of Medium A
(DMEM, 20 mM HEPES, 0.05% BSA, 0.5 mM 3-isobutylmethylxanthine) the next day,
and the cells were incubated at 37ºC for 30 min. Then, 50 μL of Medium B (DMEM, 20
mM HEPES, 0.05% BSA, 0.5 mM 3-isobutylmethylxanthine) containing GLP-1 or the
compound was added, and the cells were incubated at 37ºC for an additional 30 min. Then,
100 μL of Assay lysis buffer (Applied Bioscience) was added, and the cells were incubated at
37ºC for 30 min. The cAMP concentration was quantified using cAMP HiRange kit (Cisbio
Bioassays).
<Calculation of EC >
By setting the cAMP concentration when the human GLP-1 (7-37) was put into action
at a concentration of 1 nM to 100%, the cAMP concentration of each well was converted to a
reaction rate (%). By using a 4 parameter logistic regression analysis by XLfit (ver 5.4.0.8),
dose-response curves of the each Example Compound were created, and the half maximal
(50%) effective concentrations (EC ) were calculated. The results are shown in Table 3.
[Table 3]
Table 3. EC of each Example Compound
Example EC50 Example EC50 Example EC50
No. (nM) No. (nM) No. (nM)
1 8.8 28 1.9 55 3.7
2 5.6 29 1.4 56 3.4
3 6.1 30 1.4 57 8.1
4 12 31 0.74 58 7.6
6.1 32 0.94 59 1.5
6 2.9 33 1.6 60 4.9
7 3.2 34 3.0 61 1.6
8 2.5 35 3.2 62 1.1
9 1.8 36 2.1 63 1.1
2.8 37 2.5 64 2.0
11 1.1 38 1.7 65 3.5
12 2.7 39 1.0 66 0.81
13 3.7 40 2.2 67 1.2
14 2.3 41 2.4 68 1.8
2.2 42 1.9 69 2.8
16 0.51 43 1.5 70 1.5
17 1.0 44 1.5 71 1.3
18 1.3 45 1.6 72 2.3
19 1.3 46 3.3 73 2.5
1.9 47 2.0 74 6.2
21 1.6 48 3.0 75 6.2
22 2.3 49 3.8 76 2.4
23 1.8 50 2.9 77 1.4
24 2.5 51 8.7 78 3.6
4.0 52 6.7 79 2.4
26 0.77 53 2.9 80 2.4
27 2.3 54 3.9
<Test Example 2>:Insulin Secretion Promoting and Blood Glucose Lowering
Effects
A solution of Example Compound 67 (solvent composition: PEG400 (10 vol%):
propylene glycol (10 vol%): 100 mM Glycine-NaOH buffer, pH 9.0 (80 vol%)) was
intravenously administered to a male cynomolgus monkey under anesthesia, for 40 min.
continuously, and a steady-state drug concentration in plasma of 0.94, 1.6 or 4.8 nmol/L was
achieved. Likewise, a solution of exenatide (solvent: Tween 0.05%/PBS(-)), which is a
control drug, was administered in the same manner, and a steady-state drug concentration in
plasma of 9.2 or 23.9 pmol/L was achieved. To the vehicle control group, the solvent of
Example Compound 67 was administered. Next, a 50% glucose solution (glucose
administration weight to the monkey: 0.5 g/kg) was intravenously administered and a blood
sample was collected every 5min or 10 min to measure the plasma insulin and glucose
concentrations. The area under the curve was calculated from the time course of each
parameter after the drug administrationto evaluate the insulin secretion promoting effect and
the blood glucose lowering effect.
In the Example Compound 67 administered group, an increase in the area under the
curve of insulin (Fig. 9) and a decrease in the area under the curve of plasma glucose (Fig.
) in adose-dependent manner, were observed at a steady-state concentration in plasma of
0.94 to 4.8 nmol/L. A similar increase in the area under the curve of insulin (Fig. 9) and
decrease in the the area under the curve of plasma glucose (Fig. 10) were observed in
exenatide (control drug) administered gourp at a steady-state plasma concentrationof 9.2 to
23.9 pmol/L by the continuous intravenous administrations
Note that the 9.2 pmol/L (38.5 pg/mL) of exenatide was close to the lower limit of
the therapeutic concentration range (50-350 pg/mL) of exenatide in human diabetes patients
(Drug interview form, Byetta hypodermic injection 5 μg Pen 300, Byetta hypodermic
injection 10 μg Pen 300, September 2016 (revised ver. 9)). This result indicates that
Example Compound 67 exhibits an insulin secretion promoting effect and a blood
glucoselowering effect that are equivalent to exenatide, at a plasma concentration of 1.6
nmol/L or higher.
<Test Example 3>: Anorexigenic effects
Example Compound 67 was orally administered to male cynomolgus monkeys, for 5
consecutive days, and its effects on the food intake for 90 min. from 3 h. after
administration were evaluated everyday. Likewise, exenatide, which is a control drug, was
subcutaneously administered for 5 consecutive days, and itseffect on the food intake for 90
min. from 30 min. after administration were evaluated. To the vehicle control group, both a
solvent for oral administration of Example Compound 67 (DMSO (10 vol%): Cremophor EL
(10 vol%): PEG 400 (15 vol%): 100 mM Glycine-NaOH buffer, pH 10 (65 vol%), 1 mL/kg)
and a solvent for subcutaneous administration of exenatide (0.05 w/v% Tween/PBS(-), 0.1
mL/kg) were administered. At the same time, the solvent for subcutaneous administration
was additionally administered to the Example Compound 67 administered group
(concentration of administered drug, 0.05 or 0.1 mg/mL), and the solvent for oral
administration was additionally administered to the exenatide administered group
(concentration of administered drug, 3 or 6 μg/mL).
Example Compound 67 suppressed the food intake in a dosage dependent manner
(Fig. 11A). The degree of suppression was almost equivalent to the control drug exenatide
(Fig. 11B). The plasma concentration of drug ( mean value ± standard error) immediately
after measuring the food intake in each group were 8.0±1.0 nM (0.05 mg/kg group) and
16.3±2.3 nM (0.1 mg/kg group) for the Example Compound 67 administered group and
91±8.5 pM (0.3 μg/kg group) and 199±13.1 pM (0.6 μg/kg group) for the exenatide
administered group.
<Test Example 4> Pharmacokinetics of the Compounds
After oral administration (gavage administration using a gastric catheter) of a
calcium salt hydrate crystal (Sample 162a) suspension (Dosage: 0.05, 0.15, 0.45 and 1.35
mg/kg) prepared from Example Compound 67 obtained in Example 162 to a male
cynomolgus monkey (n=2 for each dosage), blood was sequentially collected from the vein to
obtain plasma. The plasma concentrations of the drug were determined by liquid
chromatography tandem-mass spectrometry. The lower limit of quantification was 0.3
ng/mL. The time profile of the plasma concentrations for the drug are shown in Fig. 12 and
the time to reach the maximum plasma concentration of the drug (T ), the maximum
plasma concentration of the drug (C ) and the area under the plasma concentration – time
curve of the drug up to 24 h. after administration (AUC ) are shown in Table 4.
0-24h
In all dosages, the plasma concentrations of the drug reached C at 2 h after oral
administration, and then decreased in a similar time profile pattern. The increase in the
plasma exposure of drug at dosages of 0.05, 0.15, 0.45 and 1.35 mg/kg (Dosage ratio:
1:3:9:27) was nearly proportional to the increase in the dosage (C ratio: 1.0:4.3:6.7:31,
AUC ratio: 1.0:5.7:8.8:44). It was shown that the present substance was dose-
0-24h
proportionally absorbed in the intestinal tract and eliminated.
[Table 4]
Table 4. The T , C , and AUC after oral administration of the present substance to
max max 0-24h
male cynomolgus monkeys
Dose
C AUC
max 0-24h
(mg/kg)
(Ratio) (h) (ng/mL) (Ratio) (ng·h/mL) (Ratio)
0.05 1.0 2.0 4.78 1.0 23.7 1.0
0.15 3.0 2.0 20.7 4.3 135 5.7
0.45 9.0 2.0 32.0 6.7 208 8.8
1.35 27 2.0 148 31 1040 44
Claims (16)
1. A compound represented by Formula (I): wherein, X is –N= or –CR =; R is selected from a hydrogen atom, a halogen atom, and C alkyl; Y is selected from -C(=O)-, -CHR-, and -S(=O) -; R is a hydrogen atom or C 2 1-6 alkyl; Q is C aryl or 5 to 10 membered heteroaryl, wherein C aryl and 5 to 10 6-10 6-10 membered heteroaryl are optionally substituted with one to five substituents independently selected from a halogen atom, C alkyl (wherein C alkyl is optionally substituted with one 1-6 1-6 or more halogen atoms), and C alkoxy; Q is 3 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl, wherein 3 to 12 membered heterocyclyl and 5 to 10 membered heteroaryl are optionally substituted with one to three substituents independently selected from a halogen atom, C alkyl (wherein C 1-6 1-6 Qa Qb alkyl is optionally substituted with one or more halogen atoms), C alkoxy, and -NR R , and two C alkyl groups together with a carbon atom to which they are attached may form Qa Qb C carbocyclic ring; and R and R are independently selected from a hydrogen atom, C 3-8 1-6 alkyl, and (C alkyl)calbonyl; 1 2 3 R , R and R are each independently selected from a hydrogen atom and C alkyl (wherein, C alkyl is optionally substituted with one or more substituents independently selected from a halogen atom, C alkoxy, and hydroxy); 4 5 6 R , R and R are independently selected from a hydrogen atom, a halogen atom, and C alkyl; R and R are independently a hydrogen atom or C alkyl, wherein C alkyl is 1-6 1-6 optionally substituted with one or more substituents independently selected from a halogen atom and C cycloalkyl, or R and R together with a carbon atom to which they are 3-15 attached may form C cycloalkane ring, wherein C cycloalkane ring formed by R and 3-15 3-15 R together is optionally substituted with one to three C alkyl, wherein C alkyl is 1-6 1-6 optionally substituted with one or more substituents independently selected from a halogen 7a 7b 7a 7b atom, hydroxy, -NR R , C alkoxy, and 3 to 12 membered heterocyclyl, and R and R are independently selected from a hydrogen atom, C alkyl, and (C alkyl)carbonyl; 1-6 1-6 n1 is an integer of 0 to 3; n2 is an integer of 0 to 5; R is selected from a group represented by Formula (IIa), (IIb), (IIc), (IId): 9f 9g 9h 9a 9b 9c 9d 9g -CO R , and -C(=O)-NR R ; and R , R , R , R , and R are each independently selected from a hydrogen atom, C alkyl (wherein C alkyl is optionally substituted with one or 1-6 1-6 more substituents independently selected from a halogen atom and C alkoxy), and (C 1-6 1-6 alkyl)carbonyl; R is a hydrogen atom, or C alkyl that is optionally substituted with one or 9f 9h more halogen atoms; R is a hydrogen atom or C alkyl; R is a hydrogen atom, C alkyl, 1-6 1-6 9i 9i (C alkyl)carbonyl, cyano, or -S(=O) -R ; n3 is an integer of 0 to 2; and R is C alkyl; 1-6 n3 1-6 Z is selected from a group represented by Formula (IIIa), (IIIb), (IIIc), (IIId), and (IIIe): za zb wherein R is selected from a hydrogen atom, C alkyl, and (C alkyl)carbonyl; R and 1-6 1-6 R are independently a hydrogen atom or C alkyl; n4 is an integer of 1 to 3; n5 and n6 are independently an integer of 0 to 10 (* represents a binding position with a pyrazolopyridine structure, and ** represents a binding position with Z ); Z is selected from C alkyl, C cycloalkyl, 3 to 12 membered heterocyclyl, C 1-6 3-15 6-10 aryl and 5 to 10 membered heteroaryl, wherein C cycloalkyl, 3 to 12 membered 3-15 heterocyclyl, C aryl, and 5 to 10 membered heteroaryl are optionally substituted with one 6-10 to five substituents independently selected from Group A: Group A: a) oxo, b) a halogen atom, c) cyano, zd ze zd ze d) -NR R ; wherein R and R are independently selected from a hydrogen atom, C alkyl and (C alkyl)carbonyl, wherein C alkyl is optionally substituted with one or 1-6 1-6 1-6 more substituents independently selected from hydroxy, a halogen atom and C alkoxy, zf zg zf zg e) -C(=O)-NR R ; wherein R and R are independently selected from a hydrogen atom, C alkyl and (C alkyl)carbonyl, wherein C alkyl is optionally substituted with one 1-6 1-6 1-6 or more substituents independently selected from hydroxy, a halogen atom and C alkoxy, zh zh f) -S(=O) -R ; wherein n7 is an integer of 0 to 2; and R is a hydrogen atom or C n7 1- alkyl, g) C alkyl; wherein C alkyl is optionally substituted with one or more 1-6 1-6 zi zj substituent independently selected from a halogen atom, hydroxy, -NR R , C alkoxy, and zi zj 3 to 12 membered heterocyclyl, wherein R and R are independently a hydrogen atom or C alkyl, and wherein 3 to 12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from hydroxy, C alkyl and 3 to 12 membered heterocyclyl, h) C alkoxy; wherein C alkoxy is optionally substituted with one or more 1-6 1-6 substituent independently selected from hydroxy, a halogen atom, and C alkoxy, i) 3 to 12 membered heterocyclyl; wherein 3 to 12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from C alkyl and (C alkyl)carbonyl, j) C aryl; wherein C aryl is optionally substituted with one or more (C 6-10 6-10 1-6 alkyl)carbonyl, and k) 5 to 10 membered heteroaryl; wherein 5 to 10 membered heteroaryl is optionally substituted with one or more substituents independently selected from C alkyl, C alkoxy, 1-6 1-6 zk zl zk zl -NR R , and 3 to 12 membered heterocyclyl, wherein R and R are independently selected from a hydrogen atom, C alkyl and (C alkyl)carbonyl, and wherein 3 to 12 membered 1-6 1-6 heterocyclyl is optionally substituted with one or more substituents independently selected from C alkyl and (C alkyl)carbonyl; 1-6 1-6 a salt thereof, or a solvate of either the compound or a salt of the compound.
2. The compound according to claim 1, a salt thereof, or a solvate of either the compound or a salt of the compound, wherein Q is phenyl or pyridyl, and phenyl or pyridyl is substituted with one to four substituents independently selected from a halogen atom and C alkyl.
3. The compound according to claim 1 or 2, a salt thereof, or a solvate of either the 7 8 7 8 compound or a salt of the compound, wherein R and R are both a hydrogen atom; R and R 7 8 7 8 are both C alkyl; R is a hydrogen atom and R is C alkyl; or R and R together with a 1-6 1-6 carbon atom to which they are attached form C cycloalkane ring, wherein C cycloalkyl 3-8 3-8 formed is optionally substituted with one to two C alkyl, and C alkyl is optionally 1-6 1-6 substituted with one or more substituents independently selected from hydroxy, C alkoxy, and 3 to 12 membered heterocyclyl.
4. The compound according to any one of claims 1 to 3, a salt thereof, or a solvate of either the compound or a salt of the compound, wherein Z is selected from C alkyl, C 1-6 3-15 cycloalkyl, 3 to 12 membered heterocyclyl, C aryl, and 5 to 10 membered heteroaryl, 6-10 wherein C cycloalkyl, 3 to 12 membered heterocyclyl, C aryl, and 5 to 10 membered 3-15 6-10 heteroaryl are optionally substituted with one to four substituents independently selected from Group B: Group B: a) oxo, b) a halogen atom, zd1 zel zd1 ze1 c) -NR R ; wherein R and R are independently selected from a hydrogen atom, C alkyl and (C alkyl)carbonyl, and C alkyl is optionally substituted with one or 1-6 1-6 1-6 more C alkoxy, zh1 zh1 d) -S(=O) -R ; wherein n7 is an integer of 0 to 2, R is C alkyl, n7 1-6 e) C alkyl; wherein C alkyl is optionally substituted with one or more 1-6 1-6 zi zj substituents independently selected from a halogen atom, hydroxy, -NR R , C alkoxy, and zi zj 3 to 12 membered heterocyclyl, wherein R and R are independently a hydrogen atom or C alkyl, and wherein 3 to 12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from hydroxy, C alkyl and 3 to 12 membered heterocyclyl, f) C alkoxy; wherein C alkoxy is optionally substituted with one or more 1-6 1-6 hydroxy, g) 3 to 12 membered heterocyclyl; wherein 3 to 12 membered heterocyclyl is optionally substituted with one or more (C alkyl)carbonyl, h) 5 to 10 membered heteroaryl; wherein 5 to 10 membered heteroaryl is optionally substituted with one or more substituents independently selected from C alkyl, and - zk1 zl1 zk1 zl1 NR R ; and R and R are independently selected from a hydrogen atom and C alkyl.
5. The compound according to any one of claims 1 to 4, a salt thereof, or a solvate of either the compound or a salt of the compound, wherein Y is -C(=O)-.
6. The compound according to any one of claims 1 to 5, a salt thereof, or a solvate of either the compound or a salt of the compound, wherein R is a hydrogen atom.
7. The compound according to any one of claims 1 to 6, a salt thereof, or a solvate of either the compound or a salt of the compound, wherein n1 and n2 are both 0.
8. The compound according to any one of claims 1 to 7, a salt thereof, or a solvate of either the compound or a salt of the compound, wherein R is represented by Formula (IIb):
9. The compound according to any one of claims 1 to 8, a salt thereof, or a solvate of either the compound or a salt of the compound, wherein X is -N=, -CH=, or -CF=.
10. The compound according to any one of claims 1 to 9, a salt thereof, or a solvate of either the compound or a salt of the compound, wherein Z is represented by Formula (IIIa): wherein * represents a binding position with a pyrazolopyridine structure, and ** represents a binding position with Z .
11. The compound according to claim 1, or a salt thereof, or a solvate of either the compound or a salt of the compound, represented by the formula:
12. The compound according to claim 1, or a salt thereof or a solvate thereof, of the formula:
13. A hemicalcium salt hydrate of the compound according to claim 11 or 12.
14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12, a salt thereof, or a solvate of either the compound or a salt of the compound as an active ingredient.
15. A preventive agent or a therapeutic agent for non-insulin-dependent diabetes mellitus (Type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin dependent diabetes mellitus (Type 1 diabetes), diabetic complication, obesity, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, brain infarction, non-alcoholic steatohepatitis, Parkinson's disease, or dementia, wherein the preventative agent or the therapeutic agent comprises the compound according to any one of claims 1 to 12, a salt thereof, or a solvate of either the compound or a salt of the compound as an active ingredient.
16. A preventive agent or a therapeutic agent for non-insulin-dependent diabetes mellitus (Type 2 diabetes) or obesity comprising the compound according to any one of claims 1 to 12, a salt thereof, or a solvate of either the compound or a salt of the compound as an active ingredient.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2016-187605 | 2016-09-26 | ||
JP2016187605 | 2016-09-26 | ||
PCT/JP2017/034620 WO2018056453A1 (en) | 2016-09-26 | 2017-09-26 | Pyrazolopyridine derivative having glp-1 receptor agonist effect |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ751725A NZ751725A (en) | 2021-03-26 |
NZ751725B2 true NZ751725B2 (en) | 2021-06-29 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11814381B2 (en) | Pyrazolopyridine derivative having GLP-1 receptor agonist effect | |
KR102659741B1 (en) | Fused ring heteroaryl compounds and their use as trk inhibitors | |
JP7461104B2 (en) | Pharmaceutical composition containing pyrazolopyridine derivative having GLP-1 receptor agonist activity | |
TW202115065A (en) | Kras mutant protein inhibitor | |
EP3589618B1 (en) | Pyrazole derivatives as bromodomain inhibitors | |
NZ751725B2 (en) | Pyrazolopyridine derivative having glp-1 receptor agonist effect | |
KR20230011967A (en) | 1,4,5,6-tetrahydropyrimidin-2-amine derivatives | |
US20210346336A1 (en) | Furan derivatives as bromodomain inhibitors | |
EA044109B1 (en) | PYRAZOLOPYRIDINE DERIVATIVES WITH GLP-1 RECEPTOR AGONIST EFFECT | |
WO2017215586A1 (en) | Amide derivatives, preparation process thereof and use thereof in medicine | |
TW202039458A (en) | Glp-1r agonists and uses thereof | |
KR20190027766A (en) | Tetrahydroisoquinoline substituted pyrimidine derivative, optical isomer thereof, or pharmaceutically acceptable salts thereof, and composition comprising its same for preventing or treating of cancer |