TWI723131B - 6‐雜環基‐4‐嗎啉‐4‐芳基吡啶‐2‐酮化合物 - Google Patents
6‐雜環基‐4‐嗎啉‐4‐芳基吡啶‐2‐酮化合物 Download PDFInfo
- Publication number
- TWI723131B TWI723131B TW106105178A TW106105178A TWI723131B TW I723131 B TWI723131 B TW I723131B TW 106105178 A TW106105178 A TW 106105178A TW 106105178 A TW106105178 A TW 106105178A TW I723131 B TWI723131 B TW I723131B
- Authority
- TW
- Taiwan
- Prior art keywords
- aryl
- pyridin
- 1hydro
- methylmorpholin
- compound according
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 209
- 238000011282 treatment Methods 0.000 claims abstract description 29
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 26
- 201000011510 cancer Diseases 0.000 claims abstract description 23
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 13
- 208000036142 Viral infection Diseases 0.000 claims abstract description 7
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 7
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 7
- 230000009385 viral infection Effects 0.000 claims abstract description 7
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 64
- -1 1-pyridinyl Chemical group 0.000 claims description 50
- 239000001257 hydrogen Substances 0.000 claims description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims description 49
- 238000002360 preparation method Methods 0.000 claims description 35
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 29
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 28
- 125000002950 monocyclic group Chemical group 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 23
- 229910052731 fluorine Inorganic materials 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 22
- 239000011737 fluorine Substances 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 20
- 239000000460 chlorine Substances 0.000 claims description 20
- 229910052801 chlorine Inorganic materials 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 15
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 8
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 8
- SFWWGMKXCYLZEG-RXMQYKEDSA-N (3r)-3-methylmorpholine Chemical compound C[C@@H]1COCCN1 SFWWGMKXCYLZEG-RXMQYKEDSA-N 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 102000004190 Enzymes Human genes 0.000 claims description 6
- 108090000790 Enzymes Proteins 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 6
- 208000032839 leukemia Diseases 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 201000001441 melanoma Diseases 0.000 claims description 6
- 230000004770 neurodegeneration Effects 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 208000022679 triple-negative breast carcinoma Diseases 0.000 claims description 6
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 5
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- VLJNHYLEOZPXFW-UHFFFAOYSA-N pyrrolidine-2-carboxamide Chemical compound NC(=O)C1CCCN1 VLJNHYLEOZPXFW-UHFFFAOYSA-N 0.000 claims description 3
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 102000014150 Interferons Human genes 0.000 claims description 2
- 108010050904 Interferons Proteins 0.000 claims description 2
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 239000003242 anti bacterial agent Substances 0.000 claims description 2
- 230000001093 anti-cancer Effects 0.000 claims description 2
- 230000000340 anti-metabolite Effects 0.000 claims description 2
- 229940088710 antibiotic agent Drugs 0.000 claims description 2
- 239000002256 antimetabolite Substances 0.000 claims description 2
- 229940100197 antimetabolite Drugs 0.000 claims description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 2
- 230000006806 disease prevention Effects 0.000 claims description 2
- 229940088597 hormone Drugs 0.000 claims description 2
- 239000005556 hormone Substances 0.000 claims description 2
- 239000003667 hormone antagonist Substances 0.000 claims description 2
- 229940047124 interferons Drugs 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 claims description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 claims description 2
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 10
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 5
- 125000004429 atom Chemical group 0.000 claims 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
- PUAQLLVFLMYYJJ-UHFFFAOYSA-N 2-aminopropiophenone Chemical compound CC(N)C(=O)C1=CC=CC=C1 PUAQLLVFLMYYJJ-UHFFFAOYSA-N 0.000 claims 1
- 125000006164 6-membered heteroaryl group Chemical group 0.000 claims 1
- 239000000367 immunologic factor Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 15
- 239000000203 mixture Substances 0.000 description 123
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
- 239000000047 product Substances 0.000 description 75
- 235000019439 ethyl acetate Nutrition 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000012267 brine Substances 0.000 description 26
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 26
- 238000004808 supercritical fluid chromatography Methods 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- KKDYXLUSGMODIB-SNVBAGLBSA-N (3R)-4-[2-chloro-6-[(2-methylpropan-2-yl)oxy]pyridin-4-yl]-3-methylmorpholine Chemical compound C(C)(C)(C)OC1=NC(=CC(=C1)N1[C@@H](COCC1)C)Cl KKDYXLUSGMODIB-SNVBAGLBSA-N 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 238000000926 separation method Methods 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 18
- 235000002639 sodium chloride Nutrition 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 17
- 239000011734 sodium Substances 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 15
- 101000605630 Homo sapiens Phosphatidylinositol 3-kinase catalytic subunit type 3 Proteins 0.000 description 15
- 102100038329 Phosphatidylinositol 3-kinase catalytic subunit type 3 Human genes 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 230000004900 autophagic degradation Effects 0.000 description 14
- 239000004480 active ingredient Substances 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 12
- 125000005843 halogen group Chemical group 0.000 description 12
- 125000000623 heterocyclic group Chemical group 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- 238000002953 preparative HPLC Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 239000010410 layer Substances 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 125000001153 fluoro group Chemical group F* 0.000 description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 235000011054 acetic acid Nutrition 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 150000002430 hydrocarbons Chemical group 0.000 description 7
- 239000008196 pharmacological composition Substances 0.000 description 7
- 229930195734 saturated hydrocarbon Natural products 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- 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 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 235000019253 formic acid Nutrition 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000007937 lozenge Substances 0.000 description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 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 6
- SFWWGMKXCYLZEG-UHFFFAOYSA-N 3-methylmorpholine Chemical compound CC1COCCN1 SFWWGMKXCYLZEG-UHFFFAOYSA-N 0.000 description 5
- KKDYXLUSGMODIB-UHFFFAOYSA-N 4-[2-chloro-6-[(2-methylpropan-2-yl)oxy]pyridin-4-yl]-3-methylmorpholine Chemical compound C(C)(C)(C)OC1=NC(=CC(=C1)N1C(COCC1)C)Cl KKDYXLUSGMODIB-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 125000002757 morpholinyl group Chemical group 0.000 description 5
- 125000002971 oxazolyl group Chemical group 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- QYADUJIEYPAYAV-UHFFFAOYSA-N 4-[2-chloro-6-[(2-methylpropan-2-yl)oxy]pyridin-4-yl]morpholine Chemical compound C(C)(C)(C)OC1=NC(=CC(=C1)N1CCOCC1)Cl QYADUJIEYPAYAV-UHFFFAOYSA-N 0.000 description 4
- 241000416162 Astragalus gummifer Species 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229920001615 Tragacanth Polymers 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000003973 alkyl amines Chemical class 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 150000003904 phospholipids Chemical class 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 235000010487 tragacanth Nutrition 0.000 description 4
- 239000000196 tragacanth Substances 0.000 description 4
- 229940116362 tragacanth Drugs 0.000 description 4
- 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 4
- BXZSBDDOYIWMGC-UHFFFAOYSA-N 5-fluoropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=CC(F)=C1 BXZSBDDOYIWMGC-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 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 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000007819 coupling partner Substances 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000005090 green fluorescent protein Substances 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000000465 moulding Methods 0.000 description 3
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 150000003905 phosphatidylinositols Chemical class 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000013557 residual solvent Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- SOHNHMPRMJKRJT-SSDOTTSWSA-N (3R)-4-(2,6-dichloropyridin-4-yl)-3-methylmorpholine Chemical compound ClC1=NC(=CC(=C1)N1[C@@H](COCC1)C)Cl SOHNHMPRMJKRJT-SSDOTTSWSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 2
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 2
- 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 2
- NGSKFMPSBUAUNE-UHFFFAOYSA-N 2,6-dichloro-4-iodopyridine Chemical compound ClC1=CC(I)=CC(Cl)=N1 NGSKFMPSBUAUNE-UHFFFAOYSA-N 0.000 description 2
- QGKFYRMABWIOIW-UHFFFAOYSA-N 2-(3-methoxyphenyl)pyrrolidine Chemical compound COC1=CC=CC(C2NCCC2)=C1 QGKFYRMABWIOIW-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- JUTDHSGANMHVIC-UHFFFAOYSA-N 2-phenylpyrrolidine Chemical compound C1CCNC1C1=CC=CC=C1 JUTDHSGANMHVIC-UHFFFAOYSA-N 0.000 description 2
- SOHNHMPRMJKRJT-UHFFFAOYSA-N 4-(2,6-dichloropyridin-4-yl)-3-methylmorpholine Chemical compound ClC1=NC(=CC(=C1)N1C(COCC1)C)Cl SOHNHMPRMJKRJT-UHFFFAOYSA-N 0.000 description 2
- AKXNTPCICNNILS-UHFFFAOYSA-N 4-(2,6-dichloropyridin-4-yl)morpholine Chemical compound ClC1=NC(Cl)=CC(N2CCOCC2)=C1 AKXNTPCICNNILS-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- ZHGNHOOVYPHPNJ-UHFFFAOYSA-N Amigdalin Chemical compound FC(F)(F)C(=O)OCC1OC(OCC2OC(OC(C#N)C3=CC=CC=C3)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C2OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C1OC(=O)C(F)(F)F ZHGNHOOVYPHPNJ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 2
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- 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 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000000654 additive Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- XDHNQDDQEHDUTM-JQWOJBOSSA-N bafilomycin A1 Chemical compound CO[C@H]1\C=C\C=C(C)\C[C@H](C)[C@H](O)[C@H](C)\C=C(/C)\C=C(OC)\C(=O)O[C@@H]1[C@@H](C)[C@@H](O)[C@H](C)[C@]1(O)O[C@H](C(C)C)[C@@H](C)[C@H](O)C1 XDHNQDDQEHDUTM-JQWOJBOSSA-N 0.000 description 2
- XDHNQDDQEHDUTM-ZGOPVUMHSA-N bafilomycin A1 Natural products CO[C@H]1C=CC=C(C)C[C@H](C)[C@H](O)[C@H](C)C=C(C)C=C(OC)C(=O)O[C@@H]1[C@@H](C)[C@@H](O)[C@H](C)[C@]1(O)O[C@H](C(C)C)[C@@H](C)[C@H](O)C1 XDHNQDDQEHDUTM-ZGOPVUMHSA-N 0.000 description 2
- XDHNQDDQEHDUTM-UHFFFAOYSA-N bafliomycin A1 Natural products COC1C=CC=C(C)CC(C)C(O)C(C)C=C(C)C=C(OC)C(=O)OC1C(C)C(O)C(C)C1(O)OC(C(C)C)C(C)C(O)C1 XDHNQDDQEHDUTM-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 159000000011 group IA salts Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 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 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 229960000448 lactic acid Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 229940124302 mTOR inhibitor Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 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 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 125000005429 oxyalkyl group Chemical group 0.000 description 2
- 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 2
- 238000007911 parenteral administration Methods 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 239000002691 unilamellar liposome Substances 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- VINAMCOZNJHNIH-SCSAIBSYSA-N (2r)-2-(trifluoromethyl)pyrrolidine Chemical compound FC(F)(F)[C@H]1CCCN1 VINAMCOZNJHNIH-SCSAIBSYSA-N 0.000 description 1
- WGIAUTGOUJDVEI-LLVKDONJSA-N (2r)-2-phenylpiperidine Chemical compound N1CCCC[C@@H]1C1=CC=CC=C1 WGIAUTGOUJDVEI-LLVKDONJSA-N 0.000 description 1
- JUTDHSGANMHVIC-SNVBAGLBSA-N (2r)-2-phenylpyrrolidine Chemical compound C1CCN[C@H]1C1=CC=CC=C1 JUTDHSGANMHVIC-SNVBAGLBSA-N 0.000 description 1
- VINAMCOZNJHNIH-BYPYZUCNSA-N (2s)-2-(trifluoromethyl)pyrrolidine Chemical compound FC(F)(F)[C@@H]1CCCN1 VINAMCOZNJHNIH-BYPYZUCNSA-N 0.000 description 1
- JUTDHSGANMHVIC-JTQLQIEISA-N (2s)-2-phenylpyrrolidine Chemical compound C1CCN[C@@H]1C1=CC=CC=C1 JUTDHSGANMHVIC-JTQLQIEISA-N 0.000 description 1
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- SZPQTEWIRPXBTC-KFOWTEFUSA-N 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'D-myo-inositol-3'-phosphate) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCC)COP(O)(=O)O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](OP(O)(O)=O)[C@H]1O SZPQTEWIRPXBTC-KFOWTEFUSA-N 0.000 description 1
- NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 description 1
- YHIIJNLSGULWAA-UHFFFAOYSA-N 1,4-thiazinane 1-oxide Chemical compound O=S1CCNCC1 YHIIJNLSGULWAA-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- VDQQJMHXZCMNMU-UHFFFAOYSA-N 1-phenylpyrrolidine Chemical compound C1CCCN1C1=CC=CC=C1 VDQQJMHXZCMNMU-UHFFFAOYSA-N 0.000 description 1
- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- NCXSNNVYILYEBC-UHFFFAOYSA-N 2-(2,5-difluorophenyl)pyrrolidine Chemical compound FC1=CC=C(F)C(C2NCCC2)=C1 NCXSNNVYILYEBC-UHFFFAOYSA-N 0.000 description 1
- ZPGUMFCNPREQSF-UHFFFAOYSA-N 2-(2-methoxypropan-2-yl)pyrrolidine Chemical compound COC(C)(C)C1CCCN1 ZPGUMFCNPREQSF-UHFFFAOYSA-N 0.000 description 1
- SRTPGDGQKPCDMC-UHFFFAOYSA-N 2-(3-chlorophenyl)pyrrolidine Chemical compound ClC1=CC=CC(C2NCCC2)=C1 SRTPGDGQKPCDMC-UHFFFAOYSA-N 0.000 description 1
- OADZVVBVXBBMPW-UHFFFAOYSA-N 2-(3-fluorophenyl)pyrrolidine Chemical compound FC1=CC=CC(C2NCCC2)=C1 OADZVVBVXBBMPW-UHFFFAOYSA-N 0.000 description 1
- AZAPNBMJUCBTIH-UHFFFAOYSA-N 2-(3-methoxyphenyl)-1h-pyrrole Chemical compound COC1=CC=CC(C=2NC=CC=2)=C1 AZAPNBMJUCBTIH-UHFFFAOYSA-N 0.000 description 1
- ZGWPCADYBFMCJT-UHFFFAOYSA-N 2-(3-methoxyphenyl)piperidine Chemical compound COC1=CC=CC(C2NCCCC2)=C1 ZGWPCADYBFMCJT-UHFFFAOYSA-N 0.000 description 1
- MGKPFALCNDRSQD-UHFFFAOYSA-N 2-(4-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(F)C=C1 MGKPFALCNDRSQD-UHFFFAOYSA-N 0.000 description 1
- LGGXPKQFJZIICN-UHFFFAOYSA-N 2-(5-Methyl-2-furanyl)pyrrolidine Chemical compound O1C(C)=CC=C1C1NCCC1 LGGXPKQFJZIICN-UHFFFAOYSA-N 0.000 description 1
- NAXDEFXCCITWEU-UHFFFAOYSA-N 2-(trifluoromethyl)piperidine Chemical compound FC(F)(F)C1CCCCN1 NAXDEFXCCITWEU-UHFFFAOYSA-N 0.000 description 1
- SDVTXUXMZFMOFC-UHFFFAOYSA-N 2-[3-(trifluoromethoxy)phenyl]pyrrolidine Chemical compound FC(F)(F)OC1=CC=CC(C2NCCC2)=C1 SDVTXUXMZFMOFC-UHFFFAOYSA-N 0.000 description 1
- JLVNEMRUEAMGSZ-UHFFFAOYSA-N 2-[3-(trifluoromethyl)phenyl]pyrrolidine Chemical compound FC(F)(F)C1=CC=CC(C2NCCC2)=C1 JLVNEMRUEAMGSZ-UHFFFAOYSA-N 0.000 description 1
- XXZCIYUJYUESMD-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-(morpholin-4-ylmethyl)pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)CN1CCOCC1 XXZCIYUJYUESMD-UHFFFAOYSA-N 0.000 description 1
- LPZOCVVDSHQFST-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-ethylpyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)CC LPZOCVVDSHQFST-UHFFFAOYSA-N 0.000 description 1
- FYELSNVLZVIGTI-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-5-ethylpyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1CC)CC(=O)N1CC2=C(CC1)NN=N2 FYELSNVLZVIGTI-UHFFFAOYSA-N 0.000 description 1
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 description 1
- KRDXTHSSNCTAGY-UHFFFAOYSA-N 2-cyclohexylpyrrolidine Chemical compound C1CCNC1C1CCCCC1 KRDXTHSSNCTAGY-UHFFFAOYSA-N 0.000 description 1
- XGBMQBPLWXTEPM-UHFFFAOYSA-N 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1CC1 XGBMQBPLWXTEPM-UHFFFAOYSA-N 0.000 description 1
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 1
- IAIVSLOVZSQJNL-UHFFFAOYSA-N 2-pyrrolidin-2-yl-1,3-thiazole hydrochloride Chemical compound Cl.C1CNC(C1)c1nccs1 IAIVSLOVZSQJNL-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QLADYDPROMQLCA-UHFFFAOYSA-N 3-(trifluoromethyl)morpholine Chemical compound FC(F)(F)C1COCCN1 QLADYDPROMQLCA-UHFFFAOYSA-N 0.000 description 1
- OHFRHIUJBMHGLQ-UHFFFAOYSA-N 3-(trifluoromethyl)morpholine;hydrochloride Chemical compound Cl.FC(F)(F)C1COCCN1 OHFRHIUJBMHGLQ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- KLFPQNHKRHERBF-UHFFFAOYSA-N 3-cyclopropylmorpholine Chemical compound C1CC1C1NCCOC1 KLFPQNHKRHERBF-UHFFFAOYSA-N 0.000 description 1
- MHZXKVPCJBPNKI-UHFFFAOYSA-N 3-phenylmorpholine Chemical compound N1CCOCC1C1=CC=CC=C1 MHZXKVPCJBPNKI-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- FHQRDEDZJIFJAL-UHFFFAOYSA-N 4-phenylmorpholine Chemical compound C1COCCN1C1=CC=CC=C1 FHQRDEDZJIFJAL-UHFFFAOYSA-N 0.000 description 1
- QJWGZYJFBDSKHF-UHFFFAOYSA-N 8-oxa-5-azaspiro[3.5]nonane Chemical compound C1CCC21NCCOC2 QJWGZYJFBDSKHF-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 239000012114 Alexa Fluor 647 Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- DBDLRVRXSMEMSM-UHFFFAOYSA-N CC(C)(C)P([C-]1C=CC=C1)C(C)(C)C.[CH-]1C=CC=C1.Cl.Cl.[Fe+2] Chemical compound CC(C)(C)P([C-]1C=CC=C1)C(C)(C)C.[CH-]1C=CC=C1.Cl.Cl.[Fe+2] DBDLRVRXSMEMSM-UHFFFAOYSA-N 0.000 description 1
- XOMBIBRABUIJDB-IKJXHCRLSA-N C[C@H](COCC1)N1C(C=C(N1)N(CCC2)C2c2cc(OC(F)(F)F)ccc2)=CC1=O Chemical compound C[C@H](COCC1)N1C(C=C(N1)N(CCC2)C2c2cc(OC(F)(F)F)ccc2)=CC1=O XOMBIBRABUIJDB-IKJXHCRLSA-N 0.000 description 1
- MMWHMZSFVVZXLL-UJONTBEJSA-N C[C@H](COCC1)N1c1cc(OC(C)(C)C)nc(N(CCC2)C2c2cc(F)ccc2F)c1 Chemical compound C[C@H](COCC1)N1c1cc(OC(C)(C)C)nc(N(CCC2)C2c2cc(F)ccc2F)c1 MMWHMZSFVVZXLL-UJONTBEJSA-N 0.000 description 1
- 101100190557 Caenorhabditis elegans vps-34 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000007493 Class III Phosphatidylinositol 3-Kinases Human genes 0.000 description 1
- 108010085715 Class III Phosphatidylinositol 3-Kinases Proteins 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 238000010867 Hoechst staining Methods 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000017343 Phosphatidylinositol kinases Human genes 0.000 description 1
- 108050005377 Phosphatidylinositol kinases Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 239000012391 XPhos Pd G2 Substances 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- UJQAHAANAPEYLR-UHFFFAOYSA-N [2-chloro-6-[2,4,6-tri(propan-2-yl)phenyl]phenyl]-dicyclohexylphosphane Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC(Cl)=C1P(C1CCCCC1)C1CCCCC1 UJQAHAANAPEYLR-UHFFFAOYSA-N 0.000 description 1
- 230000037374 absorbed through the skin Effects 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000007950 acidosis Effects 0.000 description 1
- 208000026545 acidosis disease Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000004908 autophagic flux Effects 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 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
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- DLIJPAHLBJIQHE-UHFFFAOYSA-N butylphosphane Chemical group CCCCP DLIJPAHLBJIQHE-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000009087 cell motility Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- RSLSVURFMXHEEU-UHFFFAOYSA-M chloropalladium(1+);dicyclohexyl-[3-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane;2-phenylaniline Chemical compound [Pd+]Cl.NC1=CC=CC=C1C1=CC=CC=[C-]1.CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC(P(C2CCCCC2)C2CCCCC2)=C1 RSLSVURFMXHEEU-UHFFFAOYSA-M 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000006184 cosolvent 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
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-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
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- LCSNDSFWVKMJCT-UHFFFAOYSA-N dicyclohexyl-(2-phenylphenyl)phosphane Chemical group C1CCCCC1P(C=1C(=CC=CC=1)C=1C=CC=CC=1)C1CCCCC1 LCSNDSFWVKMJCT-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- ZGSPNIOCEDOHGS-UHFFFAOYSA-L disodium [3-[2,3-di(octadeca-9,12-dienoyloxy)propoxy-oxidophosphoryl]oxy-2-hydroxypropyl] 2,3-di(octadeca-9,12-dienoyloxy)propyl phosphate Chemical compound [Na+].[Na+].CCCCCC=CCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COP([O-])(=O)OCC(O)COP([O-])(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COC(=O)CCCCCCCC=CCC=CCCCCC ZGSPNIOCEDOHGS-UHFFFAOYSA-L 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 230000028023 exocytosis Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- UPBDXRPQPOWRKR-UHFFFAOYSA-N furan-2,5-dione;methoxyethene Chemical compound COC=C.O=C1OC(=O)C=C1 UPBDXRPQPOWRKR-UHFFFAOYSA-N 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000002952 image-based readout Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000001071 malnutrition Effects 0.000 description 1
- 235000000824 malnutrition Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 230000034778 micropinocytosis Effects 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- REPVNSJSTLRQEQ-UHFFFAOYSA-N n,n-dimethylacetamide;n,n-dimethylformamide Chemical compound CN(C)C=O.CN(C)C(C)=O REPVNSJSTLRQEQ-UHFFFAOYSA-N 0.000 description 1
- ZUHZZVMEUAUWHY-UHFFFAOYSA-N n,n-dimethylpropan-1-amine Chemical compound CCCN(C)C ZUHZZVMEUAUWHY-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 238000012758 nuclear staining Methods 0.000 description 1
- 208000015380 nutritional deficiency disease Diseases 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 229930004090 phosphatidylinositide Natural products 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000005495 pyridazyl group Chemical group 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
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 108091008020 response regulators Proteins 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 230000037384 skin absorption Effects 0.000 description 1
- 231100000274 skin absorption Toxicity 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011255 standard chemotherapy Methods 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- WCGKHZHOGLVVPU-UHFFFAOYSA-N tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNC(C(F)(F)F)C1 WCGKHZHOGLVVPU-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical group CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- UJJLJRQIPMGXEZ-UHFFFAOYSA-N tetrahydro-2-furoic acid Chemical compound OC(=O)C1CCCO1 UJJLJRQIPMGXEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical group CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 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
- A61K31/535—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
- A61K31/435—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
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- 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
- 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
- A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
Description
本發明提供一種具有式(I)結構的新穎的6-雜環基-4-嗎啉-4-芳基-吡啶-2-酮化合物,含有這些化合物的藥理組成物,以及使用這些化合物治療包括癌症和糖尿病的疾病的方法。
屬於磷脂醯肌醇3激酶(phosphatidylinositide 3-kinases,簡稱PI3K)家族的酶是幾種重要細胞活動的調節劑。此家族包含I、II、III三類,其中第I類被視為有興趣的標靶藥物已有多年歷史,而對於第II、III類的開發與了解較少。PI3K第III類中的空泡分選蛋白34(vacuolar protein sorting 34,簡稱Vps34,以「Vps34,PIK3C3」表示)所形成的異質二聚體具有調節亞基p150(Vps 15),此二聚物於調節膜泡運輸作用佔有重要角色,如細胞自噬、內吞作用、胞吐作用、微胞飲作用(Amaravadi et al.Clin Cancer Res.2011,17:654-666;Carpentier et al.2013,Traffic)。上述激酶負責磷脂醯肌醇激酶(phosphatidylinositol,簡稱PI)轉為磷脂醯肌醇3單磷酸(phosphatidylinositol(3)-phosphate,簡稱PI3P)的磷化作用。PX與FYVE結構域間的配體結合,使這些效應蛋白(effector protein)產生募集與位移效應,因此形成囊泡、細胞延伸以及細胞運動(Backer et al.J Biochem.2008,410:1-17)。
細胞自噬是一種分解代謝,細胞組成被包在雙層膜囊泡中(自噬細胞與包含有蛋白酶的溶酶體融合)以使其分解。這是細胞處理受損胞器以及
錯誤折疊蛋白質的一種手段,藉以維持細胞功能。此路徑也是循環利用細胞物質以建立新的細胞構成(Boya et al.Nat Cell Biol 2013,15;713-720)。細胞自噬是在高壓情況下,如營養不良、酸中毒、低氧等,或是藥物治療時的一種細胞反應。因此,細胞自噬的抑制具有加強抗癌藥物以及恢復抗藥性腫瘤對藥物的敏感性之作用(Nagelkerke et al,Semin Cancer Biol 2014,31;99-105)。最晚期的癌細胞展現出高度的自噬潮(autophagic flux)表現量(Leone et al.Trends in EndocrinMetab 2013,24;209-217)。在自噬細胞上偵測到的脂化LC3蛋白自噬泡點狀圖形,是目前使用作為研究自噬潮的標記。測量LC3圖形的重新分布,得知抑制Vps34會造成細胞自噬被抑制(Dowdle et al.,Nat Cell Biol 2014,16;1069-79)。
依據近期的活體內研究(in vivo),調節亞基p150的移除會造成胰島素敏感性的上升,是由於胰島素接收器內部化的下降(Nemazanyy,Nature Commun.,2015,6:8283)。致活酶非活體異型合子動物模型以上升的葡萄糖耐受性,以及上升的胰島素敏感性,證實了上述結果(WO2013076501)。
幾種疾病狀態可受益於Vps34抑制作用,包含癌症、發炎性疾病、神經退化性疾病、心血管疾病、糖尿病、病毒性感染(Rubinsztein et al,Nat Rev 2014,11;709-730)。受惠於Vps34抑制作用的癌症包含但不限於:三陰乳腺癌、胰臟癌、白血病、黑色素瘤以及肺癌。因此,需要一種新穎且有效的Vps34抑制劑。
已知揭露關於Vps34抑制劑用於影響疾病的文獻包含WO2015150555、WO2015150557、WO2015108861、WO2015108881、WO2012085815、WO2012085244、WO2013190510、Farkas,J.Biol.Chem.,2011286(45)38904-12。
本發明的目的之一是提供一種新穎且有效的Vps34抑製劑。本發明的另一個目的是提供可用於治療癌症和其它疾病(如糖尿病)的新穎且有效的Vps34抑製劑。
依據本發明之一層面,提供一種如式(I)所示的化合物,
其中R1,R2和R3獨立地選自氫,C1-C3鹵代烷基和C1-C3烷基;A代表
其中,X代表CH2、S、SO、SO2、NR5、NCOR5、NCOR9、NCOCH2 R9、O或一個鍵;Y代表N、CH或C;n選自1、2、3和4;R4選自氫、鹵素、COR6、C1-C6烷基、C1-C3烷氧基C1-C3烷基、C1-C6烷氧基、C3-C6環烷基、C3-C6雜環基、C1-C3氰基烷基、C1-C3鹵代烷基、芳基和異芳基,二者可選擇性的被一個或多個R7取代;R5選自氫、C1-C3氟烷基、C1-C3烷基、C1-C3烷氧基C1-C3烷基和C3-C6環烷基;R6選自C1-C3烷氧基、N-C1-C3烷基氨基、N、N-二C1-C3烷基氨基、1-吡咯烷基、1-呱啶基和1-氮雜環丁烷基;R7選自C1-C6烷基、C3-C6環烷基、C1-C3烷氧基C1-C3烷基、C1-C3鹵代烷基、鹵素、N-C1-C3烷基氨基、N、N-二C1-C3烷基氨基、C1-C3鹵代烷氧基和C1-C3烷氧基;R9選自C1-C3烷基、C1-C3烷氧基、C3-C6環烷基、雜環基、苯基和單環異芳基,其中該雜環基、該苯基和該單環異芳基可選擇性地被一個或兩個R8取
代;R8選自鹵素、C1-C3鹵代烷基和C1-C3烷基;和其藥學上可接受的鹽,立體異構體和互變異構體。
於本發明上述層面的一實施例中,R4選自氫、鹵素、COR6、C1-C6烷基、C1-C3烷氧基C1-C3烷基、C1-C6烷氧基、C3-C6環烷基、C1-C3氰基烷基、C1-C3鹵代烷基、芳基和異芳基,且該異芳基可選擇性地被一個或多個R7取代。
於本發明上述層面的一實施例中,Y是N。
於本發明上述層面的一實施例中,R1和R3獨立地選自氫和甲基。
於本發明上述層面的一實施例中,R2是氫。
於本發明上述層面的一實施例中,R1是氫。
於本發明上述層面的一實施例中,R3是甲基。
於本發明上述層面的一實施例中,R3是氫。
於本發明上述層面的一實施例中,R5是C1-C3烷基。
於本發明上述層面的一實施例中,R6是N-C1-C3烷基氨基或N,N-二C1-C3烷基氨基,例如N,N-二C1-C3烷基氨基。
於本發明上述層面的一實施例中,R6是二甲基氨基。
於本發明上述層面的一實施例中,R7選自鹵素、C1-C3氟烷基、C1-C3氟烷氧基、C1-C3烷氧基、C1-C3烷基、C3-C6環烷基和N,N-二C1-C3烷基氨基。
於本發明上述層面的一實施例中,R7選自氟、氯、三氟甲基、三氟甲氧基、甲氧基、甲基、乙基、環丙基和二甲基氨基。
於本發明上述層面的一實施例中,R9選自C1-C3烷氧基、雜環基、苯基和單環異芳基,其中該雜環基、該苯基和該單環異芳基可選擇性地被一個或兩個R8取代。
於本發明上述層面的一實施例中,R9選自雜環基、苯基和單環異芳基,其中該雜環基、該苯基和該單環異芳基可選擇性地被一個或兩個R8取代。
於本發明上述層面的一實施例中,R9選自四氫呋喃基、苯基和吡啶基,各自可選擇性地被一個或兩個R8取代。
於本發明上述層面的一實施例中,R8是鹵素。
於本發明上述層面的一實施例中,R4中的該單環異芳基選自吡啶基、呋喃基、異噁唑基、吡唑基和噻唑基,各自可選擇性地被一個或多個R7取代。
於本發明上述層面的一實施例中,R7選自氟、氯、C1-C3烷氧基、C1-C3氟烷氧基、C1-C3氟烷基、C3-C6環烷基、N,N-二C1-C3烷基氨基。
於本發明上述層面的一實施例中,R7選自氟、氯、甲基、乙基、甲氧基、三氟甲氧基、三氟甲基、環丙基和N,N-二甲基氨基。
於本發明上述層面的一實施例中,X代表一個鍵。
於本發明上述層面的一實施例中,X代表CH2、SO、SO2、NR5、NCOR5、NCOR9、NCOCH2 R9或O;以及R5是C1-C3烷基。
於本發明上述層面的一實施例中,R4選自氫、C1-C6烷基、C3-C6環烷基、C1-C3鹵代烷基和苯基,其中苯基可選擇性地被一個或多個R7取代。
於本發明上述層面的一實施例中,X代表CH2、SO、SO2、NR5、NCOR5、NCOR9、NCOCH2 R9、O或一個鍵;R4選自氫、COR6、C1-C3烷基、甲氧基C1-C3烷基、C3-C6環烷基、C1-C3氟烷基、苯基和單環異芳基,其中該苯基和該單環異芳基可選擇性地被一個或兩個R7取代;R5是C1-C3烷基;R6是N,N-二C1-C3烷基氨基;且R7選自氟、氯、C1-C3烷基、C1-C3烷氧基、C1-C3氟烷氧基、C1-C3氟烷基、C3-C6環烷基和N,N-二C1-C3烷基氨基。
於本發明上述層面的一實施例中,Y是CH或C;X是O;且R4是氫。
於本發明上述層面的一實施例中,R1和R2是氫;R3是甲基;X選自CH2、O、NCOR5、NCOR9、NCOCH2 R9和鍵;Y是N;R4是氫、苯基或三氟甲基;R5是甲基;R7是甲氧基;R9選自吡啶基、苯基;且R8是氟。
於本發明上述層面的一實施例中,R1和R2是氫;R3是甲基;X選自CH2、O、NCOR5、NCOCH2 R9和鍵;Y是N;R4是苯基或三氟甲基,該苯基被一個或多個R7取代;R5是甲基;R7是甲氧基或鹵素,例如甲氧基或氯;
R9是苯基,該苯基可選擇性地地被一個或多個R8取代;且R8是鹵素,例如氟。
於本發明上述層面的一實施例中,R4是三氟甲基或苯基,該苯基被甲氧基或氯間位取代。
在一個實施方案中,根據本發明的化合物是HOS細胞中自噬的有效抑製劑,如實施例51所示。
於本發明上述層面的一實施例中,R7是甲氧基或氯;且R8是氟。
於本發明上述層面的一實施例中,R1和R2是氫;R3是甲基;X代表NCOR9或NCOCH2 R9;R4是三氟甲基或苯基,該苯基可選擇性地被甲氧基或氯取代;R9選自C1-C3烷基、C1-C3烷氧基、C3-C6環烷基、雜環基、苯基和單環異芳基,其中該雜環基、該苯基和該單環異芳基可選擇性地被一個或兩個R8取代;且R8選自氟、氯、C1-C3鹵代烷基和C1-C3烷基。
於本發明上述層面的一實施例中,R1和R2是氫;R3是甲基;X代表NCOR9或NCOCH2 R9;R4是三氟甲基;R9選自C1-C3烷基、C1-C3烷氧基、C3-C6環烷基、噁唑基、四氫呋喃基、嗎啉基、吡啶基和苯基;其中該噁唑基、該四氫呋喃基、該嗎啉基、該吡啶基和該苯基可選擇性地被一個或兩個R8取代;且R8選自氟、氯、C1-C3鹵代烷基和C1-C3烷基。
在一個實施方案中,根據本發明的化合物允許幾個可能的R9,因為該化合物的生物活性構象當與Vps34結合時,使得R9位於溶劑中,而不是位於結合口袋內部。
於本發明上述層面的一實施例中,X代表CH2、SO、SO2、NR5、NCOR5、NCOR9、NCOCH2 R9或O;R1和R3獨立地選自氫和甲基;R2是氫;R4選自
R5是C1-C3烷基;R7選自氟、氯、甲基、乙基、甲氧基、三氟甲氧基、三氟甲基、環丙基和N,N-二甲基氨基;R9選自四氫呋喃基、苯基和吡啶基,各自可選擇性地被一個或兩個R8取代;以及R8是鹵素。
於本發明上述層面的一實施例中,該化合物選自:4-嗎啉代-6-(2-苯基吡咯烷-1-芳基)-1氫-吡啶-2-酮;1-甲基-4-嗎啉代-6-(2-苯基吡咯烷-1-芳基)吡啶-2-酮;4-嗎啉代-6-[(2S)-2-苯基吡咯烷-1-芳基]-1氫-吡啶-2-酮;4-嗎啉代-6-[(2R)-2-苯基吡咯烷-1-芳基]-1氫-吡啶-2-酮;6-(3,6-二氫-2H-吡喃-4-芳基)-4-(3-甲基嗎啉-4-芳基)-1氫-吡啶-2-酮;4-(3-甲基嗎啉-4-芳基)-6-四氫吡喃-4-芳基-1氫-吡啶-2-酮;6-[2-(3-甲氧基苯基)吡咯烷-1-芳基]-4-(3-甲
基嗎啉-4-芳基)-1氫-吡啶-2-酮;4-(3-甲基嗎啉-4-芳基)-6-[2-(3-吡啶基)吡咯烷-1-芳基]-1氫-吡啶-2-酮;4-(3-甲基嗎啉-4-芳基)-6-(2-苯基吡咯烷-1-芳基)-1氫-吡啶-2-酮;N,N-二甲基-1-[4-[(3R)-3-甲基嗎啉-4-芳基]-6-氧代-1氫-吡啶-2-芳基]吡咯烷-2-甲醯胺;6-[2-(1-甲氧基-1-甲基-乙基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-(2-環己基吡咯烷-1-芳基)-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[2-(3-氟苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[2-(2,5-二氟苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-[3-(三氟甲氧基)苯基]吡咯烷-1-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-[3-(三氟甲基)苯基]吡咯烷-1-芳基]-1氫-吡啶-2-酮;6-[2-(3-甲氧基苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(2-苯基吡咯烷-1-芳基)-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-(1-甲基吡唑-4-芳基)吡咯烷-1-芳基]-1氫-吡啶-2-酮;6-[2-(1,5-二甲基吡唑-3-芳基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[2-(1-乙基吡唑-3-芳基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[2-(5-甲基-2-呋喃基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[2-[3-(二甲基氨基)苯基]吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(3-甲基嗎啉-4-芳基)-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-(三氟甲基)-1-呱啶基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(3-苯基嗎啉-4-芳基)-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(1-氧代-1,4-噻嗪烷-4-芳基)-1氫-吡啶-2-酮;6-(1,1-二氧代-1,4-噻嗪烷-4-芳基)-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-(4-乙醯基呱嗪-1-芳基)-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;
4-[(3R)-3-甲基嗎啉-4-芳基]-6-[(2R)-2-苯基-1-呱啶基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(4-甲基-2-苯基-呱嗪-1-芳基)-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[3-(三氟甲基)嗎啉-4-芳基]-1氫-吡啶-2-酮;6-(3-環丙基嗎啉-4-芳基)-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[(2S)-2-(三氟甲基)吡咯烷-1-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[(2R)-2-(三氟甲基)吡咯烷-1-芳基]-1氫-吡啶-2-酮;6-[2-(3-氯苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[2-(3-環丙基苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-(2-吡啶基)吡咯烷-1-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(2-噻唑-2-基吡咯烷-1-芳基)-1氫-吡啶-2-酮;6-[2-(5-甲基異噁唑-3-芳基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;1-甲基-4-[(3R)-3-甲基嗎啉-4-芳基]-6-[(2R)-2-(三氟甲基)-1-呱啶基]吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(8-氧雜-5-氮雜螺[3.5]壬烷-5-芳基)-1氫-吡啶-2-酮;6-[2-(3-甲氧基苯基)-1-呱啶基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[4-乙醯基-2-(三氟甲基)呱嗪-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[4-(5-氟吡啶-3-羰基)-2-(三氟甲基)呱嗪-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[4-[2-(4-氟苯基)乙酰基]-2-(三氟甲基)哌嗪-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[4-(四氫呋喃-2-羰基)-2-(三氟甲基)呱嗪-1-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[4-甲基-2-(三氟甲基)呱嗪-1-芳基]-1氫-吡啶-2-酮;和其藥學上可接受的鹽,互變異構體和立體異構體。
根據本發明之一層面,提供一種如式(I)所示的化合物,
其中R1、R2和R3獨立地選自氫、C1-C3鹵代烷基和C1-C3烷基;A代表
其中X代表CH2、S、SO、SO2、NR5、NCOR5、NCOR9、NCOCH2 R9、O或一個鍵(bond);Y代表N、CH或C;R4選自氫、鹵素、COR6、C1-C6烷基、C1-C3烷氧基C1-C3烷基、C1-C6烷氧基、C3-C6環烷基、C1-C3氰基烷基、C1-C3鹵代烷基、芳基和異芳基,或二環,並且可選擇性地被一個或多個R7取代;R5選自氫、C1-C3氟烷基、C1-C3烷基、C1-C3烷氧基C1-C3烷基和C3-C6環烷基;R6選自C1-C3烷氧基、N-C1-C3烷基氨基、N,N-二C1-C3烷基氨基、1-吡咯烷基、1-呱啶基和1-氮雜環丁烷基;R7選自C1-C6烷基、C3-C6環烷基、C1-C3烷氧基C1-C3烷基、C1-C3鹵代烷基、鹵素、N-C1-C3烷基氨基、N,N-二C1-C3烷基氨基、C1-C3鹵代烷氧基和C1-C3烷氧基;R9選自C1-C3烷基、C1-C3烷氧基、C3-C6環烷基、雜環基、苯基和單環異芳基,其中該雜環基、該苯基和該單環異芳基可選擇性地被一個或兩個R8取代;R8選自鹵素、C1-C3鹵代烷基和C1-C3烷基;和其藥學上可接受的鹽,立體異構體和互變異構體。
在A環中,“--”表示單鍵或雙鍵。當所述環中的Y為C(四價sp2雜化碳)時,該鍵為雙鍵。當所述環中的Y為N或CH時,該鍵為單鍵。
於本發明上述層面的一實施例中,R1和R2是氫;R3是甲基;X代表NCOR9或NCOCH2 R9;R4是三氟甲基;R9選自C1-C3烷基、C1-C3烷氧基、C3-C6環烷基、噁唑基、四氫呋喃基、嗎啉基、吡啶基和苯基;其中該噁唑基、該四氫呋喃基、該嗎啉基、該吡啶基和該苯基可選擇性地被一個或兩個R8取代;且R8選自氟、氯、C1-C3鹵代烷基和C1-C3烷基。
在一個實施方案中,根據本發明的化合物允許幾個可能的R9,因為該化合物的生物活性構象當與vps34結合時,使得R9位於溶劑中,而不是位於結合口袋內部。
於本發明上述層面的一實施例中,R9選自甲基、甲氧基、環丁基、2-甲基-1,3-噁唑-4-芳基、2-四氫呋喃基、4-嗎啉基、3-吡啶基、3-氟-5-吡啶基。
於本發明上述層面的一實施例中,Y是N。
於本發明上述層面的一實施例中,R1和R3獨立地選自氫和甲基。
於本發明上述層面的一實施例中,R2是氫。
於本發明上述層面的一實施例中,R1是氫。
於本發明上述層面的一實施例中,R1是甲基。
於本發明上述層面的一實施例中,R3是甲基。
於本發明上述層面的一實施例中,R3是氫。
於本發明上述層面的一實施例中,X代表CH2、SO、SO2、NR5、NCOR5、O或一個鍵;R4選自氫、COR6、C1-C3烷基、甲氧基C1-C3烷基、C3-C6環烷基、C1-C3氟烷基、苯基和單環異芳基,其中該苯基和該單環異芳基可選擇性地被一個或兩個R7取代;R5是C1-C3烷基;R6是N,N-二C1-C3烷基氨基;以及R7選自氟、氯、C1-C3烷氧基、C1-C3氟烷氧基、C1-C3氟烷基、C3-C6環烷基、N,N-二C1-C3烷基氨基。
於本發明上述層面的一實施例中,R4中的該單環異芳基選自吡啶基、呋喃基、異噁唑基、吡唑基和噻唑基。
於本發明上述層面的一實施例中,R4選自
其中R6是二甲基氨基;以及R7選自氟、氯、三氟甲基、三氟甲氧基、甲氧基、甲基、乙基、環丙基和二甲基氨基。於本發明上述層面的一實施例中,X代表一個鍵。於本發明上述層面的一實施例中,A代表:
於本發明上述層面的一實施例中,X代表CH2、SO、SO2、NR5、NCOR5或O;以及R5是C1-C3烷基。
於本發明上述層面的一實施例中,Y是CH或C;X是O;以及R4是氫。
於本發明上述層面的一實施例中R1和R2是氫;R3是甲基;X選自CH2、O和鍵;Y是N;R4是苯基或三氟甲基;以及R7選自甲氧基、三氟甲基、氯和環丙基。
於本發明上述層面的一實施例中,提供一種選自以下的化合物:4-嗎啉代-6-(2-苯基吡咯烷-1-芳基)-1氫-吡啶-2-酮;1-甲基-4-嗎啉代-6-(2-苯基吡咯烷-1-芳基)吡啶-2-酮;4-嗎啉代-6-[(2S)-2-苯基吡咯烷-1-芳基]-1氫-吡啶-2-酮;4-嗎啉代-6-[(2R)-2-苯基吡咯烷-1-芳基]-1氫-吡啶-2-酮;6-(3,6-二氫-2H-吡喃-4-芳基)-4-(3-甲基嗎啉-4-芳基)-1氫-吡啶-2-酮;4-(3-甲基嗎啉-4-芳基)-6-四氫吡喃-4-芳基-1氫-吡啶-2-酮;6-[2-(3-甲氧基苯基)吡咯烷-1-芳基]-4-(3-甲基嗎啉-4-芳基)-1氫-吡啶-2-酮;4-(3-甲基嗎啉-4-芳基)-6-[2-(3-吡啶基)吡咯烷-1-芳基]-1氫-吡啶-2-酮;4-(3-甲基嗎啉-4-芳基)-6-(2-
苯基吡咯烷-1-芳基)-1氫-吡啶-2-酮;N,N-二甲基-1-[4-[(3R)-3-甲基嗎啉-4-芳基]-6-氧代-1氫-吡啶-2-芳基]吡咯烷-2-甲醯胺;6-[2-(1-甲氧基-1-甲基-乙基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-(2-環己基吡咯烷-1-芳基)-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[2-(3-氟苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[2-(2,5-二氟苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-[3-(三氟甲氧基)苯基]吡咯烷-1-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-[3-(三氟甲基)苯基]吡咯烷-1-芳基]-1氫-吡啶-2-酮;6-[2-(3-甲氧基苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(2-苯基吡咯烷-1-芳基)-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-(1-甲基吡唑-4-芳基)吡咯烷-1-芳基]-1氫-吡啶-2-酮;6-[2-(1,5-二甲基吡唑-3-芳基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[2-(1-乙基吡唑-3-芳基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[2-(5-甲基-2-呋喃基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[2-[3-(二甲基氨基)苯基]吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(3-甲基嗎啉-4-芳基)-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-(三氟甲基)-1-呱啶基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(3-苯基嗎啉-4-芳基)-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(1-氧代-1,4-噻嗪烷-4-芳基)-1氫-吡啶-2-酮;6-(1,1-二氧代-1,4-噻嗪烷-4-芳基)-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-(4-乙醯基呱嗪-1-芳基)-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[(2R)-2-苯基-1-呱啶基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(4-甲基-2-苯基-呱嗪-1-芳基)-1氫-吡啶-2-酮;4-[(3R)-3-甲
基嗎啉-4-芳基]-6-[3-(三氟甲基)嗎啉-4-芳基]-1氫-吡啶-2-酮;6-(3-環丙基嗎啉-4-芳基)-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[(2S)-2-(三氟甲基)吡咯烷-1-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[(2R)-2-(三氟甲基)吡咯烷-1-芳基]-1氫-吡啶-2-酮;6-[2-(3-氯苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[2-(3-環丙基苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-(2-吡啶基)吡咯烷-1-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(2-噻唑-2-基吡咯烷-1-芳基)-1氫-吡啶-2-酮;6-[2-(5-甲基異噁唑-3-芳基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;1-甲基-4-[(3R)-3-甲基嗎啉-4-芳基]-6-[(2R)-2-(三氟甲基)-1-呱啶基]吡啶-2-酮;和其藥學上可接受的鹽,互變異構體和立體異構體。
依據本發明之一層面,提供一種根據本發明的化合物,其用於治療或預防疾病。
依據本發明之一層面,提供一種根據本發明的化合物,其用於治療癌症。通常,該癌症選自乳腺癌,例如三陰性乳腺癌、胰腺癌、白血病、黑素瘤和肺癌。
依據本發明之一層面,提供一種根據本發明的化合物,其用於治療糖尿病。通常,該糖尿病是II型糖尿病。
依據本發明之一層面,提供一種根據本發明的化合物,其用於治療選自發炎性疾病、神經退化性疾病、心血管疾病和病毒感染的疾病。
依據本發明之一層面,提供一種根據本發明的化合物在製備用於治療癌症的藥物中的用途。通常該癌症選自乳腺癌,例如三陰性乳腺癌、胰腺癌、白血病、黑素瘤和肺癌。
依據本發明之一層面,提供一種根據本發明的化合物在製備用於治療糖尿病的藥物中的用途。通常,該糖尿病是II型糖尿病。
依據本發明之一層面,提供一種根據本發明的化合物在製備用於治療選自發炎性疾病、神經退化性疾病、心血管疾病和病毒感染的疾病的藥物中的用途。
依據本發明之一層面,提供一種治療癌症的方法,包括了向有需要的患者施用治療有效量的根據本發明的化合物。通常,該癌症選自乳腺癌,例如三陰性乳腺癌、胰腺癌、白血病、黑素瘤和肺癌。
依據本發明之一層面,提供一種根據本發明的化合物,其用於治療癌症,其中該癌症治療進一步包括放射治療。
依據本發明之一層面,提供一種一種治療癌症的方法,包括給予有需要的患者治療有效量的根據本發明的化合物,連同放射治療。
本發明的化合物還可以用於與放射治療和/或外科手術聯合的癌症治療。一般來說,細胞毒性劑和/或細胞生長抑製劑與本發明的化合物或組合物的組合用於:(1)相較服用單獨使用單一試劑(agent),對於抑制腫瘤生長更或移除腫瘤能達到較佳的效果;(2)提供較少量的化療試劑的服用;(3)提供一種化療療法,相較於觀察到的單一化療試劑以及特定的其他組合療法,能減少有害的藥理併發症,提高病患的接受度;(4)為病發於哺乳類(尤其是人類)的各類型癌症,提供一種更為寬廣的治療方法與視野;(5)在使用的病患身上能具有良好的回應率(higher response rate among treated patients);
(6)相較於習知的標準化療方法,可以提供使用病患較長的存活時間;(7)拉長腫瘤生長的時間(longer time for tumor progression);以及/或(8)相較於其他會導致抗藥性的試劑組合的習知範例,其功效以及患者可承受度至少不輸於試劑單獨使用時的功效與患者可承受度。
依據本發明之一層面,提供一種治療糖尿病的方法,包含給予病人服用治療有效量的本發明上述化合物。一般來說,所述糖尿病為第II型糖尿病。
依據本發明之一層面,提供一種治療選自發炎性疾病、神經退化性疾病和病毒性感染的疾病的方法,包含給予病人服用治療有效量的本發明上述化合物。
依據本發明之一層面,提供一種藥理組成物,包含根據本發明的化合物和藥學上可接受的稀釋劑,載體和/或賦形劑。
依據本發明之一層面,提供一種藥理組成物,其包含治療有效量的根據本發明上述化合物和選自烷基化劑(alkylating agents)、抗代謝劑、抗癌喜樹鹼衍生物(anticancer camptothecin derivatives)、植物源抗癌試劑(plant-derived anticancer agents)、抗生素、酵素、鉑配位化合物、酪胺酸激酶抑制劑、賀爾蒙、激素拮抗劑、單克隆抗體、干擾素和生物反應調節劑。
在本文中,「C1-C6烷基」是指具有1~6個碳原子的直線或分枝鏈狀飽和烴基團。C1-C6烷基的實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、二級丁基、三級丁基、正戊基、4-甲基丁基、正己基、2-乙基丁基。在不分枝的C1-C6烷基中,典型的是甲基、乙基、正丙基、正丁基、正戊基和正己基。上述提及的分枝的烷基團包含異丙基、異丁基、二級丁基、三級丁基、4-甲基-丁基和2-乙基-丁基。
在本文中,「C1-C3烷基」是指具有1~3個碳原子的直線或分枝鏈狀飽和烴基團。C1-C3烷基的實例包括甲基、乙基、正丙基和異丙基。
在本文中,「C1-C6烷氧基」是指基團氧-烷基(O-alkyl),其中「C1-C6烷基」如上敘述。C1-C6烷氧基的實例包括但不限於甲氧基、乙氧基、異丙氧基、正丙氧基、正丁氧基、正己氧基、3-甲基-丁氧基。
在本文中,「C1-C3烷氧基」是指基團氧-烷基(O-alkyl),其中「C1-C3烷基」如上敘述。C1-C3烷氧基的實例包括但不限於甲氧基、乙氧基、異丙氧基和正丙氧基。
在本文中,「C1-C6鹵代烷基」是指具有1~6個碳原子以及至少一個或全部的氫被一種或多種鹵素取代的直線或分枝鏈狀飽和烴基團。C1-C6鹵代烷基的實例包括被1~3個鹵素原子取代的甲基、被1~5個鹵素原子取代的乙基、被1~7個鹵素原子取代的正丙基或異丙基、被1~9個鹵素原子取代的正丁基或異丁基、以及被1~9個鹵素原子取代的二級丁基或三級丁基。
在本文中,「C1-C3鹵代烷基」是指具有1~3個碳原子以及至少一個或全部的氫被一種或多種鹵素取代的直線或分枝鏈狀飽和烴基團。C1-C3鹵代烷基的實例包括被1~3個鹵素原子取代的甲基、被1~5個鹵素原子取代的乙基,以及被1~7個鹵素原子取代的正丙基或異丙基。
在本文中,「C1-C3鹵代烷氧基」是指具有1至3個碳原子和1至所有氫原子被不同或相同類型的滷素原子取代的直線或分枝鏈狀飽和烷氧基。C1-C3鹵代烷氧基的實例包括被1~3個鹵素原子取代的甲氧基,被1~5個鹵素原子取代的乙氧基和被1~7個鹵素原子取代的正丙氧基或異丙氧基。
在本文中,「C1-C3氟烷基」是指具有1~3個碳原子以及至少一個氫被氟原子取代的直線或分枝鏈狀飽和烴基團。C1-C3氟烷基的實例包括
包含被1~3個氟原子取代的甲基、被1~5個氟原子取代的乙基,以及被1~7個氟原子取代的正丙基或異丙基。
在本文中,「C1-C3氟烷氧基」是指直線或分枝鏈狀飽和烷氧基團,具有1~3個碳原子和至少一個或全部的氫原子被氟原子取代。C1-C3氟烷氧基的實例包括被1~3個氟原子取代的甲氧基,被1~5個氟原子取代的乙氧基和被1~7個氟原子取代的正丙氧基或異丙氧基。
在本文中,「C3-C6環烷基」是指具有3~6個碳原子的環狀飽和烴基。C3-C6環烷基的實例包括環丙基、環丁基、環戊基和環己基。
在本文中,「鹵素」是指氟,氯,溴或碘。
在本文中,「芳基」(aryl)是指單環或二環芳族碳環基團。芳基的實例包括苯基和萘基。萘基可以為第一或第二位置連接。在二環芳基中,一個環可以是部分飽和的。這種基團的實例包括二氫化節基(indanyl)和四氫萘基(tetrahydronaphthyl)。
在本文中,「單環芳基」是指單環芳族碳環基團。單環芳基的實例包括苯基。
在本文中,「異芳基」是指碳原子的單環或二環芳族基團,其中一至三個碳原子被一個或多個獨立地選自氮,氧或硫的雜原子替代。在二環芳基中,一個環可以是部分飽和的。這種基團的實例包括二氫吲哚基、二氫苯並呋喃基和1,3-苯並間二氧雜環戊烯基(1,3-benzodioxolyl)。
在本文中,「單環異芳基」是指碳原子的單環芳基,其中1~3個碳原子獨立地被一個或多個選自氮、氧或硫的雜原子替代。
單環異芳基的實例包括但不限於呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、惡二唑基、噻二唑基、吡啶基、三唑基、三嗪基、噠嗪基(pyridazyl)、異噻唑基、異噁唑基、吡嗪基、吡唑基和嘧啶基。
二環異芳基的實例包括但不限於喹喔啉基(quinoxalinyl)、喹唑啉基、吡啶並吡嗪基(pyridopyrazinyl)、苯並噁唑基(benzoxazolyl)、苯並噻吩基(benzothiophenyl)、苯並咪唑基、萘啶基、喹啉基、苯並呋喃基、吲哚基、吲唑基、苯並噻唑基、吡啶並嘧啶基和異喹啉基。
在本文中,「雜環基」是指碳原子的環狀基團,其中1~3個碳原子被一個或多個獨立地選自氮、氧和硫的雜原子替代。雜環基的實例包括但不限於四氫呋喃基、四氫吡喃基、吡咯烷基、呱啶基、呱嗪基、嗎啉基和二噁烷基。
依據不同取代基,式(I)所示化合物可以為鹽類,但同樣落在本發明的範圍內。適於使用於藥物治療的式(I)化合物的鹽類,其平衡離子(counterion)是藥學上可接受的。
依據本發明所述,適合的鹽類包含該些形成有有機或無機酸或鹼性的鹽類。具體而言,依據本發明所述,適合的酸性鹽類,包含形成有無機酸、強有機羧酸,例如被取代(例如被鹵素取代)或未被取代的1~4碳鏈烷羧酸、例如飽和或未飽和二羧酸、例如羥基羧酸、例如氨基酸,或是有有
機磺酸(organic sulfonic acids),例如被取代(例如被鹵素取代)或未被取代的(C1-C4)烷基或芳基磺酸(aryl sulfonic acids)。藥學上可接受的酸加成鹽包括由鹽酸、氫溴酸、硫酸、硝酸、檸檬酸、酒石酸、乙酸、磷酸、乳酸、丙酮酸、乙酸、三氟乙酸、琥珀酸、高氯酸、富馬酸、馬來酸、乙醇酸、乳酸、水楊酸、草醯乙酸、甲磺酸、乙磺酸、對甲苯磺酸、甲酸、苯甲酸、丙二酸、萘-2-磺酸、苯磺酸、羥乙磺酸、抗壞血酸、蘋果酸、鄰苯二甲酸、天冬氨酸和谷氨酸、賴氨酸和精氨酸。
藥學上可接受的鹼性鹽類包含銨鹽類、鹼金屬鹽類,例如鉀和鈉鹽類,鹼土金屬鹽類,例如鈣和鎂鹽類,以及有機鹼性鹽類,例如二環乙胺、N-甲基-D-還原葡萄糖胺(N-methyl-D-glucamine)、嗎啉、硫代嗎啉、哌啶、吡咯、單或二或三低碳數烷基胺(a mono,di- or tri lower alkylamine)(例如乙基、三級丁基、二乙基、二異丙基、三乙基、三丁基或二甲基丙胺),或是單或二或三羧基低碳數烷基胺(mono-,di- or trihydroxyloweralkylamine)(例如單、二或三乙醇胺)。相對應的內鹽(internal salts)可以進一步形成。
本發明的上述化合物可以用於預防及/或治療本身,或是用於藥理組成物中。有效成分可以被單獨服用,並且也可以存在於藥理組成物中。因此,本發明提供一種包含式(I)所示化合物的藥理組成物,以及其化藥學上可接受的稀釋劑、載體和/或賦形劑。本發明的藥理組成物可以以如下所述藥劑配方的形式表現。
用於口服給藥的示例性組合物包括可以含有例如用於賦予體積的微晶纖維素,作為懸浮劑的海藻酸或海藻酸鈉,作為粘度增強劑的甲基纖維素和本領域已知的甜味劑或調味劑的懸浮液;和可以含有例如微晶纖維素、磷酸二鈣、澱粉、硬脂酸鎂、硫酸鈣、山梨醇、葡萄糖和/或乳糖和/
或其它賦形劑、粘合劑、增量劑、崩解劑、稀釋劑和潤滑劑在本領域中是已知的。合適的粘合劑包括澱粉、明膠、天然糖如葡萄糖或β-乳糖、玉米甜味劑、天然和合成樹膠如阿拉伯膠、黃蓍膠或海藻酸鈉、羧甲基纖維素、聚乙二醇、蠟等。崩解劑包括但不限於澱粉、甲基纖維素、瓊脂、膨潤土、黃原膠等。如式(I)所示化合物也可以通過舌下和/或口腔施用通過口腔遞送。模製片、壓縮片或凍乾片是可以使用的示例性形式。示例性組合物包括用快速溶解稀釋劑如甘露醇、乳糖、蔗糖和/或環糊精配製本發明化合物的那些。還包括在這樣的組合物中的可以是高分子量賦形劑,例如纖維素(avicel)或聚乙二醇(PEG)。這種組合物還可以包括輔助粘膜粘附的賦形劑,例如羥丙基纖維素(HPC)、羥丙基甲基纖維素(HPMC)、羧甲基纖維素鈉(SCMC)、馬來酸酐共聚物(例如Gantrez)例如聚丙烯酸共聚物(例如Carbopol 934)。還可以加入潤滑劑、助流劑、矯味劑、著色劑和穩定劑以便於製造和使用。在這些劑型中使用的潤滑劑包括油酸鈉、硬脂酸鈉、硬脂酸鎂、苯甲酸鈉、乙酸鈉、氯化鈉等。對於液體形式的口服給藥、口服藥物組分可以與任何口服的、無毒的、藥學上可接受的惰性載體如乙醇、甘油、水等組合。
本發明的組合物適於口服給藥,且可以以分立的單元呈現,例如膠囊、藥包、藥丸或藥錠,每個都包含定量的有效成分/活性成分;可以是藥粉或顆粒;可以是含水或不含水的溶液或懸浮液,如酮劑(elixirs)、酊劑(tinctures)、懸浮劑或糖漿;可以是液態油水乳(oil-in-water liquid emulsion)或液態水油乳(water-in-oil liquid emulsion)。上述活性成分也可以以大丸藥(bolus)、舐劑或膏劑。
錠劑可以經由壓制或模製的方式製作,選擇性包含一或多個副成分。壓制錠劑可以經由將有效成分(或稱主成分),以散粒形式如粉狀或粒狀
壓縮於適合的機器中,並且選擇性與黏合劑、潤滑劑、惰性稀釋劑、用以潤滑或表面活性或離散的介質混合。模製定劑將惰性液態稀釋劑與粉狀化合物的混合於適合的機器中進行模塑。可以選擇性對錠劑進行封塗(coated)或是刻印,並且錠劑可以選擇性被調配成緩慢釋放或是控制釋放(長效)所包含的有效成分。本發明的化合物例如可以以一個適合的立即被釋放或是長效釋放的形式被服用。可以經由選用適合的包含本發明化合物的藥物組合物,配合使用設備例如皮下植入物或滲透泵,來達到立即釋放或長效釋放的效果,尤其是長效釋放。本發明的化合物可以藉由脂質體來服用(be administered liposomally)。
本文中以下或是對應部分中,「典型的單位劑量組成分」(typical unit dosage compositions)是為該些有效成分包含的有效劑量。
可以理解的,除了上述提及的配方,本發明的組合物可以包含其他本領域於特定形式的藥劑中通常使用的介質(agents),例如上述適合口服的藥劑可能包含調味劑(flavoring agents)。
上述組合物可以以單位劑量的方式提供,並且可以以任何藥學領域習知之方法製備。方法可以包含將有效成分混入包含一或多種副成分(或稱輔助成分)的載體中。組合物可以經由一致地或均勻地混合有效成分與液態載體或是良好切分的固態載體或是兩者來製備,之後依需要將產品塑形成想要的劑型。
本發明的化合物也可以使用脂質體(或稱微脂體或微脂粒)給藥系統(liposome delivery systems)來進行服用,例如單層小囊泡、單層大囊泡和多層囊泡。脂質體可以由不同種的磷脂質、1,2-二棕櫚醯磷脂醯膽鹼(1,2-dipalmitoylphosphatidylcholine)、磷脂醯乙醇胺(腦磷脂)、磷脂絲胺酸、磷脂醯肌醇、雙磷脂醯甘油(心磷脂)、磷脂醯膽鹼(卵磷脂)形成。
用以腸胃外給藥的組成物包括含水或不含水的無菌注射液,無菌懸浮液可以包含抗氧化劑、緩衝劑、抑菌劑,和溶質,溶質使藥劑能與接受者血液的等滲透;以及含水或不含水無菌懸浮液,無菌懸浮液可以包含懸浮劑和稠化劑(thickening agents)。組合物可以呈現於單位劑量或多劑量容器中,例如密封的安瓶和試劑瓶(vials),以及可以以凍乾方式(lyophilized)保存,僅需於使用前額外添加無菌液態載體,例如注射用鹽或注射用水。及時注射液(extemporaneous injection solutions)和懸浮液可以經由無菌粉末、顆粒、錠劑等前述之類型來製備。腸胃外給藥的典型組成物包含注射液或懸浮劑,舉例癌來說,包含無毒性、胃腸外可接受的稀釋劑或溶劑,例如聚乙二醇、乙醇、1,3-丁二醇、水、林格氏溶液(Ringer’s solution)、生理食鹽水(或稱等滲氯化鈉溶液)或其他適合的分散劑、濕潤(wetting)劑和懸浮劑,包含合成的單酸甘油酯或二酸甘油酯,以及脂肪酸,包含油酸或聚氧乙烯蓖麻油(Cremaphor)。
用以鼻腔給藥、氣霧劑給藥或吸入給藥的典型組合物包含,鹽水溶液(solutions in saline),其可以包含,舉例來說,苯甲醇或其他適合的防腐劑、吸收促進劑(absorption promoters)以提升生物可用率(bioavailability),和/或其他本領域已知的助溶劑或分散劑。
用以直腸給藥的組成物可以以塞劑(suppository)配合一般載體如可可油、合成甘油酯或聚乙二醇的方式呈現。上述載體一般來說在常溫下為固態,但其會液化並/或溶解於直腸腔室中,以釋放藥物。
用以使用於口中的局部給藥的組成物,例如頰給藥或舌下給藥,包括含片,含片包含調味的上述有效成分,例如蔗糖和阿拉伯樹膠(acacia)或黃蓍膠(tragacanth);和糖果錠劑,糖果錠劑在具有明膠(gelatin)和甘油或蔗糖和黃蓍膠的基礎上,包含上述有效成分。用以局部給藥的典型組成物
包括局部載體(topical carrier)如樹脂基質(Plastibase)(礦物油與聚乙烯膠化)(mineral oil gelled with polyethylene)。
式(I)所示化合物可以做為藥劑被單獨服用,或是與其他一或多個添加治療劑搭配使用,並且搭配使用不會產生無法接受的不良反應。此藥劑組合物包括單一藥物劑量配方的施用,配方包含式(I)所示化合物,以及一或多個添加的治療劑,也包括式(I)所示化合物和每一具有不同藥物劑型的添加治療劑的施用。例如式(I)所示的化合物和治療劑,可以於單一口服劑量組合物中一起被病人服用,例如膠囊或錠片,或每一藥劑可以以分開的劑量配方/劑量劑型的方式被服用。
當使用分開的劑量組合物,式(I)所示化合物和一或多個添加治療劑基本上可以同時(例如在同一時段中(concurrently)),或是於錯列分開的時段中(如依序(sequentially))被服用。
需要達到治療作用的有效成分的量,理所當然地,會依據不同化合物、服用途徑、治療標的而有所不同,例如治療標的的類型(type)、物種(species)、年齡、體重、性別和體況(medical condition)、腎和肝功能、是否具有治療中的其他特殊疾病(disorder or disease)以及疾病的嚴重性等。本領域具有通常知識的內科醫師、獸醫師或臨床醫師可以容易地判斷所需的藥物有效量並開設處方,以預防、克服或減緩病況。
為了能達到指示功效(indicated effects),以一個成人來說,本發明的口服劑量介於0.01毫克(mg)每公斤(kg)體重每天(mg/kg/day)~大約100mg/kg/day,較佳為0.01毫克(mg)每公斤(kg)體重每天(mg/kg/day)~10mg/kg/day,且更佳0.1~5.0mg/kg/day。以口服給藥來說,組合物的型式可以是具有離散單位(discrete units)型式的錠劑或其他劑型,離散單位包含0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、100和500
毫克的有效成分,以依據被治療病人的症狀調整劑量。藥劑一般包含約0.01mg至約500mg的有效成分,較佳約1mg至約100mg的有效成分。以靜脈注射來說,較佳劑量介於約0.1~約10mg/kg/分鐘的穩定輸注速率。本發明的化合物可以每日服用一次,或是將每日劑量分為二、三或四次服用,再者,本發明的化合物可以鼻內方式,經由使用局部的適合的鼻內運輸,或經由皮膚吸收的途徑,本領域具同常知識者可利用已知的經皮膚吸收的敷料。為了經由透皮給藥系統來進行施用,在給藥的過程中,劑量的施用為持續性的而非間歇性的。
實例
下面是本發明的許多非限制性實施例。
下表列出了本節中使用的縮寫。
化合物的製備
下面描述的方案1和2說明瞭本發明如式(I)所示化合物的一般合成路徑,但並非用以限制本發明。本發明中的化合物可以製備為遊離鹼(free base)或其藥學上可接受的鹽。經由以下對於流程的說明可以理解,可以加入適合的、相配的保護基,並且於後續步驟中,通過有機合成領域中技術人員習知或可以理解的手段,將其從多樣的反應物與中間產物中移除。常規流程中使用的保護基以及實施例中適合的保護基例如記載於Protective Groups in Organic Synthesis by T.W.Greene,P.G.M Wutz,4th Edition,Wiley-Interscience,New York,2006。可以理解的,可以選擇性使用微波作為加熱反應混合物的手段。
除非另有說明,否則A、R1、R2、R3、R4、R5、R6、R7、R8和R9如式(I)中所定義。
(i)對應如式(III)所示化合物的形成
通過從例如式(II)的化合物開始(方案一),可以獲得式(III)的化合物,其中LG代表離去基團例如鹵素(例如氯、溴或碘),或烷基、芳基或鹵代烷基磺酸酯(例如三氟甲磺酸酯),並使式(II)的化合物與合適的偶聯配偶體A *反應,代表作為遊離鹼的合適的環胺或鹽(例如HCl或TFA或乙酸酸),或在例如Metal-Catalyzed Cross-Coupling Reactions,2nd,Completely Revised and Enlarged Edition by A.de Meijere and F.Diederich,Wiley VCH,2004所描述的過渡金屬催化劑的影響下,合適的硼酸或硼酸衍生物。
該反應可以通過將式(II)的化合物與合適的偶聯配偶體A *偶聯進行。該反應可以使用合適的金屬催化劑,如鈀催化劑,如二-三級丁基膦基二茂鐵二氯化鈀(II)、四(三苯基膦)鈀(0)、二苯基膦二茂鐵二氯化鈀、乙酸鈀(II)二亞芐基丙酮)鈀(0)。合適的配體可以選擇性的使用,例如三苯基膦、三三級丁基膦或2-(二環己基膦基)聯苯或2-二環己基膦基-2',4',6'-三異丙基聯苯。在該反應中可以使用合適的鹼,例如烷基胺,例如三乙胺,或鹼金屬或鹼土金屬碳酸鹽或氫氧化物或磷酸鹽,例如碳酸鉀、碳酸鈉、碳酸絕或氫氧化鈉或磷酸鉀。該反應可在+20℃至+160℃的溫度範圍內,並進行於適合的溶劑中,如甲苯、四氫呋喃、2-甲基-四氫呋喃、二噁烷、二甲氧基乙烷、乙腈、水、乙醇、N,N-二甲基甲醯胺-二甲基乙醯胺或N,N-二甲基甲醯胺,或其混合物。若鏡像異構地純或濃縮的化合物(II)被使用於此反應,可以獲得鏡像異構地純的或是鏡像異構地濃縮的化合物(III)。
(ii)對應如式(I)所示化合物的形成
通過從例如式(III)的化合物開始,可以獲得如式(I)所示的化合物(方案二),其中R10可以是F、OCH3、OC(CH3)3或OSi R’R”R'''(其中R’、R”
和R'''獨立地為芳基(如苯基)或烷基(如甲基或三級丁基)。如果R10是氟,則轉化為(I)可以通過例如使用HCl水溶液的酸性水解進行。如果R10是OCH3,則轉化為(I)可以通過與例如TMSI在合適的溶劑如氯仿中反應或通過與HBr在合適的溶劑如乙酸中反應或通過與BBr3在合適的溶劑作為二氯甲烷。如果R10是OC(CH3)3,則轉化為(I)可以通過與例如三氟乙酸在合適的溶劑如二氯甲烷中反應進行。如果R10是OSi R’R”R''',(I)的轉化可以通過例如在合適的溶劑如甲醇中的HCl或通過在四氫呋喃中使用氟化四丁基銨進行。若鏡像異構地純的或濃縮的化合物(III)被用於此反應,可以獲得鏡像異構地純的或是鏡像異構地濃縮的化合物(I)。
式(II),(III)和偶聯配偶體A *的化合物是市售可得的化合物,或者是文獻中已知的,或者它們通過本領域已知的標準方法製備。式(I)、(II)或(III)的化合物可以通過本領域已知的標準方法通過例如在手性固定相色譜法(chromatography on a chiral stationary phase)分離成其對映異構體。
通用方法
所使用的所有溶劑均為分析級,並且市售可得的無水溶劑,常規用於反應中。原料可從商業來源獲得,或根據文獻程序製備。室溫指+20~25℃。溶劑混合物組合物以體積百分吡或是體積吡例來表示。
在Biotage Initiator微波腔中進行微波加熱,持續產生2.45GHz的輻射。可以理解地,微波可以用於加熱反應混合物。
直相色譜法(straight phase chromatography)在Merck矽膠60(0.040-0.063mm)上手動進行,或者利用使用指定溶劑系統的SiliaSep TM正相快速柱,自動使用ISCO Combiflash Companion TM系統。
在裝有適當構型的探針的400MHz(或更高頻)NMR光譜儀上記錄NMR光譜。除非另有說明,否則光譜是在環境溫度下記錄。NMR光譜在
CDCl3、DMSO-d6或CD3OD中被獲得。化學位移以TMS(0.00ppm)為基準的向下和向上磁場表示。使用以下參考信號:DMSO-d5 δ 2.5的剩餘溶劑訊號或CHCl3 δ 7.26的剩餘溶劑訊號或CD2HOD δ 3.31的剩餘溶劑。共振多樣性以s、d、t、q、m和br表示單峰、雙峰、三峰、四峰、多峰與闊峰(board)。
在反相柱上進行高壓(性能)液相色譜(HPLC)。使用例如流動相A(0.1%NH3水溶液或0.1%醋酸水溶液或0.1%甲酸水溶液)和B(乙腈或甲醇),以套用線性梯度。使用電噴灑游離法(ES+)以正離子模式進行質譜儀(MS)分析。
製備色譜法使用Gilson-PREP GX271或GX281上,用Trilution Ic作為軟體,在反相柱上進行。使用例如流動相A(0.1%NH 3水溶液或0.1%醋酸水溶液或0.1%甲酸水溶液)和B(乙腈或甲醇),以套用線性梯度。
為使對映異構體分離,製備手性色譜法進行於That SFC,於手性固定相上使用超臨界流體色譜法。藉由使用流動相A(二氧化碳)以及B(乙腈或甲醇或乙醇或2-丙醇或上述任一組合),以套用線性梯度。添加物(例如二乙胺或異丙胺或氨水或甲酸或TFA)可以被使用。
化合物命名使用Accelrys Draw 4.1 SP1。
中間體實施例1
4-(2,6-二氯-4-吡啶基)嗎啉
將2,6-二氯-4-碘-吡啶(6g,21.91mmol),嗎啉(2ml,23.12mmol),PPh3(350mg,1.33mmol),Pd(OAc)2(150mg,0.67mmol)和新鮮研磨的K3PO4(13g,61.24mmol)溶於DMF(40ml)中,將所得混合物劇烈攪拌,同時用氮氣
脫氣5分鐘。將混合物降至預熱的油浴中並在100℃下攪拌1小時。當冷卻至室溫(rt)時,將混合物倒入水(150ml)和EtOAc(50ml)中。分離有機層,水層用EtOAc(3×30ml)萃取。將合併的有機物用鹽水洗滌,用Na2 SO4乾燥,過濾,濃縮並在矽膠柱上純化,用10-60%EtOAc/庚烷洗脫,得到標題化合物(2.53g,49%)。MS ES+ m/z 233[M+H]+。
中間體實施例2
4-(2-叔丁氧基-6-氯-4-吡啶基)嗎啉
將4-(2,6-二氯-4-吡啶基)嗎啉(3.2g,13.73mmol),KOtBu(3.85g,34.32mmol)和4Å分子篩(~10珠(beads),4-8目(mesh))加入anh.甲苯(50ml),在90℃下攪拌2小時。當冷卻至室溫時,將混合物用EtOAc(30ml),鹽水(40ml)和水(20ml)稀釋。分離有機層,水層用EtOAc(2×25ml)萃取。將合併的有機物用鹽水洗滌,用Na2SO4乾燥,過濾,濃縮並在矽膠柱上純化,用0-40%EtOAc/庚烷洗脫,得到標題化合物(3.4g,91%)。MS ES+ m/z 271[M+H]+。
中間體實施例3
4-[2-叔丁氧基-6-(2-苯基吡咯烷-1-芳基)-4-吡啶基]嗎啉
4-(2-叔丁氧基-6-氯-4-吡啶基)嗎啉(3.55g,13.11mmol),2-苯基吡咯烷(2.8g,19.02mmol),PEPPSITM-iPr(460mg,0.68mmol)和KOtBu(2.5g,22.28mmol)溶於無水THF中。1,4-二噁烷(50ml),用氮氣脫氣5分鐘。將所得混合物在50℃下攪拌1小時。當冷卻至室溫鹽水(25ml)時,加入水(15ml)和EtOAc(25ml)。分離有機層,水層用EtOAc(2×20ml)萃取。將合併的有機物用鹽水洗滌,用Na2SO4乾燥,過濾,濃縮並在矽膠柱上純化,用0-50%EtOAc/庚烷洗脫,得到標題化合物(5g,99%)。MS ES+ m/z 382[M+H]+。
實施例1
4-嗎啉代-6-(2-苯基吡咯烷-1-芳基)-1氫-吡啶-2-酮
將4-[2-叔丁氧基-6-(2-苯基吡咯烷-1-芳基)-4-吡啶基]嗎啉(5g,13.11mmol)溶於DCM(40ml)中,並在室溫下緩慢加入TFA(2.92ml,39.32mmol)。將所得混合物在室溫下攪拌1小時。加入更多的TFA(2ml,26.92mmol),並在室溫下繼續攪拌2.5小時。將混合物濃縮,將殘餘物溶於EtOAc(50ml)中並冷卻至0℃。緩慢加入28%NH 4 OH(30ml),將混合物劇烈攪拌10分鐘。濾出沉澱,用水(2×5ml),EtOAc(2×5ml)洗滌並乾燥。將固體懸浮於EtOAc:庚烷(1:1,30ml)中並在室溫下攪拌15分鐘,然後過濾。濾餅用EtOAc:庚烷(1:1,2×10ml)洗滌,然後懸浮於戊烷(10ml)中,過濾並乾燥,得到標題化合物(2.3g,54%)。1H NMR(500MHz,DMSO-d 6)δ 7.30(t,2H),7.24-7.16(m,3H),5.07-4.98(m,2H),4.91(s,1H),3.78-3.71(m,1H),3.67-3.55(m,4H),3.52-3.42(m,1H),3.11-3.01(m,2H),3.01-2.95(m,2H),2.36-2.29
(m,1H),1.94-1.82(m,2H),1.82-1.75(m,1H).MS ES+ m/z 326[M+H]+。
實施例2
1-甲基-4-嗎啉代-6-(2-苯基吡咯烷-1-芳基)吡啶-2-酮
將4-嗎啉代-6-(2-苯基吡咯烷-1-芳基)-1氫-吡啶-2-酮(75mg,0.23mmol)和K2CO3(50mg,0.36mmol)溶於MeCN(1ml)。加入碘甲烷(0.02ml,0.32mmol),將混合物在室溫下攪拌30分鐘。加入DMAc(0.5ml),將混合物在室溫下攪拌過夜。加入MeOH(1ml)和碘甲烷(0.05ml,0.8mmol),在室溫下繼續攪拌過夜。將混合物過濾並通過製備型HPLC純化,得到標題化合物(5mg,6%)。MS ES+ m/z 340[M+H]+。
中間體實施例4
4-[2-叔丁氯基-6-[(2S)-2-苯基吡咯烷-1-芳基]-4-吡啶基]嗎啉
將4-(2-叔丁氧基-6-氯-4-吡啶基)嗎啉(120mg,0.44mmol),(2S)-2-苯基吡咯烷(98mg,0.66mmol),Pd 2(dba)0.02mmol),XantPhos(25mg,0.04mmol)和KOtBu(150mg,1.33mmol)溶於甲苯(3ml)中,並將所得混合物在100℃下攪拌過週末。加入更多的Pd2(dba)3(20mg,0.02mmol),XantPhos(25mg,
0.04mmol)和KOtBu(150mg,1.33mmol),並在100℃繼續攪拌過夜。加入更多Pd2(dba)3(20mg,0.02mmol),XantPhos(25mg,0.04mmol)和KOtBu(150mg,1.33mmol),並在100℃繼續攪拌5小時。當冷卻至室溫時,加入EtOAc(5ml)和鹽水(10ml)。將混合物過濾,分離有機層,水層用EtOAc(2×5ml)萃取。將合併的有機物用Na2SO4乾燥,過濾,濃縮並在矽膠柱上純化,用0-40%EtOAc/庚烷洗脫,得到標題化合物(75mg,44%)。MS ES+ m/z 382[M+H]+。
實施例3
4-嗎啉代-6-[(2S)-2-苯基吡咯烷-1-芳基]-1氫-吡啶-2-酮
將4-[2-叔丁氧基-6-[(2S)-2-苯基吡咯烷-1-芳基]-4-吡啶基]嗎啉(75mg,0.2mmol)溶於DCM(3ml),0.98mmol)。將所得混合物在室溫下攪拌3小時,濃縮並通過製備型HPLC純化,得到標題化合物(23mg,36%)。1H NMR(500MHz,DMSO-d 6)δ 7.38-7.26(m,2 H),7.26-7.12(m,3 H),5.08-4.94(m,2 H),4.88(s,1 H),3.78-3.68(m,1 H),3.65-3.52(m,4 H),3.50-3.41(m,1 H),3.13-2.89(m,4 H),2.38-2.27(m,1 H),1.96-1.82(m,2 H),1.82-1.71(m,1 H).MS ES+ m/z 326[M+H]+。
實施例4
4-嗎啉代-6-[(2R)-2-苯基吡咯烷-1-芳基]-1氫-吡啶-2-酮
將4-(2-叔丁氧基-6-氯-4-吡啶基)嗎啉(300mg,1.11mmol),(2R)-2-苯基吡咯烷(245mg,1.66mmol),Pd2(dba)3(51mg,0.06mmol),XPhos(53mg,0.11mmol)和KOtBu(373mg,3.32mmol)溶於甲苯(5ml)中,將所得混合物在105℃下攪拌2小時。當冷卻至室溫時,加入EtOAc(5ml)和鹽水(10ml)。將混合物過濾,分離有機層,水層用EtOAc(2×5ml)萃取。將合併的有機物用Na2 O4乾燥,過濾,濃縮並在矽膠柱上純化,用0-40%EtOAc的庚烷溶液洗脫。將所得物質溶於DCM(5ml)中,加入TFA(0.31ml,4.19mmol)。將反應混合物在室溫下攪拌45分鐘。加入更多的TFA(0.31ml,4.19mmol),繼續攪拌1小時。將混合物濃縮,將殘餘物溶於EtOAc(5ml)和2M HCl水溶液(2ml)中。分離有機層,水層用EtOAc(2×3ml)萃取。將合併的有機物用鹽水洗滌,用Na2SO4乾燥,過濾,濃縮並通過製備型HPLC純化,得到標題化合物(52mg,19%)。1H NMR(500MHz,DMSO-d 6)δ 9.50(br s,1 H),7.34-7.27(m,2 H),7.24-7.15(m,3 H),5.04-4.96(m,2 H),4.88(br s,1 H),3.78-3.68(m,1 H),3.63-3.53(m,4 H),3.49-3.41(m,1 H),3.07-3.00(m,2 H),3.00-2.93(m,2 H),2.38-2.26(m,1 H),1.94-1.81(m,2 H),1.78(dd,1 H).MS ES+ m/z 326[M+H]+。
中間體實施例5
4-(2,6-二氯-4-吡啶基)-3-甲基-嗎啉
將2,6-二氯-4-碘-吡啶(1.5g,5.48mmol),3-甲基嗎啉(0.61ml,6.02mmol),PPh3(144mg,0.55mmol),Pd(OAc)2(61mg,0.27mmol)和新鮮研磨的K3PO4(3.49g,16.43mmol)溶於DMF(30ml)中,將所得混合物在100℃下攪拌1小時。當冷卻至室溫時,將混合物倒入水(50ml)中,並用EtOAc(3×15ml)萃取。將合併的有機物用鹽水洗滌,用Na2SO4乾燥,過濾,濃縮並在矽膠柱上純化,用0-60%EtOAc/庚烷洗脫,得到標題化合物(800mg,59%)。MS ES+ m/z 247[M+H]+。
中間體實施例6
4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉
將4-(2,6-二氯-4-吡啶基)-3-甲基-嗎啉(2.2g,8.9mmol),KOtBu(2.5g,22.26mmol)和分子篩(~10珠,4-8目)加入anh.甲苯(40ml),在90℃下攪拌2小時。當冷卻至室溫時,將混合物用EtOAc(30ml),鹽水(40ml)和水(20ml)稀釋。分離有機層,水層用EtOAc(2×25ml)萃取。將合併的有機物用鹽水洗滌,用Na2SO4乾燥,過濾,濃縮並在矽膠柱上純化,用0-40%EtOAc/庚烷洗脫,得到標題化合物(2.2g,87%)。MS ES+ m/z 285[M+H]+。
實施例5
6-(3,6-二氫-2H-吡喃-4-芳基)-4-(3-甲基嗎啉-4-芳基)-1氫-吡啶-2-酮
將4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(0.2g,0.7mmol),2-(3,6-二氫-2H-吡喃-4-芳基)-4,4.5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(0.18g,0.84mmol),PdCl2(amphos)(4.97mg,7.02μmol)和K2CO3(291.18mg,2.11mmol)溶於2-MeTHF(3ml)和水(1ml),將所得混合物在微波反應器中在135℃加熱1小時。當冷卻至室溫時,加入鹽水(5ml),水(4ml)和EtOAc(5ml)。分離有機層,水層用EtOAc(2×10ml)萃取。將合併的有機物用鹽水洗滌,用MgSO4乾燥,過濾並濃縮。將粗物質吸收在DCM(5ml)中,加入TFA(345.93mg,3.03mmol)。將反應混合物在室溫下攪拌過夜。將混合物濃縮,將所得殘餘物溶於EtOAc中,用飽和aq.NaHCO3(2×10ml)洗滌。將有機層濃縮並通過製備型HPLC純化,得到固體產物(80mg,41%)。1H NMR(400MHz,DMSO-d 6)δ 10.46(br s,1 H),6.51(br s,1 H),5.99(s,1 H),5.32(s,1 H),4.18(br s,2 H),3.96(br d,1 H),3.88(br d,1 H),3.79-3.57(m,4 H),3.49-3.33(m,2 H),3.02(td,1 H),2.37(br s,2 H),1.08(d,3 H).MS ES+ m/z 277[M+H]+。
實施例6
(3-甲基嗎啉-4-芳基)-6-四氫吡喃-4-芳基-1氫-吡啶-2-酮
加入6-(3,6-二氫-2H-吡喃-4-芳基)-4-(3-甲基嗎啉-4-芳基)-1氫-吡啶-2-酮(80mg,0.29mmol),10%Pd/碳(120mg,1.16mmol)和甲酸銨(110mg,1.74mmol)溶於MeOH(4ml)中,將所得混合物在50℃下攪拌1小時。當冷卻至室溫時,將混合物過濾並在製備型HPLC上純化,得到固體形式的產物
(30mg,37%)。1H NMR(400MHz,CD3OD)δ 6.05(s,1 H),5.54(s,1 H),4.06-3.94(m,4 H),3.80-3.68(m,2 H),3.61-3.42(m,4 H),3.20(td,1 H),2.76-2.66(m,1 H),1.86-1.72(m,4 H),1.26-1.18(m,3 H).MS ES+ m/z 279[M+H]+。
實施例7
6-[2-(3-甲氧基苯基)吡咯烷-1-芳基]-4-(3-甲基嗎啉-4-芳基)-1氫-吡啶-2-酮
4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(200mg,0.7mmol),2-(3-甲氧基苯基)吡咯烷(150mg,0.84mmol),PEPPSITMiPr(24mg,0.04mmol)和KOtBu(160mg,1.4mmol)溶於amh.1,4-二噁烷(5ml)中並用氮氣脫氣5分鐘。將所得混合物在90℃下攪拌1小時。當冷卻至室溫時,加入鹽水(5ml)、水(4ml)和EtOAc(5ml)。分離有機層,水層用EtOAc(2×10ml)萃取。將合併的有機物用鹽水洗滌,過濾並濃縮。將所得殘餘物溶於DCM(10ml)中,並在室溫下緩慢加入TFA(0.38ml,5.06mmol)。將所得混合物在室溫下攪拌過夜。將混合物濃縮並通過製備型HPLC純化,得到標題化合物(90mg,37%)。1H NMR(500MHz,DMSO-d 6)δ 9.50(br s,1 H),7.23(td,1 H),6.71-6.82(m,3 H),4.90-5.02(m,1 H),4.88(br s,1 H),4.81(br s,1 H),3.68-3.84(m,5 H),3.57-3.67(m,2 H),3.33-3.55(m,4 H),3.18(br d,1 H),3.09(br d,1 H),2.81-2.93(m,1 H),2.27-2.48(m,1 H),1.83-1.95(m,2 H),1.79(br dd,1 H),1.05(d,1 H),0.77(br d,2 H).MS ES+ m/z 370[M+H]+。
實施例8
4-(3-甲基嗎啉-4-芳基)-6-[2-(3-吡啶基)吡咯烷-1-芳基]-1氫-吡啶-2-酮
如在實施例7中標題化合物的製備所述,從4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(200mg,0.7mmol)和3-吡咯烷-2-芳基-(120mg,0.84mmol)反應,得到產物(80mg,34%)。1H NMR(500MHz,DMSO-d 6)δ 10.72(br s,1 H),8.40-8.49(m,2 H),7.57(t,1 H),7.33(dt,1 H),5.10(br d,1 H),4.96-5.05(m,1 H),4.93(br s,1 H),3.72-3.86(m,2 H),3.59-3.70(m,2 H),3.37-3.55(m,3 H),3.16-3.31(m,1 H),3.11(br d,1 H),2.87(qd,1 H),2.30-2.48(m,1 H),1.81-1.97(m,6 H),1.04(d,2 H),0.76(br d,1 H).MS ES+ m/z 341[M+H]+。
實施例9
4-(3-甲基嗎啉-4-芳基)-6-(2-苯基吡咯烷-1-芳基)-1氫-吡啶-2-酮
如在實施例7中標題化合物的製備所述,從4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(200mg,0.7mmol)和2-苯基吡咯烷(120mg,0.84mmol)開始,得到產物(110mg,46%)。1H NMR(500MHz,DMSO-d 6)δ 9.54(br s,1 H),
7.26-7.36(m,2 H),7.17-7.26(m,3 H),4.89-5.06(m,2 H),4.73-4.88(m,1 H),3.70-3.86(m,2 H),3.55-3.65(m,2 H),3.33-3.55(m,4 H),3.17(br d,1 H),3.08(br d,1 H),2.79-2.94(m,1 H),2.28-2.48(m,1 H),2.08(s,1 H),1.84-1.97(m,2 H),1.75-1.84(m,1 H),1.04(d,1 H),0.74(br d,2 H).MS ES+ m/z 340[M+H]+。
中間體實施例7
(3R)-4-(2,6-二氯-4-吡啶基)-3-甲基-嗎啉
如在中間實施例5中標題化合物的製備所述,用(R)-3-甲基嗎啉代替3-甲基嗎啉,得到產物(900mg,66%)。MS ES+ m/z 247[M+H]+。
中間體實施例8
(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉
如在中間實施例6中所述,從(3R)-4-(2,6-二氯-4-吡啶基)-3-甲基-嗎啉(700mg)開始製備標題化合物,得到產物(510mg,63%)。1H NMR(400MHz,CDCl3)δ 6.29(s,1 H),5.92-5.81(m,1 H),4.04-3.92(m,1 H),385-3.69(m,3 H),3.65-3.52(m,1 H),3.29-3.10(m,2 H),1.59-1.53(m,9 H),1.21(d,3 H).MS ES+ m/z 285[M+H]+。
中間體實施例9
1-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]-N,N-二甲基-吡咯烷-2-甲醯胺
(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(250mg,0.88mmol),N,N-二甲基吡咯烷-2-甲醯胺HCl鹽(188mg,1.05mmol),PEPPSI TM-iPr(30mg,0.044mmol)和KOtBu(197mg,1.76mmol)被加入anh.1,4-二噁烷(5ml)中並用氮氣脫氣5分鐘。將所得混合物在90℃下攪拌1小時。當冷卻至室溫時,將混合物通過矽藻土過濾,並將濾液用水稀釋,並用乙酸乙酯萃取。將合併的有機物用鹽水洗滌,用Na2SO4乾燥,過濾,濃縮並在矽膠柱上純化,用20%EtOAc/石油醚洗脫,得到標題化合物(160mg,46%)。MS ES+ m/z 391[M+H]+。
實施例10
N,N-二甲基-1-[4-[(3R)-3-甲基嗎啉-4-芳基]-6-氧代-1氫-吡啶-2-芳基]吡咯烷-2-甲醯胺
將TFA(0.29ml,3.8mmol)加入到1-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]-N,N-二甲基-吡咯烷-2-甲醯胺(150mg,0.38mmol)的DCM(3ml)
溶液中,並將所得混合物在室溫下攪拌過夜。將反應混合物用sat.aq.NaHCO3鹼化,並用DCM萃取。將合併的有機物用鹽水洗滌,用Na2SO4乾燥,過濾,濃縮並在矽膠柱上純化,用5%MeOH/DCM洗脫,得到標題化合物(50mg,39%)。1H NMR(400MHz,CDCl 3)δ 5.21-5.02(m,2H),4.83(s,1H),3.95(br d,1H),3.81-3.69(m,3H),3.64-3.53,3.41(dt,1H),3.27-3.14(m,2H),3.09(s,3H),2.92(d,3H),2.39-2.32(m,1H),2.09-1.93(m,3H),1.27-1.15(m,3H)。MS ES+m/z 335[M+H]+。
中間體實施例10
(3R)-4-[2-叔丁氧基-6-[2-(1-甲氧基-1-甲基-乙基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉
如在中間實施例9中標題化合物的製備所述,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(500mg,1.76mmol)和2-(1-甲氧基-1-甲基-乙基)吡咯烷(302mg,2.11mmol),得到產物(375mg,54%)。MS ES+ m/z 392[M+H]+。
實施例11
(R)和(S)6-[2-(1-甲氧基-1-甲基-乙基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-2-酮
標題化合物的製備如實施例10所述,從(3R)-4-[2-叔丁氧基-6-[2-(1-甲氧基-1-甲基-乙基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉(350mg,0.89mmol),得到作為非對映異構體混合物的產物(170mg,57%)。1H NMR(400MHz,CDCl3)δ 10.48(br s,1 H),5.25(s,1 H),4.94-4.91(m,1 H),3.96(br dd,1 H),3.83-3.72(m,4 H),3.62-3.54(m,1 H),3.37-3.15(m,7 H),2.07-1.86(m,4 H),1.32-1.18(m,6 H),1.08(d,3 H).MS ES+ m/z 336[M+H]+。通過SFC的手性分離(chiral separation)得到兩種異構體。
實施例11-1,第一異構體洗脫,未知絕對構型:
1H NMR(400MHz,CDCl3)δ 10.70-10.44(m,1 H),5.33-5.21(m,1 H),4.99-4.88(m,1 H),3.96(br dd,1 H),3.85-3.71(m,4 H),3.58(td,1 H),3.39-3.29(m,5 H),3.28-3.16(m,2 H),2.08-1.85(m,4 H),1.27-1.19(m,6 H),1.09(s,3 H).MS ES+ m/z 336[M+H]+。
實施例11-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 10.62-10.40(m,1 H),5.25(s,1 H),4.93(s,1 H),3.96(br dd,1 H),3.85-3.68(m,4 H),3.58(td,1 H),3.41-3.26(m,5 H),3.19(td,1 H),2.10-1.87(m,5 H),1.28-1.17(m,6 H),1.08(s,3 H).MS ES+ m/z 336[M+H]+。
中間體實施例11
(3R)-4-[2-叔丁氧基-6-(2-環己基吡咯烷-1-芳基)-4-吡啶基]-3-甲基-嗎啉
標題化合物的製備如中間體實施例9所述,開始於(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(500mg,1.76mmol)和2-環己基吡咯烷(323mg,2.11mmol),得到產物(310mg,44%)。MS ES+ m/z 402[M+H]+。
實施例12
(R)和(S)6-(2-環己基吡咯烷-1-芳基)-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮
標題化合物的製備如實施例10所述,開始於(3R)-4-[2-叔丁氧基-6-(2-環己基吡咯烷-1-芳基)-4-吡啶基]-3-甲基-嗎啉(300 0.75mmol),得到作為非對映異構體混合物的產物(218mg,81%)。1H NMR(400MHz,CDCl3)δ 5.19(s,1 H),4.82(br s,1 H),3.97(br d,1 H),3.83-3.72(m,3 H),3.68-3.55(m,2 H),3.39(br s,1 H),3.33-3.18(m,3 H),2.04-1.88(m,4 H),1.80-1.61(m,7 H),1.27-1.22(m,3 H),1.16-0.96(m,4 H).MS ES+ m/z 346[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例12-1,第一異構體洗脫,具有未知絕對構型:
1H NMR(400MHz,CDCl3)δ 5.17(br s,1H),4.81(br s,1H),3.97(br d,1H),3.81-3.70(m,3H),3.68-3.56(m,2H),3.38(br s,1H),3.31-3.17(m,3H),2.06-1.87(m,4H),1.81-1.50(m,8H),1.23(br d,3H),1.17-1.08(m,3H).MS ES+ m/z 346[M+H]+。
實施例12-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 5.19(br s,1H),4.82(br s,1H),3.97(br d,1H),3.82-3.56(m,5H),3.39(br s,1H),3.32-3.16(m,3H),1.99(br s,4H),1.74(br s,8H),1.24(br d,3H),1.14-1.00(m,3H).MS ES+ m/z 346[M+H]+。
中間體實施例12
(3R)-4-[2-叔丁氧基-6-[2-(3-氟苯基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉
標題化合物的製備如在中間體實施例9中所述,除了將混合物從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(1.0g)開始攪拌3小時,650mg,2.28mmol)和2-(3-氟苯基)吡咯烷(453mg,2.74mmol),得到產物(373mg,39%)。MS ES+ m/z 414[M+H]+。
實施例13
(R)和(S)6-[2-(3-氟苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮
標題化合物的製備如實施例10所述,從(3R)-4-[2-叔丁氧基-6-[2-(3-氟苯基)吡咯烷-1-芳基]-4-吡啶基]-3-(430mg,1.04mmol)開始,得到產物,為非對
映異構體混合物(300mg,81%)。1H NMR(400MHz,CDCl3)δ 7.29(br d,1H),6.99-6.94(m,2H),6.88(br d,1H),5.14(dd,1H),4.81-4.64(m,2H),3.95-3.88(m,1H),3.77-3.64(m,3H),3.58-3.45(m,3H),3.19-3.05(m,2H),2.49-2.37(m,1H),2.08-1.92(m,3H),1.20(d,1.5 H),0.97(br d,1.5 H).MS ES+ m/z 358[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例13-1,第一異構體洗脫,具有未知絕對構型:
1H NMR(400MHz,CDCl3)δ 7.31(br d,1H),7.01-6.94(m,2H),6.87(br d,1H),5.16(br s,1H),4.79-4.72(m,2H),3.92(br d,1H),3.73-3.62(m,4H),3.58-3.45(m,2H),3.19-3.06(m,2H),2.48-2.38(m,1H),2.08-1.94(m,3H),1.20(br d,3H).MS ES+ m/z 358[M+H]+。
實施例13-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 7.30(br d,1H),7.00-6.93(m,2H),6.88(br d,1H),5.16(s,1H),4.75(br dd,1H),4.67(s,1H),3.92(br d,1H),3.75(br d,1H),3.67(s,2H),3.59-3.47(m,3H),3.13-3.08(m,2H),2.45(qd,1H),2.10-1.94(m,3H),0.98(d,3H).MS ES+ m/z 358[M+H]+。
中間體實施例13
(3R)-4-[2-叔丁氧基-6-[2-(2,5-二氟苯基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉
標題化合物的製備如中間體實施例9所述,除了是將混合物從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉開始攪拌16小時。700mg,2.46mmol)和2-(2,5-二氟苯基)吡咯烷(541mg,2.95mmol),得到產物(600mg,57%)。MS ES+ m/z 432[M+H]+。
實施例14
(R)和(S)6-[2-(2,5-二氟苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從(3R)-4-[2-叔丁氧基-6-[2-(2,5-二氟苯基)吡咯烷-1-芳基]-4-吡啶基]-(650mg,1.5mmol)開始,得到產物,為非對映異構體混合物(450mg,80%)。1H NMR(400MHz,CDCl3)δ 7.06(dt,1H),6.95(br s,1H),6.78-6.71(m,1H),5.50(br s,1H),5.13-5.05(m,1H),4.93(br d,1H),4.00-3.91(m,2H),3.75-3.46(m,5H),3.25-3.06(m,2H),2.54-2.42(m,1H),2.17-2.00(m,3H),1.26-1.19(m,1.5 H),0.98(d,1.5 H).MS ES+ m/z 376[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例14-1,第一異構體洗脫,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 7.31(br d,1H),7.01-6.94(m,2H),6.87(br d,1H),5.16(br s,1H),4.79-4.72(m,2H),3.92(br d,1H),3.73-3.62(m,4H),3.58-3.45(m,2H),3.19-3.06(m,2H),2.48-2.38(m,1H),2.08-1.94(m,3H),1.20(br d,3H).MS ES+ m/z 358[M+H]+。
實施例14-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 7.30(br d,1H),7.00-6.93(m,2H),6.88(br d,1H),5.16(s,1H),4.75(br dd,1H),4.67(s,1H),3.92(br d,1H),3.75(br d,1H),3.67(s,2H),3.59-3.47(m,3H),3.13-3.08(m,2H),2.45(qd,1H),2.10-1.94(m,3H),0.98(d,3H).MS ES+ m/z 358[M+H]+。
中間體實施例14
(3R)-4-[2-叔丁氧基-6-[2-[3-(三氟甲氧基)苯基]吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉
標題化合物的製備如在實施例9中所述,不同的是將混合物攪拌16小時,由(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基嗎啉(500mg,1.76mmol)和2-[3-(三氟甲氧基)苯基]吡咯烷(488mg,2.11mmol),得到產物(170mg,20%)。1H NMR(400MHz,CDCl3)δ 7.38-7.33(m,1H),7.12(br d,,2H),7.04(br s,1H),5.14(dd,1H),4.77(ddd,1H),4.68-4.59(m,1H),3.93-3.74(m,2H),3.70-3.46(m,5H),3.16-3.01(m,2H),2.50-2.39(m,1H),2.09-2.01(m,2H),1.98-1.91(m,1H),1.19(d,1.5H),0.92(d,1.5H).MS ES+ m/z 424[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例15
(R)和(S)4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-[3-(三氟甲氧基)苯基]吡咯烷-1-芳基]-1氫-吡啶-2-酮
按照實施例10所述製備標題化合物,由(3R)-4-[2-叔丁氧基-6-[2-(2,5-二氟苯基)吡咯烷-1-芳基]-4-吡啶基]-(225mg,0.46mmol),得到作為非對映異構體混合物的產物(120mg,60%)。1H NMR(400MHz,CDCl3)δ 7.38-7.33(m,1H),7.12(br d,,2H),7.04(br s,1H),5.14(dd,1H),4.77(ddd,1H),4.68-4.59(m,1H),3.93-3.74(m,2H),3.70-3.46(m,5H),3.16-3.01(m,2H),2.50-2.39(m,1H),2.09-2.01(m,2H),1.98-1.91(m,1H),1.19(d,1.5H),0.92(d,1.5H).MS ES+ m/z 424[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例15-1,第一異構體洗脫,具有未知絕對構型:
1H NMR(400MHz,CDCl3)δ 7.38-7.34(m,1H),7.12(br d,2H),7.05(s,1H),5.14(d,1H),4.75(dd,1H),4.61(d,,1H),3.90(br d,1H),3.82-3.76(m,1H),3.65(s,2H),3.59-3.46(m,3H),3.10-3.07(m,2H),2.46(qd,1H),2.09-1.91(m,3H),0.92(d,3H).MS ES+ m/z 424[M+H]+。
實施例15-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 7.40-7.34(m,1H),7.13(br t,2H),7.05-6.99(m,1H),5.15(s,1H),4.77(br d,1H),4.69(s,1H),3.91(br d,1H),3.74-3.46(m,6H),3.17-3.02(m,2H),2.50-2.40(m,1H),2.08-1.93(m,3H),1.19(br d,,3H).MS ES+ m/z 424[M+H]+。
中間體實施例15
(3R)-4-[2-叔丁氧基-6-[2-[3-(三氟甲基)苯基]吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉
標題化合物的製備如在中間體實施例9中所述,除了混合物是攪拌3小時,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(700mg,2.46mmol)和2-[3-(三氟甲基)苯基]吡咯烷(636mg,2.95mmol)開始,得到產物(800mg,70%)。MS ES+ m/z 464[M+H]+。
實施例16
(R)和(S)4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-[3-(三氟甲基)苯基]吡咯烷-1-芳基]-1氫-吡啶-2-酮
標題化合物如在實施例10中所述,從(3R)-4-[2-叔丁氧基-6-[2-[3-(三氟甲基)苯基]吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉(800mg,1.72mmol)開始,得到產物,為非對映異構體混合物(300mg,42%)。1H NMR(400MHz,CDCl3)δ 7.54-7.51(m,1H),7.47-7.42(m,2H),7.39-7.35(m,1H),5.14(dd,1H),4.89-4.78(m,1H),4.68-4.58(m,1H),3.93-3.76(m,2H),3.71
-3.45(m,5H),3.16-3.01(m,2H),2.52-2.41(m,1H),2.10-2.00(m,2H),1.98-1.92(m,1H),1.19(d,1.5H),0.88(br d,1.5H).MS ES+ m/z 408[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例16-1,第一異構體洗脫,具有未知絕對構型:
1H NMR(400MHz,CDCl3)δ 7.55-7.51(m,1H),7.49-7.44(m,2H),7.37(br d,1H),5.13(s,1H),4.79(br dd,1H),4.62(s,1H),3.90(br d,1H),3.80-3.74(m,1H),3.65(s,2H),3.58-3.46(m,3H),3.09(br d,2H),2.54-2.44(m,1H),2.11-2.04(m,2H),2.00-1.93(m,1H),0.92(d,3H).MS ES+ m/z 408[M+H]+。
實施例16-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 7.56-7.44(m,3H),7.37(br d,1H),5.16(s,1H),4.82(br d,1H),4.71(s,1H),3.91(br d,1H),3.71-3.47(m,6H),3.17-3.03(m,2H),2.50-2.43(m,1H),2.09-1.98(m,3H),1.20(br d,3H).MS ES+ m/z 408[M+H]+。
中間體實施例16
(3R)-4-[2-叔丁氧基-6-[2-(3-甲氧基苯基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉
標題化合物的製備如在中間體實施例9中所述,除了是將混合物在110℃下攪拌6小時,起始於(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3--2-甲基嗎啉
(500mg,1.76mmol)和2-(3-甲氧基苯基)吡咯烷(374mg,2.1mmol),得到產物(550mg,73%)。MS ES+ m/z 426[M+H]+。
實施例17
(R)和(S)6-[2-(3-甲氧基苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,起始於(3R)-4-[2-叔丁氧基-6-[2-(3-甲氧基苯基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基嗎啉(500mg,1.17mmol),得到產物,為非對映異構體混合物(325mg,75%)。1H NMR(400MHz,CDCl3-d)δ 7.25-7.22(m,1 H)6.81-6.75(m,2 H)6.70(s,1 H)5.13(dd,1 H)4.77-4.69(m,2 H)3.95-3.89(m,1 H)3.79(d,3 H)3.75-3.65(m,4 H)3.60-3.43(m,3 H)3.21-3.06(m,2 H)2.47-2.36(m,1 H)2.12-1.93(m,3 H)1.20(d,1 H)1.00(d,1 H).MS ES+ m/z 370[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例17-1,第一異構體洗脫,具有未知絕對構型:
1H NMR(400MHz,CDCl3)δ 7.27(br s,0.5H)7.23(s,0.5 H)6.81-6.75(m,2 H)6.70(s,1 H)5.13(d,1 H)4.77-4.71(m,2 H)3.92(br dd,1 H)3.79(s,3 H)3.72-3.65(m,4 H)3.58-3.43(m,2 H)3.21-3.06(m,2 H)2.46-2.36(m,1 H)2.08-1.93(m,3 H)1.20(d,3 H).MS ES+ m/z 370[M+H]+。
實施例17-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 7.24-7.22(m,1 H)6.80-6.75(m,2 H)6.71(s,1 H)5.12(d,1 H)4.72-4.68(m,2 H)3.91(br d,1 H)3.78(s,3 H)3.73(td,1 H)3.67(d,2 H)3.60-3.47(m,3 H)3.16-3.05(m,2 H)2.47-2.37(m,1 H)2.10-1.93(m,3 H)0.99(d,3 H).MS ES+ m/z 370[M+H]+。
中間體實施例17
(3R)-4-[2-叔丁氧基-6-(2-苯基吡咯烷-1-芳基)-4-吡啶基]-3-甲基嗎啉
標題化合物的製備如在中間體實施例9中所述,除了是將混合物在110℃下攪拌6小時,起始於(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基嗎啉(400mg,1.4mmol)和2-苯基吡咯烷(384mg,2.53mmol),得到產物(325mg,58%)。MS ES+ m/z 396[M+H]+。
實施例18
(R)和(S)4-[(3R)-3-甲基嗎啉-4-芳基]-6-(2-苯基吡咯烷-1-芳基)-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,起始於(3R)-4-[2-叔丁氧基-6-(2-苯基吡咯烷-1-芳基)-4-吡啶基]-3-甲基-嗎啉(320 0.86mmol),得到作為非對
映異構體混合物的產物(230mg,55%)。1H NMR(400MHz,CDCl3)δ ppm 7.32(br dd,3 H)7.17(br d,2 H)5.13(dd,1 H)4.79-4.67(m,2 H)3.94-3.88(m,1 H)3.72-3.45(m,6 H)3.19-3.05(m,2 H)2.48-2.37(m,1 H)2.11-1.94(m,3 H)1.25(s,1 H)1.20(br d,1 H)0.97(d,1 H).MS ES+ m/z 340[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例18-1,第一異構體洗脫,具有未知絕對構型:
1H NMR(400MHz,CDCl3)δ 7.36-7.28(m,3 H)7.17(br d,2 H)5.13(d,1 H)4.79-4.73(m,2 H)3.91(br dd,1 H)3.71-3.45(m,6 H)3.19-3.04(m,2 H)2.47-2.37(m,1 H)2.08-1.93(m,3 H)1.27(dd,1 H)1.20(d,2 H).MS ES+ m/z 340[M+H]+。
實施例18-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 7.34-7.29(m,2 H)7.25-7.15(m,3 H)5.12(d,1 H)4.76-4.66(m,2 H)3.90(br d,1 H)3.75(td,1 H)3.65(s,2 H)3.57-3.46(m,3 H)3.13-3.07(m,2 H)2.49-2.39(m,1 H)2.10-1.93(m,3 H)0.95(d,3 H).MS ES+ m/z 340[M+H]+。
中間體實施例18
(3R)-4-[2-叔丁氧基-6-[2-(1-甲基吡唑-4-芳基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉
標題化合物的製備如在中間體實施例9中所述,除了是將混合物在90℃下攪拌16小時,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(1g,
3.42mmol)和1-甲基-4-吡咯烷-2-芳基-吡唑(638mg,4.2mmol),得到產物(800mg,57%)。MS ES+ m/z 400[M+H]+。
實施例19
(R)和(S)4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-(1-甲基吡唑-4-芳基)吡咯烷-1-芳基]-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從(3R)-4-[2-叔丁氧基-6-[2-(1-甲基吡唑-4-芳基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉(800mg,1.99mmol),得到產物,為非對映異構體混合物(500mg,73%)。1H NMR(400MHz,CDCl3)δ 7.32(s,1H),7.19(d,1H),5.15(s,1H),4.80(dd,2H),3.94(br d,1H),3.84(d,3H),3.71(s,3H),3.61-3.51(m,2H),3.41-3.32(m,1H),3.25-3.11(m,2H),2.36-2.24(m,1H),2.10-2.02(m,2H),1.97-1.91(m,1H),1.22(d,1.5 H),1.14(br d,1.5 H).MS ES+ m/z 344[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例19-1,第一異構體洗脫,具有未知絕對構型:
1H NMR(400MHz,CDCl3)δ 7.32(s,1H),7.19(s,1H),5.15(d,1H),4.84-4.80(m,2H),3.94(br dd,1H),3.84(s,3H),3.74-3.66(m,3H),3.61-3.52(m,2H),3.36(q,1H),3.25-3.11(m,2H),2.34-2.24(m,1H),2.08-2.02(m,2H),1.96-1.90(m,1H),1.21(d,3H).MS ES+ m/z 344[M+H]+。
實施例19-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 7.32(s,1H),7.19(s,1H),5.15(d,1H),4.83-4.79(m,2H),3.96-3.91(m,1H),3.83(s,3H),3.73-3.68(m,3H),3.63-3.51(m,2H),3.38(q,1H),3.22-3.11(m,2H),2.35-2.26(m,1H),2.10-2.01(m,2H),1.97-1.91(m,1H),1.13(d,3H).MS ES+ m/z 344[M+H]+。
中間體實施例19
(3R)-4-[2-叔丁氧基-6-[2-(1,5-二甲基吡唑-3-芳基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉
標題化合物的製備如在中間體實施例9中所述,除了是將混合物在100℃下攪拌2小時,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(500mg,1.76mmol)和1,5-二甲基-3-吡咯烷-2-芳基-吡唑(342mg,2.1mmol),得到產物(400mg,55%)。MS ES+ m/z 414[M+H]+。
實施例20
(R)和(S)6-[2-(1,5-二甲基吡唑-3-芳基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-2-酮
標題化合物的製備如在實施例10中所述,從(3R)-4-[2-叔丁氧基-6-[2-(1,5-二甲基吡唑-3-芳基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉(400mg,0.96mmol),得到作為非對映異構體混合物的產物(200mg,58%)。1H NMR(400MHz,CDCl3)δ 5.82(d,1 H)5.15(br s,1 H)4.87(br s,1 H)4.77(br d,1 H)3.94(br dd,1 H)3.77-3.70(m,6 H)3.59-3.51(m,2 H)3.35(br s,1 H)3.26-3.14(m,2 H)2.35-2.29(m,1 H)2.22-2.09(m,6 H)1.20(d,1.5 H)1.14(d,1.5 H).MS ES+ m/z 358[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例20-1,第一異構體洗脫,具有未知絕對構型:
1H NMR(400MHz,CDCl3)δ 5.83(s,1 H)5.15(d,1 H)4.87(d,1 H)4.78-4.75(m,1 H)3.94(br dd,1 H)3.77-3.68(m,6 H)3.60-3.49(m,2 H)3.37-3.30(m,1 H)3.26-3.11(m,2 H)2.34-2.29(m,1 H)2.21(s,3 H)2.17-2.05(m,3 H)1.20(d,3 H).MS ES+ m/z 358[M+H]+。
實施例20-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 5.81(s,1 H)5.14(d,1 H)4.87(d,1 H)4.76(dd,1 H)3.94(dd,1 H)3.77-3.68(m,6 H)3.59-3.51(m,2 H)3.39-3.33(m,1 H)3.25-3.11(m,2 H)2.37-2.29(m,1 H)2.22-2.04(m,6 H)1.14(d,3 H).MS ES+ m/z 358[M+H]+。
中間體實施例20
(3R)-4-[2-叔丁氧基-6-[2-(1-乙基吡唑-3-芳基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉
標題化合物的製備如在中間體實施例9中所述,除了是將混合物攪拌10小時,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉500mg,1.76mmol)和1-乙基-3-吡咯烷-2-芳基-吡唑(348mg,2.11mmol),得到產物(380mg,52%)。MS ES+ m/z 414[M+H]+。
實施例21
(R)和(S)6-[2-(1-乙基吡唑-3-芳基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮
如在實施例10中標題化合物的製備所述,從(3R)-4-[2-叔丁氧基-6-[2-(1-乙基吡唑-3-芳基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉(370mg,0.89mmol),得到作為非對映異構體混合物的產物(260mg,81%)。1H NMR(400MHz,CDCl3)δ 7.31-7.29(m,1 H)6.03(d,1 H)5.15(br d,1 H)4.85(br d,2 H)4.16-4.12(m,2 H)3.93(br dd,1 H)3.76-3.70(m,3 H)3.55-3.51(m,2 H)3.35(br d,1 H)3.25-3.15(m,2 H)2.19(d,1 H)2.14-1.88(m,3 H)1.50-1.47(m,3 H)1.20(d,3 H).MS ES+ m/z 358[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例21-1,第一異構體洗脫,未知絕對構型:
1H NMR(400MHz,CDCl3)δ 7.30(s,1 H)6.03(d,1 H)5.14(s,1 H)4.85(br s,2 H)4.13(q,2 H)3.93(br d,1 H)3.75-3.69(m,3 H)3.58-3.52(m,2 H)3.41-3.34(m,1 H)3.24-3.14(m,2 H)2.39-2.32(m,1 H)2.17(br d,3 H)1.48(t,3 H)1.13(br d,3 H).MS ES+ m/z 358[M+H]+。
實施例21-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 7.31(s,1 H)6.05(s,1 H)5.16(s,1 H)4.87-4.83(m,2 H)4.14(q,2 H)3.93(br d,1 H)3.76-3.69(m,3 H)3.54(br d,2 H)3.35(br d,1 H)3.25-3.13(m,2 H)2.37-2.31(m,1 H)2.20(br d,3 H)1.51-1.47(m,3 H)1.20(br d,3 H).MS ES+ m/z 358[M+H]+。
中間體實施例21
(3R)-4-[2-叔丁氧基-6-[2-(5-甲基-2-呋喃基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉
標題化合物的製備如在中間體實施例9中所述,除了是將混合物攪拌16小時,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(600mg,2.11mmol)和2-(5-甲基-2-呋喃基)吡咯烷(383mg,2.53mmol)開始,得到產物(420mg,50%)。MS ES+ m/z 400[M+H]+。
實施例22
(R)和(S)6-[2-(5-甲基-2-呋喃基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從(3R)-4-[2-叔丁氧基-6-[2-(5-甲基-2-呋喃基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉(420mg,1.05mmol),得到產物,為非對映異構體混合物(250mg,69%)。1H NMR(400MHz,CDCl3)δ 6.06-6.03(m,1H),5.86(br s,1H),5.17-5.15(m,1H),4.87(d,1H),4.75(br d,,1H),3.95(br dd,1H),3.78-3.70(m,3H),3.61-3.53(m,2H),3.41-3.33(m,1H),3.24-3.12(m,2H),2.27-2.15(m,6H),2.08-2.01(m,1H),1.24-1.14(m,3H).MS ES+ m/z 344[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例22-1,第一異構體洗脫,具有未知絕對構型:
1H NMR(400MHz,CDCl3)δ 6.04(d,1H),5.86(br s,1H),5.16(s,1H),4.86(s,1H),4.74(br d,1H),3.95(br d,1H),3.72(s,3H),3.60-3.52(m,2H),3.39-3.34(m,1H),3.25-3.16(m,2H),2.27-2.16(m,6H),2.06(br s,1H),1.16(br d,3H).MS ES+ m/z 344[M+H]+。
實施例22-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 6.05(d,1H),5.87(br s,1H),5.17(s,1H),4.87(s,1H),4.74(br d,1H),3.95(br d,1H),3.78-3.71(m,3H),3.61-3.51(m,2H),3.37-3.18(m,3H),2.27-2.16(m,6H),2.06(br s,1H),1.22(d,3H).MS ES+ m/z 344[M+H]+。
中間體實施例22
3-[1-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]吡咯烷-2-芳基]-N,N-二甲基-苯胺
標題化合物的製備如在中間體實施例9中所述,除了混合物是在70℃下攪拌2小時,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基嗎啉(100mg,0.35mmol)和N,N-二甲基-3-吡咯烷-2-芳基-苯胺(100mg,0.53mmol),得到產物(136mg,88%)。MS ES+ m/z 439[M+H]+。
實施例23
(R)和(S)6-[2-[3-(二甲基氨基)苯基]吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從3-[1-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]吡咯烷-2-芳基]-N,N-二甲基-苯胺(136mg,0.31mmol),得到產物,為非對映異構體混合物(33mg,28%)。1H NMR(500MHz,DMSO-d 6)δ 7.14-7.04(m,1 H),6.63-6.53(m,2 H),6.50-6.39(m,1 H),4.94-4.74(m,3 H),3.86-3.79(m,1 H),3.75-3.69(m,1 H),
3.62(br d,2 H),3.56-3.42(m,4 H),3.18(br d,1 H),3.08(br d,1 H),2.88-2.85(m,6 H),2.39-2.25(m,1 H),1.97-1.87(m,2 H),1.80(br d,1 H),1.09-1.00(m,1.5 H),0.77(br d,1.5 H).MS ES+ m/z 383[M+H]+。
中間體實施例23
(3R)-4-[2-叔丁氧基-6-(3-甲基嗎啉-4-芳基)-4-吡啶基]-3-甲基-嗎啉
標題化合物的製備如在中間體實施例9中所述,除了是將混合物在110℃下攪拌6小時,起始於(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基嗎啉(500mg,1.76mmol)和3-甲基嗎啉(213mg,2.1mmol),得到產物(470mg,76%)。MS ES+ m/z 350[M+H]+。
實施例24
(R)和(S)4-[(3R)-3-甲基嗎啉-4-芳基]-6-(3-甲基嗎啉-4-芳基)-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從(3R)-4-[2-叔丁氧基-6-(3-甲基嗎啉-4-芳基)-4-吡啶基]-3-甲基-嗎啉(500 100mg,1.42mmol),得到作為非對映異構體混合物的產物(230mg,55%)。1H NMR(400MHz,CDCl3)δ 5.30(s,1 H)5.08(d,1 H)4.00-3.55(m,10 H)3.32-3.16(m,3 H)3.08(br
t,1 H)1.26-1.17(m,6 H).MS ES+ m/z 294[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例24-1,第一異構體洗脫,未知絕對構型:
1H NMR(400MHz,CDCl3)δ 5.29(d,1H),5.07(d,1H),3.95(br d,3H),3.85-3.69(m,7H),3.25-3.19(m,3H),3.05(br d,1H),1.22-1.17(m,6H).MS ES+ m/z 294[M+H]+。
實施例24-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 5.28(br s,1H),5.03(br s,1H),3.99-3.72(m,10H),3.33-3.18(m,4H),1.25-1.18(m,6H).MS ES+ m/z 294[M+H]+。
中間體實施例24
(3R)-4-[2-叔丁氧基-6-[2-(三氟甲基)-1-呱啶基]-4-吡啶基]-3-甲基-嗎啉
標題化合物的製備如在中間實施例9中所述,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(500mg,1.76mmol)和2-(三氟甲基)呱啶(323mg,2.11mmol),得到產物(575mg,81%)。MS ES+ m/z 402[M+H]+。
實施例25
(R)和(S)4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-(三氟甲基)-1-呱啶基]-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從(3R)-4-[2-叔丁氧基-6-[2-(三氟甲基)-1-呱啶基]-4-吡啶基]-3-甲基-嗎啉(500mg,1.24mmol),得到產物,為非對映異構體混合物(230mg,53%)。1H NMR(300MHz,DMSO-d 6)δ 9.71(br s,1 H),5.59-5.55(m,1 H),5.32(br s,2 H),3.89(br s,3 H),3.69-3.65(m,2 H),3.61(br s,2 H),3.34-3.32(m,2 H),1.91(br s,1 H),1.65(br s,5 H),1.06(br s,3 H)。通過SFC的手性分離得到兩種異構體。
實施例25-1,第一異構體洗脫,具有未知絕對構型:
1H NMR(400MHz,CDCl3)δ 5.29(d,1 H),5.20(d,1 H),4.78-4.74(m,1 H),3.99-3.95(m,1 H),3.83-3.75(m,3 H),3.63-3.58(m,1 H),3.39(br d,1 H),3.24-3.18(m,3 H),2.13-2.03(m,2 H),1.80-1.69(m,4 H),1.21(d,3 H).MS ES+ m/z 346[M+H]+。
實施例25-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 5.30(d,1 H),5.20(d,1 H),4.75-4.70(m,1 H),3.97(br dd,1 H),3.81-3.74(m,3 H),3.64-3.59(m,1 H),3.39(br d,1 H),3.31-3.20(m,3 H),2.11-1.99(m,2 H),1.80-1.69(m,4 H),1.23(d,3 H).MS ES+ m/z 346[M+H]+。
中間體實施例25
4-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]-3-苯基-嗎啉
標題化合物的製備如在中間實施例9中所述,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(400mg,1.4mmol)和3-苯基嗎啉(275mg,1.69mmol),得到產物(360mg,62%)。MS ES+ m/z 412[M+H]+。
實施例26
(R)和(S)4-[(3R)-3-甲基嗎啉-4-芳基]-6-(3-苯基嗎啉-4-芳基)-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從4-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]-3-苯基-嗎啉(350mg,0.85mmol),得到產物,為非對映異構體混合物(100mg,33%)。1H NMR(400MHz,CDCl3)δ 7.36-7.27(m,3 H),7.25-7.19(m,2 H),5.35-5.21(m,1 H),5.08-4.98(m,1 H),4.49-4.43(m,0.5 H),4.33-4.27(m,0.5 H),4.01-3.82(m,4 H),3.74-3.58(m,3 H),3.57-3.38(m,3 H),3.15-2.93(m,3 H),1.17-1.06(m,1.5 H),0.78-0.63(m,1.5 H).MS ES+ m/z 356[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例26-1,第一異構體洗脫,具有未知絕對構型:
1H NMR(400MHz,CDCl3)δ 7.36-7.28(m,3 H),7.25-7.19(m,2 H),5.26(br s,1 H),5.02(br s,1 H),4.35-4.26(m,1 H),4.00-3.87(m,4 H),3.72-3.62(m,4 H),3.52-3.42(m,2 H),3.00(br s,3 H),0.76-0.66(m,3 H).MS ES+ m/z 356[M+H]+。
實施例26-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 7.40-7.27(m,3 H),7.23(br s,2 H),5.35-5.21(m,1 H),5.09-4.90(m,1 H),4.57-4.36(m,1 H),4.11-3.73(m,5 H),3.71-3.29(m,4 H),3.71-3.29(m,1 H),3.20-2.90(m,3 H),1.13(br d,3 H).MS ES+ m/z 356[M+H]+。
中間體實施例26
4-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]-1,4-噻嗪烷1-氧化物
標題化合物的製備如在中間實施例9中所述,除了是將混合物在70℃下攪拌過夜,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(100mg,0.35mmol)和1,4-噻嗪烷1-氧化物(67mg,0.56mmol),得到產物(70mg,54%)。MS ES+ m/z 368[M+H]+。
實施例27
4-[(3R)-3-甲基嗎啉-4-芳基]-6-(1-氧代-1,4-噻嗪烷-4-芳基)-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從4-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]-1,4-噻嗪烷1-氧化物(70mg,0.19mmol)反應,得到產物(14mg,24%)。1H NMR(500MHz,DMSO-d 6)δ 5.61(br s,1 H),5.27(s,1 H),3.95-3.84(m,4 H),3.82-3.73(m,2 H),3.71-3.64(m,1 H),3.64-3.57(m,1 H),3.52-3.42(m,1 H),2.99(td,1 H),2.92-2.81(m,2 H),2.67-2.59(m,2 H),2.04-2.11(m,2 H),1.07(d,3 H).MS ES+ m/z 312[M+H]+。
中間體實施例27
4-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]-1,4-噻嗪烷1,1-二氧化物
標題化合物的製備如在中間實施例9中所述,除了是將混合物在70℃下攪拌過夜,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(100mg,0.35mmol)和1,4-噻嗪烷1,1-二氧化物(71mg,0.53mmol)反應,得到產物(86mg,64%)。MS ES+ m/z 384[M+H]+。
實施例28
6-(1,1-二氧代-1,4-噻嗪烷-4-芳基)-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從4-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]-1,4-噻嗪烷-1(86mg,0.22mmol),得到產物(38mg,52%)。1H NMR(500MHz,DMSO-d 6)δ 5.72(br s,1 H),5.37(br s,1 H),3.96-3.86(m,6 H),3.72-3.65(m,1 H),3.63-3.57(m,1 H),3.50-3.43(m,1 H),3.38(m,2 H),3.18(br d,1 H),3.09-3.05(m,3 H),3.03-2.94(m,1 H),1.07(d,3 H).MS ES+ m/z 328[M+H]+。
中間體實施例28
1-[4-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]呱嗪-1-芳基]乙酮
標題化合物的製備如在中間實施例9中所述,除了是將混合物在70℃下攪拌2小時,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基嗎啉(100mg,0.35mmol)和1-呱嗪-1-芳基乙酮(67mg,0.562mmol)反應,得到產物(67mg,48%)。MS ES+ m/z 378[M+H]+。
實施例29
6-(4-乙醯基呱嗪-1-芳基)-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從1-[4-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]呱嗪-1-芳基]乙酮(67mg,0.18mmol)反應,得到產物(31mg,54%)。1H NMR(500MHz,DMSO-d 6)δ 5.42(br s,1 H),5.20(br s,1 H),3.97-3.83(m,2 H),3.76-3.63(m,1 H),3.63-3.54(m,1 H),3.54-339(m,5 H),3.32-3.28(m,2 H),327-3.16(m,3 H),2.99(td,1 H),2.03(s,3 H),1.07(d,3 H).MS ES+ m/z 321[M+H]+。
中間體實施例29
(3R)-4-[2-叔丁氧基-6-[(2R)-2-苯基-1-呱啶基]-4-吡啶基]-3-甲基-嗎啉
標題化合物的製備如在中間實施例9中所述,除了將混合物在70℃下攪拌2小時,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基嗎啉(100mg,0.35mmol)和(2R)-2-苯基呱啶(85mg,0.53mmol)反應,得到產物(137mg,91%)。MS ES+ m/z 410[M+H]+。
實施例30
4-[(3R)-3-甲基嗎啉-4-芳基]-6-[(2R)-2-苯基-1-呱啶基]-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從(3R)-4-[2-叔丁氧基-6-[(2R)-2-苯基-1-呱啶基]-4-吡啶基]-3-甲基-嗎啉(137mg,0.33mmol),得到產物(30mg,25%)。1H NMR(500MHz,DMSO)δ 10.07(br s,1 H),7.39-7.09(m,5H),5.42-5.27(m,1H),5.12-5.04(m,1H),5.03-4.92(m,1H),3.87-3.78(m,1H),3.75-3.69(m,1H),3.63-3.58(m,1H),3.57-3.52(m,1H),3.52-3.45(m,1H),3.42-3.29(m,2H),3.26-3.19(m,1H),3.15-3.09(m,1H),2.93-2.83(m,1H),2.01-1.91(m,1H),1.87-1.78(m,1H),1.71-1.55(m,1H),1.54-1.43(m,2H),0.86-0.73(m,3H).MS ES+ m/z 354[M+H]+。
中間體實施例30
(3R)-4-[2-叔丁氧基-6-(4-甲基-2-苯基-呱嗪-1-芳基)-4-吡啶基]-3-甲基-嗎啉
標題化合物的製備如在中間實施例9中所述,除了是將混合物在70℃下攪拌2小時,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基嗎啉(100mg,
0.35mmol)和1-甲基-3-苯基-呱嗪(93mg,0.53mmol)反應,得到產物(149mg,95%)。MS ES+ m/z 425[M+H]+。
實施例31
4-[(3R)-3-甲基嗎啉-4-芳基]-6-(4-甲基-2-苯基-呱嗪-1-芳基)-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從(3R)-4-[2-叔丁氧基-6-(4-甲基-2-苯基-呱嗪-1-芳基)-4-吡啶基]-3-甲基嗎啉(149mg,0.35mmol),得到產物(42mg,32%)。1H NMR(500MHz,DMSO)δ 7.41-7.09(m,5H),5.84-5.68(m,1H),5.41-5.20(m,1H),5.19-4.88(m,1H),3.88-3.78(m,1H),3.78-3.68(m,1H),3.65-3.50(m,2H),3.47-3.08(m,5H),3.02-2.94(m,0.5H),2.94-2.81(m,1H),2.73-2.63(m,1H),2.61-2.55(m,0.5H),2.45-2.38(m,0.5H),2.37-2.28(m,0.5H),2.17(s,3H),1.09-0.97(m,1.5H),0.84-0.71(m,1.5H).MS ES+ m/z 369[M+H]+。
中間體實施例31
4-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]-3-(三氟甲基)嗎啉
標題化合物的製備如在中間實施例9中所述,除了將混合物在70℃下攪拌過夜,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(100mg,0.35mmol)和3-(三氟甲基)嗎啉鹽酸鹽(101mg,0.53mmol),得到產物(74mg,52%)。MS ES+ m/z 404[M+H]+。
實施例32
4-[(3R)-3-甲基嗎啉-4-芳基]-6-[3-(三氟甲基)嗎啉-4-芳基]-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從4-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]-3-(三氟甲基)嗎啉(74mg,0.18mmol),得到產物(16mg,26%)。1H NMR(500MHz,DMSO)δ 6.39-6.32(m,0.5H),5.87-5.79(m,0.5H),5.69-5.58(m,1H),5.44-5.36(m,1H),5.24-5.09(m,1H),4.21-4.09(m,1H),3.99-3.82(m,3H),3.75-3.63(m,3H),3.63-3.55(m,1H),3.55-3.27(m,4H),3.26-3.15(m,1H),3.08-2.92(m,1H),1.16-0.99(m,3H).MS ES+ m/z 348[M+H]+。
中間體實施例32
(3R)-4-[2-叔丁氧基-6-(3-環丙基嗎啉-4-芳基)-4-吡啶基]-3-甲基-嗎啉
如在中間實施例9中標題化合物的製備所述,除了將混合物在70℃下攪拌2小時,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-嗎啉(100mg,0.35mmol)和3-環丙基嗎啉(67mg,0.56mmol),得到產物(93mg,70%)。MS ES+ m/z 376[M+H]+。
實施例33
6-(3-環丙基嗎啉-4-芳基)-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從4-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]-3-(三氟甲基)嗎啉(93mg,0.25mmol),得到產物(6mg,7%)。1H NMR(500MHz,CD3OD)δ 5.30(d,1 H),5.15(t,1 H),3.84-3.73(m,5 H),3.70-3.53(m,4 H),3.52-3.46(m,1 H),3.46-3.36(m,1 H),3.33-3.18(m,3 H),3.08-2.99(m,1 H),2.91-2.78(m,2 H),2.73-2.63(m,1 H),1.32-1.21(m,1 H),1.08(d,1 H),1.05(d,2 H),0.37-0.22(m,3 H),0.14--0.07(m,3 H).MS ES+ m/z 320[M+H]+。
中間體實施例33
(3R)-4-[2-叔丁氧基-6-[(2S)-2-(三氟甲基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉
標題化合物的製備如在中間實施例9中所述,除了將混合物在70℃下攪拌2小時,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(100mg,0.35mmol)和(2S)-2-(三氟甲基)吡咯烷(73mg,0.53mmol),得到產物(79mg,58%)。MS ES+ m/z 388[M+H]+。
實施例34
4-[(3R)-3-甲基嗎啉-4-芳基]-6-[(2S)-2-(三氟甲基)吡咯烷-1-芳基]-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從(3R)-4-[2-叔丁氧基-6-[(2S)-2-(三氟甲基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基嗎啉(79mg,0.2mmol)反應,得到產物(36mg,53%)。1H NMR(500MHz,DMSO-d 6)δ 9.74(br s,1 H),5.44(s,1 H),5.34(s,1 H),4.99(m,1 H),3.94-3.83(m,2 H),3.72-3.64(m,1 H),3.64-3.54(m,2 H),3.46(td,1 H),3.39-3.34(m,2 H),3.31-3.22(m,1 H),2.99(td,1 H),2.05-1.97(m,3 H),1.07(d,3 H).MS ES+ m/z 332[M+H]+。
中間體實施例34
(3R)-4-[2-叔丁氧基-6-[(2R)-2-(三氟甲基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉
標題化合物的製備如在中間實施例9中所述,除了將混合物在70℃下攪拌2小時,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基嗎啉(100mg,0.35mmol)和(2R)-2-(三氟甲基)吡咯烷(73mg,0.53mmol),得到產物(76mg,56%)。MS ES+ m/z 388[M+H]+。
實施例35
4-[(3R)-3-甲基嗎啉-4-芳基]-6-[(2R)-2-(三氟甲基)吡咯烷-1-芳基]-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從(3R)-4-[2-叔丁氧基-6-[(2R)-2-(三氟甲基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基嗎啉(76mg,0.2mmol),得到產物(34mg,52%)。1H NMR(500MHz,DMSO-d 6)δ 9.75(br s,1 H),5.44(s,1 H),5.33(s,1 H),4.98(m,1 H),3.89(m,2 H),3.73-3.65(m,1 H),3.65-3.55(m,2 H),3.46(td,1 H),3.32-3.24(m,2 H),2.99(td,1 H),2.12-1.95(m,4 H),1.07(d,3 H).MS ES+ m/z 332[M+H]+。
實施例36
(R)和(S)6-[2-(3-氯苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮
(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基嗎啉(1g,3.52mmol),2-(3-氯苯基)吡咯烷(764mg,4.2mmol),氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)[2-(2'-氨基-1,1'-聯苯)]鈀(11)0.35mmol)和K3PO4(1.5g,7.04mmol)被加入anh.1,4-二噁烷(10ml)中並用氮氣脫氣5分鐘。將所得混合物在微波反應器中在100℃加熱1小時。當冷卻至室溫時,將混合物通過矽藻土過濾,並將濾液用水稀釋,並用EtOAc萃取。將合併的有機物用鹽水洗滌,過濾,濃縮並在矽膠柱上純化,用20%EtOAc/石油醚洗脫。將中間體溶於DCM(10ml)中並在0℃緩慢加入TFA(1.87ml,24.5mmol)。將反應混合物在室溫下攪拌1小時,然後用sat.aq.NaHCO3鹼化,並用DCM萃取。將合併的有機物用鹽水洗滌,用Na2SO4乾燥,過濾,濃縮並在矽膠柱上純化,用5%MeOH/DCM洗脫,得到標題化合物(190mg,14%)。1H NMR(400MHz,CDCl3)δ 7.27(br s,1H),7.25-7.24(m,1H),7.17(s,1H),7.07(br d,1H),5.15(dd,1H),4.77-4.64(m,2H),3.95-3.89(m,1H),3.76-3.65(m,3H),3.59-3.45(m,3H),3.20-3.06(m,2H),2.49-2.38(m,1H),2.08-1.91(m,3H),1.21(d,1.5 H),0.99(d,1.5 H).MS ES+ m/z 374[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例36-1,第一異構體洗脫,具有未知絕對構型:
1H NMR(400MHz,DMSO-d 6)δ 7.33(d,1H),7.29-7.26(m,1H),7.22(s,1H),7.15(br d,1H),5.05-4.90(m,3H),3.83(br dd,1H),3.73-3.40(m,
6H),3.19(br d,1H),2.86(dt,1H),2.35-2.27(m,1H),1.93-1.77(m,3H),1.04(d,3H).MS ES+ m/z 374[M+H]+。
實施例36-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,DMSO-d 6)δ 7.33(d,1H),7.28-7.24(m,2H),7.17(br d,1H),4.99-4.79(m,3H),3.84-3.73(m,2H),3.62-3.33(m,5H),3.10(br d,1H),2.88(dt,1H),2.38-2.30(m,1H),1.93-1.75(m,3H),0.77(br d,3H).MS ES+ m/z 374[M+H]+。
實施例37
6-[2-(3-環丙基苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮
2-環丙基-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(189mg,1.13mmol),氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)[2-(2'-氨基-1,1'-聯苯)]鈀(II)(29mg,0.09mmol)和0.5M K3PO4(5ml)溶於THF(10ml)中,所得混合物用氬氣脫氣15分鐘。加入6-[2-(3-氯苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮(350mg,0.93mmol)將所得混合物在微波反應器中在100℃加熱1小時。將反應混合物通過矽藻土過濾,濾液用水稀釋,用乙酸乙酯萃取。將合併的有機物用鹽水洗滌,用Na2SO4乾燥,過濾,濃縮並通過製備型HPLC(使用0.1%甲酸的MeCN溶液)純化。將粗產物在矽膠柱上進一步純化,用5%MeOH/DCM洗脫,得到標題化合物(45mg,4%)。1H NMR
(400MHz,CDCl3)δ 7.19(td,,1H),6.95-6.88(m,3H),5.12(dd,1H),4.77-4.66(m,2H),3.95-3.89(m,1H),3.72-3.64(m,3H),3.59-3.43(m,3H),3.21-3.09(m,2H),2.41(br dd,1H),2.10-1.92(m,3H),1.86(td,1H),1.21(br d,2H),1.00-0.93(m,3H),0.88-0.83(m,2H).MS ES+ m/z 380[M+H]+。
中間體實施例35
(3R)-4-[2-叔丁氧基-6-[2-(2-吡啶基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基-嗎啉
(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(750mg,2.64mmol),2-吡咯烷-2-芳基吡啶(469mg,3.16mmol)和將KOtBu(591mg,5.3mmol)溶於無水THF中。1,4-二噁烷(10ml),所得反應混合物用氮氣脫氣15分鐘。然後加入XPhos(207mg,0.26mmol)和Pd(OAc)2(59mg,0.26mmol),將反應混合物在110℃下在密封管中攪拌16小時。當冷卻至室溫時,將混合物通過矽藻土過濾,並將濾液用水稀釋,並用EtOAc萃取。將合併的有機物用鹽水洗滌,過濾,濃縮並在矽膠柱上純化,用20%EtOAc/石油醚洗脫,得到標題化合物(470mg,45%)。MS ES+ m/z 397[M+H]+。
實施例38
(R)和(S)4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-(2-吡啶基)吡咯烷-1-芳基]-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從(3R)-4-[2-叔丁氧基-6-[2-(2-吡啶基)吡咯烷-1-芳基]-4-吡啶基]-3-甲基嗎啉(470mg,1.18mmol),得到產物,為非對映異構體混合物(230mg,57%)。1H NMR(400MHz,CDCl3)δ 8.61-8.57(m,1H),7.69-7.63(m,1H),7.19(br t,2H),5.15(br d,1H),4.88-4.82(m,1H),4.73-4.67(m,1H),3.90(br d,1H),3.82-3.74(m,1H),3.71-3.46(m,5H),3.17-3.02(m,2H),2.54-2.41(m,1H),2.21-2.05(m,3H),1.17(br d,1.5H),0.93(br d,1.5H).MS ES+ m/z 341[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例38-1,第一異構體洗脫,具有未知絕對構型:
1H NMR(400MHz,CDCl3)δ 8.60(d,1H),7.66(dt,1H),7.23-7.17(m,2H),5.16(d,1H),4.87(dd,1H),4.73(d,1H),3.91(dd,1H),3.77-3.62(m,4H),3.56-3.48(m,2H),3.18-3.02(m,2H),2.46(qd,1H),2.22-2.06(m,3H),1.18(d,3H).MS ES+ m/z 341[M+H]+。
實施例38-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 8.58(dd,1H),7.64(dt,1H),7.21-7.16(m,2H),5.14(d,1H),4.84(dd,1H),4.67(d,1H),3.92-3.80(m,2H),3.66-3.46(m,5H),3.14-3.03(m,2H),2.54-2.44(m,1H),2.18-2.05(m,3H),0.93(d,3H).MS ES+ m/z 341[M+H]+。
中間體實施例36
(3R)-4-[2-叔丁氧基-6-(2-噻唑-2-基吡咯烷-1-芳基)-4-吡啶基]-3-甲基-嗎啉
標題化合物的製備如在中間實施例35中所述,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(400mg,1.4mmol)和2-吡咯烷-2-基噻唑鹽酸鹽(321mg,1.69mmol),得到產物(110mg,19%)。MS ES+ m/z 403[M+H]+。
實施例39
(R)和(S)4-[(3R)-3-甲基嗎啉-4-芳基]-6-(2-噻唑-2-基吡咯烷-1-芳基)-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從(3R)-4-[2-叔丁氧基-6-(2-噻唑-2-基吡咯烷-1-芳基)-4-吡啶基]-3-甲基(100mg,0.24mmol),得到作為非對映異構體混合物的產物(10mg,12%)。1H NMR(400MHz,CDCl3)δ 7.75(dd,1 H)5.25-5.12(m,2 H)4.88(br s,1 H)3.92(br d,1 H)3.72-3.64(m,4 H)3.54-3.48(m,2 H)3.21-3.11(m,2 H)2.48(br d,1 H)2.28-2.14(m,4 H)1.25(s,1 H)1.19(br d,1 H)1.01(br d,1 H).MS ES+ m/z 347[M+H]+。
實施例40
(R)和(S)6-[2-(5-甲基異噁唑-3-芳基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮
(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(500mg,1.76mmol),5-甲基-3-吡咯烷-2-芳基-異噁唑(3.11mg,2.11mmol)和KOtBu(3.94mg,3.5mmol)溶於甲苯(10ml)中,所得反應混合物用氮氣脫氣15分鐘。然後加入XPhos(138mg,0.17mmol)和Pd(OAc)2(39mg,0.17mmol),將反應混合物在110℃下在密封管中攪拌16小時。當冷卻至室溫時,將混合物通過矽藻土過濾,並將濾液用水稀釋,並用EtOAc萃取。將合併的有機物用鹽水洗滌,過濾,濃縮並通過製備型HPLC(使用0.1%甲酸的MeCN溶液)純化,得到作為非對映異構體混合物的產物(200mg,33%)。1H NMR(400MHz,CDCl3)δ 5.83(br d,1 H)5.17(br s,1 H)4.92-4.87(m,2 H)3.94(br d,1 H)3.74-3.68(m,4 H)3.52(br d,2 H)3.24-3.10(m,2 H)2.38(d,4 H)2.12(br s,3 H)1.20(br d,1.5 H)1.05(br d,1.5 H).MS ES+ m/z 345[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例40-1,第一異構體洗脫,具有未知絕對構型:
1H NMR(400MHz,CDCl3)δ 5.84(s,1 H)5.16(s,1 H)4.92-4.89(m,2 H)3.94(br dd,1 H)3.75-3.68(m,4 H)3.55-3.49(m,2 H)3.24-3.19(m,1 H)3.12(br dd,1 H)2.38(s,4 H)2.12(br t,3 H)1.20(br d,3 H).MS ES+ m/z 345[M+H]+。
實施例40-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 5.83(s,1 H)5.16(br s,1 H)4.90(br s,2 H)3.92(br s,1 H)3.70(br d,4 H)3.53(br s,2 H)3.16(br s,2 H)2.37(s,4 H)2.12(br s,3 H)1.06(br s,3 H).MS ES+ m/z 345[M+H]+。
實施例41
1-甲基-4-[(3R)-3-甲基嗎啉-4-芳基]-6-[(2R)-2-(三氟甲基)-1-呱啶基]
將LiOtBu(111mg,1.39mmol)和碘甲烷(0.19ml,1.39mmol)加入到4-[(3R)-3-甲基嗎啉-4-芳基]-6-[(2R)-2-(三氟甲基)-1-哌啶基]-1氫-吡啶-2-酮(240mg,0.7mmol)在丙酮(10ml)中的溶液中,將所得混合物在80℃下攪拌1小時。當冷卻至室溫時,將混合物濃縮。加入水(10ml),混合物用EtOAc(3×10ml)萃取。將合併的有機物用鹽水洗滌,用Na2SO4乾燥,過濾,濃縮並通過製備型HPLC純化,得到固體形式的產物(40mg,12%)。1H NMR(400MHz,DMSO-d6)VT 90℃:δ 5.80(s,1H),5.31(d,1H),4.04-3.85(m,3H),3.67-3.61(m,2H),3.50-3.43(m,1H),3.26-3.18(m,5H),3.06-3.02(m,1H),2.88-2.85(m,1H),2.00-1.99(m,1H),1.83-1.81(m,1H),1.70-1.60(m,4H),1.08(d,3H).MS ES+ m/z 360[M+H]+。
中間體實施例37
5-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]-8-氧雜-5-氮雜螺[3.5]壬烷
標題化合物的製備如在中間體實施例9中所述,除了將混合物在微波反應器中在130℃下加熱2小時,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基))-3-甲基-嗎啉(100mg,0.35mmol)和8-氧雜-5-氮雜螺[3.5]壬烷(54mg,0.42mmol),得到產物(86mg,65%)。MS ES+ m/z 376[M+H]+。
實施例42
4-[(3R)-3-甲基嗎啉-4-芳基]-6-(8-氧雜-5-氮雜螺[3.5]壬烷-5-芳基)-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從5-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]-8-氧雜-5-氮雜螺[3.5]壬烷(130mg,0.35mmol),得到產物(35mg,31%)。1H NMR(500MHz,DMSO-d6):δ 10.21(br.s,1H),5.21(s,1H),5.11(s,1H),3.88-3.83(m,2H),3.69-3.58(m,4H),3.48-3.42(m,3H),3.31-3.28(m,1H),3.18-3.17(m,2H),2.99-2.96(m,1H),2.08-2.00(m,4H),1.64-1.61(m,2H),1.07(d,3H).MS ES+ m/z 320[M+H]+。
中間體實施例38
4-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]-3-(三氟甲基)嗎啉
標題化合物的製備如在中間體實施例9中所述,除了將混合物在微波反應器中在150℃下加熱3小時,起始於(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(400mg,1.4mmol)和3-(三氟甲基)嗎啉(330mg,1.68mmol),得到產物(330mg,58%)。MS ES+ m/z 404[M+H]+。
實施例43
4-[(3R)-3-甲基嗎啉-4-芳基]-6-[3-(三氟甲基)嗎啉-4-芳基]-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從4-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]-3-(三氟甲基)嗎啉(350mg,0.87mmol),得到作為非對映異構體混合物的產物(200mg,65%)。MS ES+ m/z 348[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例43-1,第一異構體洗脫,未知絕對構型:
1H NMR(400MHz,DMSO-d6):δ 9.9-9.6(br.s,1H),5.62(d,1H),5.38(s,1H),5.15(br.s,1H),4.13(d,1H),3.91-3.86(m,2.3H),3.67-3.58(m,3H),3.5-3.4(m,2H),3.38-3.25(m,3H),3.17(q,1H),3.01-2.95(m,1H),1.06(d,3H).MS ES+ m/z 348[M+H]+。
實施例43-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,DMSO-d6):δ 9.9-9.6(br.s,1H),5.62(s,1H),5.38(s,1H),5.15(br.s,1H),4.13(d,1H),3.91-3.86(m,3H),3.68-3.57(m,4H),3.49-3.42(m,2H),3.286(s,1H),3.17(q,1H),3.01-2.94(m,1H),1.06(d,3H).MS ES+ m/z 348[M+H]+。
中間體實施例39
(3R)-4-[2-叔丁氧基-6-[2-(3-甲氧基苯基)-1-呱啶基]-4-吡啶基]-3-甲基-嗎啉
標題化合物的製備如在中間體實施例9中所述,除了將混合物攪拌4小時,從(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(500mg,1.7mmol)和2-(3-甲氧基苯基)呱啶(404mg,2.11mmol)開始,得到產物(460mg,61%)。MS ES+ m/z 440[M+H]+。
實施例44
6-[2-(3-甲氧基苯基)-1-呱啶基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從(3R)-4-[2-叔丁氧基-6-[2-(3-甲氧基苯基)-1-呱啶基]-4-吡啶基]-3-甲基(460mg,1mmol),得到產物,為非對映異構體混合物(390mg,98%)。MS ES+ m/z 384[M+H]+。通過SFC的手性分離得到兩種異構體。
實施例44-1,第一異構體洗脫,未知絕對構型:
1H NMR(500MHz,CDCl3)δ 7.20(t,1H),6.83-6.71(m,3H),5.21(d,1H),5.11(d,1H),4.28(br dd,1H),3.92(br d,1H),3.75(s,3H),3.68(d,2H),3.59-3.43(m,3H),3.16-3.03(m,3H),2.01-1.85(m,2H),1.81-1.70(m,4H),0.89(d,3H).MS ES+ m/z 384[M+H]+。
實施例44-2,洗脫的第二異構體,具有未知的絕對構型:
1H NMR(400MHz,CDCl3)δ 7.26-7.20(m,1H),6.84-6.74(m,3H),5.22(d,1H),5.11(d,1H),4.56(br t,1H),3.92(br dd,1H),3.77(s,3H),3.72-3.62(m,3H),3.54(dt,1H),3.41-3.31(m,2H),3.20-3.04(m,2H),2.10-1.93(m,2H),1.73(br dd,4H),1.19(d,3H).MS ES+ m/z 384[M+H]+。
中間體實施例40
4-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]-3-(三氟甲基)呱嗪-1-甲酸叔丁酯
標題化合物的製備如在中間體實施例9中所述,除了將混合物在微波反應器中在130℃下加熱3小時,起始於(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-嗎啉(200mg,0.7mmol)和3-(三氟甲基)呱嗪-1-甲酸叔丁酯(214mg,0.84mmol),得到產物(150mg,43%)。MS ES+ m/z 503[M+H]+。
中間體實施例41
4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-(三氟甲基)呱嗪-1-芳基]-1氫-吡啶-2-酮
標題化合物的製備如在實施例10中所述,從4-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]-3-(三氟甲基))呱嗪-1-甲酸叔丁酯(300mg,0.6mmol)反應,得到產物(150mg,72%)。MS ES+ m/z 347[M+H]+。
實施例45
6-[4-乙醯基-2-(三氟甲基)呱嗪-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮
將乙醯氯(0.04ml,0.53mmol)和Et3 N(0.1ml,0.7mmol)加入到4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-(三氟甲基)吡啶-1-芳基]-1氫-吡啶-2-酮(100mg,0.35mmol)的DCM(2ml)溶液中。將混合物在0℃下攪拌30分鐘。加入水
(5ml),並用DCM(3×5ml)萃取混合物。將合併的有機物用鹽水洗滌,用Na2SO4乾燥,過濾並濃縮。將殘餘物溶於EtOH(1ml)中,並在室溫下加入3M EtOH中的甲胺(3ml)。將所得混合物在室溫下攪拌1小時,濃縮並通過製備型HPLC純化,得到產物(60mg,53%)。1H NMR(400MHz,DMSO-d6):δ 9.77(br.s,1H),5.65(s,1H),5.43(s,1H),5.33(bs,1H),3.90-3.86(m,4H),3.67-3.63(m,2H),3.51-3.45(m,2H),3.34-3.28(m,3H),3.20-3.18(m,2H),3.08-3.01(m,2H),2.01(s,2H),1.10-1.08(m,3H).MS ES+ m/z 389[M+H]+。
實施例46
6-[4-(5-氟吡啶-3-羰基)-2-(三氟甲基)呱嗪-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮
在0℃向攪拌的4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-(三氟甲基)呱嗪-1-芳基]-1氫-啶-2-酮(100mg,0.3mmol)和5-氟吡啶-3-甲酸(45mg,0.32mmol)的DMF(2ml)溶液中加入DIPEA(0.15ml,0.87mmol)和T3P(0.17ml,0.58mmol)。將反應混合物在室溫下攪拌1小時。將混合物倒入冰冷的水(10mL)中並用EtOAc(3×10mL)萃取。將合併的有機物用鹽水洗滌,用Na2SO4乾燥,過濾,濃縮並通過製備型HPLC純化,得到產物(30mg,22%)。1H NMR(400MHz,DMSO-d6)VT at 90℃:δ 9.40(br.s,1H),8.64(d,1H),8.43(s,1H),7.77(d,1H),5.67(s,1H),5.44(s1H),5.40(br.s,1H),4.31(br.s,1H),
3.93-3.67(m,4H),3.67-3.60(m,2H),3.50-3.45(m,2H),3.34-2.23(m,3H),3.07-2.96(m,1H),1.10-1.07(m,3H).MS ES+ m/z 470[M+H]+。
實施例47
6-[4-[2-(4-氟苯基)乙醯基]-2-(三氟甲基)呱嗪-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮
標題化合物的製備如實施例49所述,用2-(4-氟苯基)乙酸(49mg,0.32mmol)代替5-氟吡啶-3-甲酸,得到產物(40mg,28%)。1H NMR(400MHz,DMSO-d6)VT 90℃:δ 9.40(br.s,1H),7.22(t,2H),7.06(t,2H),5.64(s,1H),5.43(s,1H),5.34(br.s,1H),4.46(br.s,1H),4.00-3.86(m,4H),3.76-3.60(m,4H),3.48(t,1H),3.34-3.03(m,5H),1.09(t,3H).MS ES+ m/z 483[M+H]+。
實施例48
4-[(3R)-3-甲基嗎啉-4-芳基]-6-[4-(四氫呋喃-2-羰基)-2-(三氟甲基)呱嗪-1-芳基]-1氫-吡啶-2-酮
如實施例49標題化合物的製備所述,用四氫呋喃-2-羧酸(36mg,0.32mmol)代替5-氟吡啶-3-甲酸。SFC的純化提供兩種產品。
實施例48-1,洗脫的具有未知絕對構型的第一異構體(10mg,8%):
1H NMR(400MHz,DMSO-d6)VT at 90℃:δ 9.40(br.s,1H),5.65(s,1H),5.42(s,1H),5.34(br.s,1H),4.62-4.59(m,1H),4.49(br.s,1H),4.11-4.08(m,1H),3.93-3.85(m,3H),3.75(t,2H),3.67-3.60(m,2H),3.50-3.45(m,1H),3.34-3.17(m,3H),3.08-3.04(m,2H),2.15-2.11(m,1H),1.97-1.90(m,1H),1.87-1.81(m 2H),1.10-1.08(m,3H).MS ES+ m/z 445[M+H]+。
實施例48-2,洗脫的第二異構體,具有未知絕對構型(15mg,12%):
1H NMR(400MHz,DMSO-d6)VT at 90℃:δ 9.45(br s,1H),5.65(s,1H),5.42(s,1H),5.34(br.s,1H),4.66-4.62(m,1H),4.49(br.s,1H),4.04-4.02(m,1H),3.89-3.85(m,3H),3.82-3.71(m,2H),3.67-3.60(m,2H),3.51-3.45(m,1H),3.34-3.28(m,1H),3.20-3.18(m,2H),3.08-3.04(m,2H),2.05-2.00(m,2H),1.88-1.80(m,2H),1.11-1.08(m,3H).MS ES+ m/z 445[M+H]+。
中間體實施例42
(3R)-4-[2-叔丁氧基-6-[2-(三氟甲基)呱嗪-1-芳基]-4-吡啶基]-3-甲基-嗎啉
將氫化鋁鋰(56mg,1.5mmol)加入到4-[6-叔丁氧基-4-[(3R)-3-甲基嗎啉-4-芳基]-2-吡啶基]-3-(三氟甲基)呱嗪-1-羧酸叔丁酯(250mg,0.5mmol)的THF(5ml)溶液中。將反應混合物在室溫下攪拌過夜,並用sat.aq.Na2SO4和EtOAc中止反應。將混合物通過矽藻土過濾,並將濾液濃縮,得到產物(120mg,60%)。MS ES+ m/z 403[M+H]+。
中間體實施例43
(3R)-4-[2-叔丁氧基-6-[4-甲基-2-(三氟甲基)呱嗪-1-芳基]-4-吡啶基]-3-甲基-嗎啉
在室溫下將37%的aq.甲醛(0.05ml,0.56mmol)和乙酸(0.03ml,0.56mmol)加入到(3R)-4-[2-叔丁氧基-6-[2-(三氟甲基)呱嗪-1-芳基]-4-吡啶基]-3-甲基-嗎啉(75mg,0.19mmol)在MeOH(2ml)中的溶液中。10分鐘後,加入NaBH3CN(35mg,0.56mmol),並將混合物在室溫下攪拌1小時。將混合物濃縮,將所得殘餘物溶於水(10ml)和EtOAc(10ml)中。分離有機層,水層用EtOAc(2×10ml)萃取。將合併的有機物用鹽水洗滌,用Na2SO4乾燥,過濾,濃縮並通過製備型HPLC純化,得到固體產物(30mg,38%)。MS ES+ m/z 417[M+H]+。
實施例49
4-[(3R)-3-甲基嗎啉-4-芳基]-6-[4-甲基-2-(三氟甲基)呱嗪-1-芳基]-1氫-吡啶-2-酮
如在實施例10中標題化合物的製備所述,從(3R)-4-[2-叔丁氧基-6-[4-甲基-2-(三氟甲基)呱嗪-1-芳基]-4-吡啶基]-(60mg,0.14mmol),得到產物(25mg,48%)。1H NMR(400MHz,DMSO-d6):δ 9.33(br.s,1H),5.57(s,1H),5.36(s,1H),5.26-5.24(m,1H),3.87-3.66(m 3H),3.63-3.59(m,2H),3.50-3.44(m,1H),3.33-3.17(m,2H),3.06-3.01(m,2H),2.77-2.75(m,1H),2.19(s,3H),2.15-2.12(m,1H),1.94-1.89(m,1H),1.10-1.07(m,3H).MS ES+ m/z 361[M+H]+。
實施例50:Vps34生化測定
在DMSO中以100倍於最終測定濃度(n1=n0/3,10點)製備本發明化合物的稀釋系列。將化合物進一步稀釋至測定緩衝液(Life technologies buffer Q,PV5125,用2mM DTT和2mM MnCl 2稀釋5倍)中的測定濃度的4倍。將2.5μl稀釋的化合物加入384孔測定板中,然後加入2.5μl 16.5nM Vps34酶(Life technologies,PV5126)。將酶和化合物在室溫預孵育15分鐘。然後向含有化合物和酶的孔中加入5μl含有在測定緩衝液中的20μ MATP(Life technologies,PV3227)和200μ MPI:PS基質(Life technologies,PV5122)的基質混合物。通過多次吸移進行混合。將反應在室溫下孵育1小時。然後加入含有Adapta Eu-anti-ADP抗體(2.3nM)、Alexa Fluor 647 ADP示蹤劑(9nM)和EDTA(30μM)的Adapta激酶測定試劑盒說明書(Life technologies,PV5099)中該製備的5μl終止-檢測混合物mM)在TR-FRET緩衝液中的溶液,以中止反應。通過吸移進行多次混合。然後將測定板在室溫下溫育30
分鐘,並用Artemis微量板讀數器讀數。計算與DMSO處理的對照樣品相比的化合物的抑制百分比。通過使用Dotmatics軟體,擬合化合物濃度對抑制百分比以產生IC50值。
實施例化合物有效抑制Vps34,測定結果示於表1中(中值IC50 μ MAdapta)。
實施例51
高內涵篩選自噬測定(High Content Screening Autophagy assay)
使用穩定表現綠螢光蛋白(GFP)標記的LC3(GFP-LC3)的人類骨髓瘤細胞株(HOS)來測定專有化合物對自體吞噬的抑製作用。為此目的,通過在5nM下在Bafilomycin A1(Sigma-Aldrich)的存在下,使用mTOR抑製劑KU-0063794以500nM來活化細胞自噬作用。簡而言之,將細胞培養於透明96微量多孔盤中並添加培養液(DMEM-High Modified media)(Hi-Clone Cat # SH30285.01)過夜。在實驗開始時,除去培養基並用含有mTOR抑製劑,巴佛洛黴素A1和載體或所示測試化合物的新鮮培養基替換。6小時後,除去培養基,用冰磷酸鹽緩衝生理鹽水(PBS)潤洗細胞兩次,並在室溫下用4%多聚甲醛固定20分鐘。然後用冰冷的PBS潤洗細胞兩次,然後在PBS中加入1μg/ml的赫斯特染劑(Hoechst 33342)用於核染色。在4℃下孵育過夜後,用PBS潤洗細胞一次以除去過量的染劑,並向每個孔中加入100μl PBS。使用ImageXpress自動顯微鏡(Molecular Devices Inc.)以20x放大率,每孔6個圖像獲取圖像,並用MetaXpress軟體分析以鑑定LC3-GFP病灶。使用Foci面積
/細胞值產生劑量反應曲線,並使用GraphPad Prism軟體中的非線性擬合分析計算IC50值。
所測試的實施例化合物有效抑制HOS細胞中的自噬。測定結果示於表2(中位數IC50 μ MHOS-LC3)。
Claims (42)
- 一種如式(I)所示之化合物
- 如請求項1所述的化合物,其中Y是N。
- 如請求項1所述的化合物,其中R1和R3獨立地選自氫和甲基。
- 如請求項1所述的化合物,其中R2是氫。
- 如請求項1所述的化合物,其中R1是氫。
- 如請求項1所述的化合物,其中R3是甲基。
- 如請求項1所述的化合物,其中R3是氫。
- 如請求項1所述的化合物,其中R5是C1-C3烷基。
- 如請求項1所述的化合物,其中R6是二甲基氨基。
- 如請求項1所述的化合物,其中R7選自氟,氯,三氟甲基,三氟甲氧基,甲氧基,甲基,乙基,環丙基和二甲基氨基。
- 如請求項1所述的化合物,其中R9選自C1-C3烷氧基,5-6元雜環基,苯基和單環5-6元異芳基,其中該5-6元雜環基,該苯基和該單環5-6元異芳基可選擇性地被一個或兩個R8取代。
- 如請求項1所述的化合物,其中R9選自5-6元雜環基,苯基和單環5-6元異芳基,其中該5-6元雜環基,該苯基和該單環5-6元異芳基可選擇性地被一個或兩個R8取代。
- 如請求項1所述的化合物,其中R9選自四氫呋喃基,苯基和吡啶基,各自可選擇性地被一個或兩個R8取代。
- 如請求項1所述的化合物,其中R8是鹵素。
- 如請求項1所述的化合物,其中該R4中的單環5-6元異芳基選自吡啶基,呋喃基,異噁唑基,吡唑基和噻唑基,各自可選擇性地被一個或多個R7取代。
- 如請求項1所述的化合物,其中R7選自氟,氯,C1-C3烷氧基,C1-C3氟烷氧基,C1-C3氟烷基,C3-C6環烷基,N,N-二C1-C3烷基氨基。
- 如請求項16所述的化合物,其中R7選自氟,氯,甲基,乙基,甲氧基,三氟甲氧基,三氟甲基,環丙基和N,N-二甲基氨基。
- 如請求項1所述的化合物,其中X代表一個鍵。
- 如請求項1所述的化合物,其中 X代表CH2,SO,SO2,NR5,NCOR5,NCOR9,NCOCH2 R9或O;且R5是C1-C3烷基。
- 如請求項22所述的化合物,其中R4選自氫,C1-C6烷基,C3-C6環烷基,C1-C3鹵代烷基和苯基,被一個或多個R7取代。
- 如請求項1所述的化合物,其中X代表CH2,SO,SO2,NR5,NCOR5,NCOR9,NCOCH2 R9,O或一個鍵;R4選自氫,COR6,C1-C3烷基,甲氧基C1-C3烷基,C3-C6環烷基,C1-C3氟烷基,苯基和單環5-6元異芳基,其中該苯基和該單環5-6元異芳基可選擇性地被一個或兩個R7取代;R5是C1-C3烷基; R6是N,N-二C1-C3烷基氨基;且R7選自氟,氯,C1-C3烷基,C1-C3烷氧基,C1-C3氟烷氧基,C1-C3氟烷基,C3-C6環烷基和N,N-二C1-C3烷基氨基。
- 如請求項1所述的化合物,其中Y是CH或C;X是O;且R4是氫。
- 如請求項1所述的化合物,其中R1和R2是氫;R3是甲基;X選自CH2,O,NCOR5,NCOR9,NCOCH2 R9和鍵;Y是N;R4是氫,苯基或三氟甲基;R5是甲基;R7是甲氧基;R9選自吡啶基,苯基;且R8是氟。
- 如請求項1所述的化合物,該化合物選自:4-嗎啉代-6-(2-苯基吡咯烷-1-芳基)-1氫-吡啶-2-酮;1-甲基-4-嗎啉代-6-(2-苯基吡咯烷-1-芳基)吡啶-2-酮;4-嗎啉代-6-[(2S)-2-苯基吡咯烷-1-芳基]-1氫-吡啶-2-酮;4-嗎啉代-6-[(2R)-2-苯基吡咯烷-1-芳基]-1氫-吡啶-2-酮;6-(3,6-二氫-2H-吡喃-4-芳基)-4-(3-甲基嗎啉-4-芳基)-1氫-吡啶-2-酮;4-(3-甲基嗎啉-4-芳基)-6-四氫吡喃-4-芳基-1氫-吡啶-2-酮; 6-[2-(3-甲氧基苯基)吡咯烷-1-芳基]-4-(3-甲基嗎啉-4-芳基)-1氫-吡啶-2-酮;4-(3-甲基嗎啉-4-芳基)-6-[2-(3-吡啶基)吡咯烷-1-芳基]-1氫-吡啶-2-酮;4-(3-甲基嗎啉-4-芳基)-6-(2-苯基吡咯烷-1-芳基)-1氫-吡啶-2-酮;N,N-二甲基-1-[4-[(3R)-3-甲基嗎啉-4-芳基]-6-氧代-1氫-吡啶-2-芳基]吡咯烷-2-甲醯胺;6-[2-(1-甲氧基-1-甲基-乙基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-(2-環己基吡咯烷-1-芳基)-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[2-(3-氟苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[2-(2,5-二氟苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-[3-(三氟甲氧基)苯基]吡咯烷-1-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-[3-(三氟甲基)苯基]吡咯烷-1-芳基]-1氫-吡啶-2-酮;6-[2-(3-甲氧基苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(2-苯基吡咯烷-1-芳基)-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-(1-甲基吡唑-4-芳基)吡咯烷-1-芳基]-1氫-吡啶-2-酮; 6-[2-(1,5-二甲基吡唑-3-芳基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[2-(1-乙基吡唑-3-芳基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[2-(5-甲基-2-呋喃基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[2-[3-(二甲基氨基)苯基]吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(3-甲基嗎啉-4-芳基)-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-(三氟甲基)-1-呱啶基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(3-苯基嗎啉-4-芳基)-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(1-氧代-1,4-噻嗪烷-4-芳基)-1氫-吡啶-2-酮;6-(1,1-二氧代-1,4-噻嗪烷-4-芳基)-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-(4-乙醯基呱嗪-1-芳基)-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[(2R)-2-苯基-1-呱啶基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(4-甲基-2-苯基-呱嗪-1-芳基)-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[3-(三氟甲基)嗎啉-4-芳基]-1-氫-吡啶-2-酮;6-(3-環丙基嗎啉-4-芳基)-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮; 4-[(3R)-3-甲基嗎啉-4-芳基]-6-[(2S)-2-(三氟甲基)吡咯烷-1-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[(2R)-2-(三氟甲基)吡咯烷-1-芳基]-1氫-吡啶-2-酮;6-[2-(3-氯苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[2-(3-環丙基苯基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[2-(2-吡啶基)吡咯烷-1-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(2-噻唑-2-基吡咯烷-1-芳基)-1氫-吡啶-2-酮;6-[2-(5-甲基異噁唑-3-芳基)吡咯烷-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;1-甲基-4-[(3R)-3-甲基嗎啉-4-芳基]-6-[(2R)-2-(三氟甲基)-1-呱啶基]吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-(8-氧雜-5-氮雜螺[3.5]壬烷-5-芳基)-1氫-吡啶-2-酮;6-[2-(3-甲氧基苯基)-1-呱啶基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[4-乙醯基-2-(三氟甲基)呱嗪-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;6-[4-(5-氟吡啶-3-羰基)-2-(三氟甲基)呱嗪-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮; 6-[4-[2-(4-氟苯基)乙醯基]-2-(三氟甲基)呱嗪-1-芳基]-4-[(3R)-3-甲基嗎啉-4-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[4-(四氫呋喃-2-羰基)-2-(三氟甲基)呱嗪-1-芳基]-1氫-吡啶-2-酮;4-[(3R)-3-甲基嗎啉-4-芳基]-6-[4-甲基-2-(三氟甲基)呱嗪-1-芳基]-1氫-吡啶-2-酮;和其藥學上可接受的鹽,互變異構體和立體異構體。
- 如請求項1~29中任一項所述的化合物,其用於治療或預防疾病。
- 如請求項1~29中任一項所述的化合物,用於治療癌症。
- 如請求項1~29中任一項所述的化合物,用於治療癌症,該癌症選自三陰性乳腺癌,胰腺癌,白血病,黑素瘤和肺癌。
- 如請求項1~29中任一項所述的化合物,其用於治療糖尿病。
- 如請求項1~29中任一項所述的化合物,用於治療糖尿病,該糖尿病是II型糖尿病。
- 如請求項1~29中任一項所述的化合物,用於治療疾病,該疾病選自發炎性疾病,神經退化性疾病,心血管疾病和病毒感染。
- 一種如請求項1~29中任一項所述的化合物在製備用於治療癌症的藥物中的用途。
- 一種如請求項1~29中任一項所述的化合物在製備用於治療癌症的藥物中的用途,該癌症選自三陰性乳腺癌,胰腺癌,白血病,黑素瘤和肺癌。
- 一種如請求項1~29中任一項所述的化合物在製備用於治療糖尿病的藥物中的用途。
- 一種如請求項1~29中任一項所述的化合物在製備用於治療糖尿病的藥物中的用途,該糖尿病是II型糖尿病。
- 一種如請求項1~29中任一項所述的化合物在製備用於治療選自發炎性疾病,神經退化性疾病,心血管疾病和病毒感染的疾病的藥物中的用途。
- 一種藥學組成物,其包含一種如請求項1~29中任一項所述的化合物和藥學上可接受的稀釋劑,載體和/或賦形劑。
- 一種藥學組成物,其包含治療有效量的如請求項1所述的化合物和選自烷基化劑,抗代謝物,抗癌喜樹鹼衍生物,植物源抗癌試劑,抗生素,酵素,鉑配位化合物,酪氨酸激酶抑製劑,賀爾蒙、激素拮抗劑,單克隆抗體,干擾素和生物反應調節劑。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP16156533 | 2016-02-19 | ||
EP16156533.8 | 2016-02-19 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201731843A TW201731843A (zh) | 2017-09-16 |
TWI723131B true TWI723131B (zh) | 2021-04-01 |
Family
ID=55404646
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW106105178A TWI723131B (zh) | 2016-02-19 | 2017-02-17 | 6‐雜環基‐4‐嗎啉‐4‐芳基吡啶‐2‐酮化合物 |
Country Status (19)
Country | Link |
---|---|
US (2) | US11179399B2 (zh) |
EP (1) | EP3416957B1 (zh) |
JP (1) | JP6858984B2 (zh) |
CN (1) | CN108884067B (zh) |
AU (1) | AU2017219847B2 (zh) |
CA (1) | CA3015005A1 (zh) |
CY (1) | CY1123349T1 (zh) |
DK (1) | DK3416957T3 (zh) |
ES (1) | ES2821400T3 (zh) |
HR (1) | HRP20201430T1 (zh) |
HU (1) | HUE051059T2 (zh) |
LT (1) | LT3416957T (zh) |
PL (1) | PL3416957T3 (zh) |
PT (1) | PT3416957T (zh) |
RS (1) | RS60900B1 (zh) |
RU (1) | RU2762968C2 (zh) |
SI (1) | SI3416957T1 (zh) |
TW (1) | TWI723131B (zh) |
WO (1) | WO2017140843A1 (zh) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA3015005A1 (en) * | 2016-02-19 | 2017-08-24 | Sprint Bioscience Ab | 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes |
IL302356A (en) | 2017-08-23 | 2023-06-01 | Sprint Bioscience Ab | Pyridylpyridone compounds |
EP3672967B1 (en) | 2017-08-23 | 2021-10-06 | Sprint Bioscience AB | Azaindolylpyridone and diazaindolylpyridone compounds |
WO2019038390A1 (en) * | 2017-08-23 | 2019-02-28 | Sprint Bioscience Ab | MORPHOLINYLPYRIDONE COMPOUNDS |
ES2929424T3 (es) | 2017-08-23 | 2022-11-29 | Sprint Bioscience Ab | Compuestos de piridinamina-piridona y pirimidinamina-piridona |
US11236079B2 (en) | 2018-04-10 | 2022-02-01 | Neuropore Therapies, Inc. | Morpholine derivates as inhibitors of Vps34 |
MX2020010576A (es) | 2018-04-10 | 2021-03-02 | Neuropore Therapies Inc | Derivados tri sustituidos de arilo y heteroarilo como moduladores de p13-kinasa y rutas de autofagia. |
WO2020008046A1 (en) | 2018-07-06 | 2020-01-09 | Sprint Bioscience Ab | Biomarker |
EP4069366A1 (en) | 2019-12-04 | 2022-10-12 | CHDI Foundation, Inc. | Atm kinase inhibitors and compositions and methods of use thereof |
WO2022115562A1 (en) * | 2020-11-25 | 2022-06-02 | Deciphera Pharmaceuticals, Llc | Morpholino derivatives as vsp34 inhibitors for use in the treatment of a viral infection |
CA3199988A1 (en) | 2020-11-25 | 2022-06-02 | Daniel L. Flynn | Pyridylpyridone derivatives as vsp34 inhibitors for use in the treatment of a viral infection |
TW202320797A (zh) | 2021-08-13 | 2023-06-01 | 美商迪賽孚爾製藥有限公司 | 使用vps34抑制劑之組合療法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013190510A2 (en) * | 2012-06-22 | 2013-12-27 | Sanofi | NOVEL 2,3-DIHYDRO-1H-IMIDAZO{1,2-a}PYRIMIDIN-5-ONE and this1,2,3,4-TETRAHYDROPYRIMIDO{1,2-a}PYRIMIDIN-6-ONE DERIVATIVES COMPRISING A SUBSTITUTED MORPHOLINE, PREPARATION THEREOF AND PHARMACEUTICAL USE THEREOF |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2003295776B2 (en) | 2002-11-21 | 2011-05-12 | Novartis Vaccines And Diagnostics, Inc. | 2,4,6-trisubstituted pyrimidines as phosphotidylinositol (PI) 3-kinase inhibitors and their use in the treatment of cancer |
GB2465405A (en) | 2008-11-10 | 2010-05-19 | Univ Basel | Triazine, pyrimidine and pyridine analogues and their use in therapy |
US8846670B2 (en) | 2009-07-02 | 2014-09-30 | Sanofi | 1,2,3,4-tetrahydro-pyrimido(1,2-a)pyrimidin-6-one derivatives, preparation thereof, and pharmaceutical use thereof |
JP2014500308A (ja) | 2010-12-21 | 2014-01-09 | ノバルティス アーゲー | Vps34阻害剤としてのビヘテロアリール化合物 |
SI2655375T1 (sl) | 2010-12-23 | 2015-03-31 | Sanofi | Derivati pirimidinona, njihova priprava in njihova farmacevtska uporaba |
GB201120317D0 (en) | 2011-11-24 | 2012-01-04 | Queen Mary & Westfield College | Screening method |
US9242969B2 (en) | 2013-03-14 | 2016-01-26 | Novartis Ag | Biaryl amide compounds as kinase inhibitors |
JP6074043B2 (ja) | 2013-08-29 | 2017-02-01 | 富士フイルム株式会社 | 新規なモルホリン誘導体またはその塩 |
US10202373B2 (en) | 2014-01-14 | 2019-02-12 | Millennium Pharmaceuticals, Inc. | Heteroaryls and uses thereof |
GEP20196983B (en) | 2014-01-14 | 2019-06-25 | Millennium Pharm Inc | Heteroaryls and uses thereof |
MA39823A (fr) | 2014-04-03 | 2018-01-09 | Janssen Pharmaceutica Nv | Dérivés de pyridine macrocyclique |
MA39822A (fr) | 2014-04-03 | 2018-02-06 | Janssen Pharmaceutica Nv | Dérivés de pyrimidine bicycle |
CA2960790A1 (en) | 2014-09-17 | 2016-03-24 | Verseon Corporation | Pyrazolyl-substituted pyridone compounds as serine protease inhibitors |
CA3015005A1 (en) * | 2016-02-19 | 2017-08-24 | Sprint Bioscience Ab | 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes |
DK3416945T3 (da) * | 2016-02-19 | 2020-09-21 | Sprint Bioscience Ab | 6-aryl-4-(morpholin-4-yl)-1h-pyridin-2-on-forbindelser anvendelige ved behandlingen af cancer og diabetes |
-
2017
- 2017-02-17 CA CA3015005A patent/CA3015005A1/en active Pending
- 2017-02-17 CN CN201780015103.7A patent/CN108884067B/zh active Active
- 2017-02-17 PL PL17704791T patent/PL3416957T3/pl unknown
- 2017-02-17 ES ES17704791T patent/ES2821400T3/es active Active
- 2017-02-17 RS RS20201061A patent/RS60900B1/sr unknown
- 2017-02-17 AU AU2017219847A patent/AU2017219847B2/en active Active
- 2017-02-17 WO PCT/EP2017/053614 patent/WO2017140843A1/en active Application Filing
- 2017-02-17 EP EP17704791.7A patent/EP3416957B1/en active Active
- 2017-02-17 SI SI201730405T patent/SI3416957T1/sl unknown
- 2017-02-17 PT PT177047917T patent/PT3416957T/pt unknown
- 2017-02-17 LT LTEP17704791.7T patent/LT3416957T/lt unknown
- 2017-02-17 RU RU2018131766A patent/RU2762968C2/ru active
- 2017-02-17 US US15/999,432 patent/US11179399B2/en active Active
- 2017-02-17 TW TW106105178A patent/TWI723131B/zh active
- 2017-02-17 DK DK17704791.7T patent/DK3416957T3/da active
- 2017-02-17 HU HUE17704791A patent/HUE051059T2/hu unknown
- 2017-02-17 JP JP2018562702A patent/JP6858984B2/ja active Active
-
2020
- 2020-09-08 HR HRP20201430TT patent/HRP20201430T1/hr unknown
- 2020-09-15 CY CY20201100870T patent/CY1123349T1/el unknown
-
2021
- 2021-10-14 US US17/501,407 patent/US11963963B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013190510A2 (en) * | 2012-06-22 | 2013-12-27 | Sanofi | NOVEL 2,3-DIHYDRO-1H-IMIDAZO{1,2-a}PYRIMIDIN-5-ONE and this1,2,3,4-TETRAHYDROPYRIMIDO{1,2-a}PYRIMIDIN-6-ONE DERIVATIVES COMPRISING A SUBSTITUTED MORPHOLINE, PREPARATION THEREOF AND PHARMACEUTICAL USE THEREOF |
Also Published As
Publication number | Publication date |
---|---|
DK3416957T3 (da) | 2020-09-21 |
AU2017219847B2 (en) | 2021-02-04 |
EP3416957B1 (en) | 2020-07-01 |
PT3416957T (pt) | 2020-09-25 |
TW201731843A (zh) | 2017-09-16 |
JP6858984B2 (ja) | 2021-04-14 |
EP3416957A1 (en) | 2018-12-26 |
PL3416957T3 (pl) | 2021-02-08 |
LT3416957T (lt) | 2020-11-25 |
RU2762968C2 (ru) | 2021-12-24 |
HUE051059T2 (hu) | 2021-03-01 |
US20210161906A1 (en) | 2021-06-03 |
CA3015005A1 (en) | 2017-08-24 |
HRP20201430T1 (hr) | 2020-11-27 |
AU2017219847A1 (en) | 2018-10-04 |
US11179399B2 (en) | 2021-11-23 |
RU2018131766A (ru) | 2020-03-20 |
ES2821400T3 (es) | 2021-04-26 |
CN108884067A (zh) | 2018-11-23 |
US11963963B2 (en) | 2024-04-23 |
US20220175788A1 (en) | 2022-06-09 |
RU2018131766A3 (zh) | 2020-03-24 |
JP2019505595A (ja) | 2019-02-28 |
CN108884067B (zh) | 2021-01-08 |
SI3416957T1 (sl) | 2020-11-30 |
RS60900B1 (sr) | 2020-11-30 |
CY1123349T1 (el) | 2021-12-31 |
WO2017140843A1 (en) | 2017-08-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI723131B (zh) | 6‐雜環基‐4‐嗎啉‐4‐芳基吡啶‐2‐酮化合物 | |
TWI794190B (zh) | 含有取代的吡啶酮之三環化合物及其使用方法 | |
AU2021215234B2 (en) | 6-Aryl-4-Morpholin-1-Ylpyridone Compounds Useful For The Treatment Of Cancer And Diabetes | |
TWI801517B (zh) | 經取代的2-吡啶酮三環化合物、其類似物及其使用方法 | |
IL267299B (en) | cdk4/6 inhibitor | |
TWI787335B (zh) | 吡啶基吡啶酮化合物 | |
WO2022194269A1 (zh) | 新型egfr降解剂 | |
CA3207392A1 (en) | Cdk inhibitor | |
CN111315750A (zh) | 作为mTORC1/2双激酶抑制剂的吡啶并嘧啶类化合物 | |
TWI803511B (zh) | 嗎啉基吡啶酮化合物 | |
KR20230157467A (ko) | 모세혈관 확장성 운동실조증 돌연변이(atm) 키나아제의 선택적 조절제 및 이의 용도 | |
CN116969944A (zh) | 乙氨基取代的三环杂环化合物及其组合物、制剂和用途 |