IL300525A - תרכובות אזאציקלוהקסיל חומצה אצטית מותמרות בטריאזול–פירידיניל כאנטגוניסטים לקולטן lpa - Google Patents

Info

Publication number

IL300525A

IL300525A IL300525A IL30052523A IL300525A IL 300525 A IL300525 A IL 300525A IL 300525 A IL300525 A IL 300525A IL 30052523 A IL30052523 A IL 30052523A IL 300525 A IL300525 A IL 300525A

Authority

IL

Israel

Prior art keywords

compound

substituted

ring

methyl

occurrence

Prior art date

2020-08-11

Links

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• 102000004137 Lysophosphatidic Acid Receptors Human genes 0.000 title description 8
• 108090000642 Lysophosphatidic Acid Receptors Proteins 0.000 title description 8
• 239000002464 receptor antagonist Substances 0.000 title description 2
• 229940044551 receptor antagonist Drugs 0.000 title description 2
• 125000000218 acetic acid group Chemical class C(C)(=O)* 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 363
• 229910052739 hydrogen Inorganic materials 0.000 claims description 167
• 239000001257 hydrogen Substances 0.000 claims description 166
• -1 C2- ealkynyl Chemical group 0.000 claims description 154
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 140
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 118
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 114
• 229910052757 nitrogen Inorganic materials 0.000 claims description 103
• 125000000623 heterocyclic group Chemical group 0.000 claims description 100
• 229910052736 halogen Inorganic materials 0.000 claims description 92
• 150000002367 halogens Chemical class 0.000 claims description 90
• 125000005842 heteroatom Chemical group 0.000 claims description 77
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 69
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 67
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 65
• 229910052760 oxygen Inorganic materials 0.000 claims description 64
• 229910052799 carbon Inorganic materials 0.000 claims description 63
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 62
• 239000001301 oxygen Chemical group 0.000 claims description 62
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 61
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 57
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 55
• 229920006395 saturated elastomer Polymers 0.000 claims description 54
• 229910052717 sulfur Chemical group 0.000 claims description 53
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 51
• 239000011593 sulfur Chemical group 0.000 claims description 51
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 50
• 150000001721 carbon Chemical group 0.000 claims description 44
• 150000003839 salts Chemical class 0.000 claims description 42
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 40
• 238000000034 method Methods 0.000 claims description 39
• 229910003827 NRaRb Inorganic materials 0.000 claims description 36
• 125000001072 heteroaryl group Chemical group 0.000 claims description 36
• 125000006413 ring segment Chemical group 0.000 claims description 36
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 32
• 125000003118 aryl group Chemical group 0.000 claims description 31
• 229910052705 radium Inorganic materials 0.000 claims description 29
• 229910052701 rubidium Inorganic materials 0.000 claims description 29
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 26
• 201000010099 disease Diseases 0.000 claims description 26
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 25
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 25
• 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 24
• 239000008194 pharmaceutical composition Substances 0.000 claims description 24
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 21
• 206010016654 Fibrosis Diseases 0.000 claims description 17
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
• 125000004429 atom Chemical group 0.000 claims description 16
• 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 16
• 102100040607 Lysophosphatidic acid receptor 1 Human genes 0.000 claims description 15
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
• 230000004761 fibrosis Effects 0.000 claims description 14
• 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 13
• 125000004043 oxo group Chemical group O=* 0.000 claims description 10
• 239000003937 drug carrier Substances 0.000 claims description 9
• 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 8
• 101710149745 Lysophosphatidic acid receptor 1 Proteins 0.000 claims description 8
• 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 8
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
• 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 7
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 6
• 201000009594 Systemic Scleroderma Diseases 0.000 claims description 5
• 206010042953 Systemic sclerosis Diseases 0.000 claims description 5
• 230000008482 dysregulation Effects 0.000 claims description 5
• 210000004185 liver Anatomy 0.000 claims description 5
• 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 4
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
• 230000000747 cardiac effect Effects 0.000 claims description 4
• 208000020832 chronic kidney disease Diseases 0.000 claims description 4
• 208000033679 diabetic kidney disease Diseases 0.000 claims description 4
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 4
• 230000001575 pathological effect Effects 0.000 claims description 4
• 230000002685 pulmonary effect Effects 0.000 claims description 4
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
• 108010081348 HRT1 protein Hairy Proteins 0.000 claims description 3
• 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 3
• 150000002431 hydrogen Chemical class 0.000 claims 30
• JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims 1
• 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 250
• 239000000203 mixture Substances 0.000 description 229
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 148
• 238000000132 electrospray ionisation Methods 0.000 description 145
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 138
• 235000019439 ethyl acetate Nutrition 0.000 description 121
• 239000000543 intermediate Substances 0.000 description 121
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 114
• 239000000243 solution Substances 0.000 description 112
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 91
• 238000005160 1H NMR spectroscopy Methods 0.000 description 90
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 84
• 229910001868 water Inorganic materials 0.000 description 75
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 74
• 239000007832 Na2SO4 Substances 0.000 description 65
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 65
• 229910052938 sodium sulfate Inorganic materials 0.000 description 65
• 235000011152 sodium sulphate Nutrition 0.000 description 65
• 239000012267 brine Substances 0.000 description 63
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 63
• 239000004698 Polyethylene Substances 0.000 description 59
• 235000011054 acetic acid Nutrition 0.000 description 55
• 239000007787 solid Substances 0.000 description 51
• 239000012299 nitrogen atmosphere Substances 0.000 description 49
• 235000002639 sodium chloride Nutrition 0.000 description 45
• 125000004432 carbon atom Chemical group C* 0.000 description 40
• 238000003818 flash chromatography Methods 0.000 description 40
• 125000001424 substituent group Chemical group 0.000 description 39
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 39
• 239000012044 organic layer Substances 0.000 description 37
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 37
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 35
• 238000006243 chemical reaction Methods 0.000 description 33
• 238000003786 synthesis reaction Methods 0.000 description 33
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 32
• 239000003921 oil Substances 0.000 description 32
• 235000019198 oils Nutrition 0.000 description 32
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
• 230000015572 biosynthetic process Effects 0.000 description 30
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 28
• 239000002585 base Substances 0.000 description 28
• 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 27
• 239000000651 prodrug Substances 0.000 description 27
• 229940002612 prodrug Drugs 0.000 description 27
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 26
• 101150041968 CDC13 gene Proteins 0.000 description 26
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
• 239000011541 reaction mixture Substances 0.000 description 25
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
• 239000000741 silica gel Substances 0.000 description 23
• 229910002027 silica gel Inorganic materials 0.000 description 23
• 239000000126 substance Substances 0.000 description 23
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
• 230000002829 reductive effect Effects 0.000 description 22
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 20
• 150000001243 acetic acids Chemical class 0.000 description 20
• 125000000217 alkyl group Chemical group 0.000 description 20
• 239000000706 filtrate Substances 0.000 description 19
• 150000002148 esters Chemical class 0.000 description 17
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
• 239000003795 chemical substances by application Substances 0.000 description 16
• 238000004587 chromatography analysis Methods 0.000 description 16
• 239000002904 solvent Substances 0.000 description 16
• 239000002253 acid Substances 0.000 description 15
• 238000010511 deprotection reaction Methods 0.000 description 15
• BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 15
• AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 14
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
• 150000003254 radicals Chemical class 0.000 description 14
• 238000011282 treatment Methods 0.000 description 14
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 13
• 239000012230 colorless oil Substances 0.000 description 13
• 125000005843 halogen group Chemical group 0.000 description 13
• 235000017557 sodium bicarbonate Nutrition 0.000 description 13
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
• 125000003342 alkenyl group Chemical group 0.000 description 12
• 125000000304 alkynyl group Chemical group 0.000 description 12
• 230000008901 benefit Effects 0.000 description 12
• 239000003814 drug Substances 0.000 description 12
• 125000006239 protecting group Chemical group 0.000 description 12
• 238000003419 tautomerization reaction Methods 0.000 description 12
• KORIJXKQGMTQTO-UHFFFAOYSA-N 1h-pyrrol-2-ylmethanol Chemical compound OCC1=CC=CN1 KORIJXKQGMTQTO-UHFFFAOYSA-N 0.000 description 11
• 241001553178 Arachis glabrata Species 0.000 description 11
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 11
• 238000005516 engineering process Methods 0.000 description 11
• 229910000027 potassium carbonate Inorganic materials 0.000 description 11
• 239000012453 solvate Substances 0.000 description 11
• 208000024891 symptom Diseases 0.000 description 11
• 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 10
• 125000004122 cyclic group Chemical group 0.000 description 10
• 235000015320 potassium carbonate Nutrition 0.000 description 10
• 230000001225 therapeutic effect Effects 0.000 description 10
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
• 125000003545 alkoxy group Chemical group 0.000 description 9
• 125000004452 carbocyclyl group Chemical group 0.000 description 9
• 239000003153 chemical reaction reagent Substances 0.000 description 9
• 238000002360 preparation method Methods 0.000 description 9
• 150000001412 amines Chemical class 0.000 description 8
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 8
• 210000004027 cell Anatomy 0.000 description 8
• 238000004440 column chromatography Methods 0.000 description 8
• 239000002552 dosage form Substances 0.000 description 8
• 238000001727 in vivo Methods 0.000 description 8
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
• 210000001519 tissue Anatomy 0.000 description 8
• 230000009466 transformation Effects 0.000 description 8
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
• 101000966782 Homo sapiens Lysophosphatidic acid receptor 1 Proteins 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
• MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 7
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
• 235000019270 ammonium chloride Nutrition 0.000 description 7
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 7
• 235000019441 ethanol Nutrition 0.000 description 7
• 125000000524 functional group Chemical group 0.000 description 7
• 231100000252 nontoxic Toxicity 0.000 description 7
• 230000003000 nontoxic effect Effects 0.000 description 7
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 7
• 125000003367 polycyclic group Chemical group 0.000 description 7
• 239000011734 sodium Substances 0.000 description 7
• 229910052708 sodium Inorganic materials 0.000 description 7
• KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 6
• SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 6
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
• 229920000858 Cyclodextrin Polymers 0.000 description 6
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
• MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical group O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 6
• OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
• 238000006887 Ullmann reaction Methods 0.000 description 6
• 239000003054 catalyst Substances 0.000 description 6
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
• 208000035475 disorder Diseases 0.000 description 6
• 238000009472 formulation Methods 0.000 description 6
• 150000004677 hydrates Chemical class 0.000 description 6
• 239000005457 ice water Substances 0.000 description 6
• SUGXRJHYTSXVGY-LURJTMIESA-N methyl 2-[(3S)-5,5-difluoropiperidin-3-yl]acetate Chemical compound COC(C[C@@H](C1)CNCC1(F)F)=O SUGXRJHYTSXVGY-LURJTMIESA-N 0.000 description 6
• 230000000069 prophylactic effect Effects 0.000 description 6
• 238000010898 silica gel chromatography Methods 0.000 description 6
• HVDJHGCGCDVLEY-UHFFFAOYSA-N 5-cyclopropyl-4-methyl-1H-pyridin-2-one Chemical compound CC(C(C1CC1)=CN1)=CC1=O HVDJHGCGCDVLEY-UHFFFAOYSA-N 0.000 description 5
• 241000699670 Mus sp. Species 0.000 description 5
• 229910020667 PBr3 Inorganic materials 0.000 description 5
• 229910019142 PO4 Inorganic materials 0.000 description 5
• 239000013543 active substance Substances 0.000 description 5
• 239000002671 adjuvant Substances 0.000 description 5
• MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 5
• 150000007942 carboxylates Chemical class 0.000 description 5
• 239000000969 carrier Substances 0.000 description 5
• 229940079593 drug Drugs 0.000 description 5
• 238000010828 elution Methods 0.000 description 5
• 125000001188 haloalkyl group Chemical group 0.000 description 5
• 230000007062 hydrolysis Effects 0.000 description 5
• 238000006460 hydrolysis reaction Methods 0.000 description 5
• 125000004356 hydroxy functional group Chemical group O* 0.000 description 5
• 229910052740 iodine Inorganic materials 0.000 description 5
• 230000000670 limiting effect Effects 0.000 description 5
• 239000007788 liquid Substances 0.000 description 5
• 238000004519 manufacturing process Methods 0.000 description 5
• 239000002480 mineral oil Substances 0.000 description 5
• 235000010446 mineral oil Nutrition 0.000 description 5
• 125000002950 monocyclic group Chemical group 0.000 description 5
• IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 5
• 230000008569 process Effects 0.000 description 5
• 125000004076 pyridyl group Chemical group 0.000 description 5
• 239000000725 suspension Substances 0.000 description 5
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
• VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical compound N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 description 4
• YFTHTJAPODJVSL-UHFFFAOYSA-N 2-(1-benzothiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(SC=C2)C2=C1 YFTHTJAPODJVSL-UHFFFAOYSA-N 0.000 description 4
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