US20220105091A1 - Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals - Google Patents
Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals Download PDFInfo
- Publication number
- US20220105091A1 US20220105091A1 US17/551,080 US202117551080A US2022105091A1 US 20220105091 A1 US20220105091 A1 US 20220105091A1 US 202117551080 A US202117551080 A US 202117551080A US 2022105091 A1 US2022105091 A1 US 2022105091A1
- Authority
- US
- United States
- Prior art keywords
- compound
- alkyl
- compounds
- halo
- membered
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000003443 antiviral agent Substances 0.000 title description 10
- 229940121357 antivirals Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 259
- 238000000034 method Methods 0.000 claims abstract description 78
- 241000700721 Hepatitis B virus Species 0.000 claims abstract description 66
- 150000003839 salts Chemical class 0.000 claims abstract description 66
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 29
- 239000003814 drug Substances 0.000 claims description 45
- 239000002955 immunomodulating agent Substances 0.000 claims description 38
- 229940121354 immunomodulator Drugs 0.000 claims description 37
- 125000001072 heteroaryl group Chemical group 0.000 claims description 31
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 230000002584 immunomodulator Effects 0.000 claims description 26
- 125000005843 halogen group Chemical group 0.000 claims description 25
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 229940124597 therapeutic agent Drugs 0.000 claims description 21
- 239000003112 inhibitor Substances 0.000 claims description 19
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 17
- 239000003937 drug carrier Substances 0.000 claims description 14
- 125000001475 halogen functional group Chemical group 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 239000000556 agonist Substances 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 230000010076 replication Effects 0.000 claims description 7
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 6
- 108010050904 Interferons Proteins 0.000 claims description 6
- 102000014150 Interferons Human genes 0.000 claims description 6
- 208000002672 hepatitis B Diseases 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 229940079322 interferon Drugs 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 108700024845 Hepatitis B virus P Proteins 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 229940123066 Polymerase inhibitor Drugs 0.000 claims description 3
- 229940118555 Viral entry inhibitor Drugs 0.000 claims description 3
- 210000000234 capsid Anatomy 0.000 claims description 3
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 claims description 3
- 230000029302 virus maturation Effects 0.000 claims description 3
- 239000000203 mixture Substances 0.000 abstract description 92
- 208000015181 infectious disease Diseases 0.000 abstract description 30
- 208000036142 Viral infection Diseases 0.000 abstract description 7
- 230000009385 viral infection Effects 0.000 abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- 239000000243 solution Substances 0.000 description 54
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 43
- 238000011282 treatment Methods 0.000 description 41
- -1 amino, hydroxy Chemical group 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- 235000019439 ethyl acetate Nutrition 0.000 description 34
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 28
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 26
- 239000003795 chemical substances by application Substances 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 239000000047 product Substances 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 19
- 229910052805 deuterium Inorganic materials 0.000 description 19
- 201000010099 disease Diseases 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 101100519207 Mus musculus Pdcd1 gene Proteins 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 108010074708 B7-H1 Antigen Proteins 0.000 description 17
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 239000002253 acid Substances 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- 229940079593 drug Drugs 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 13
- 102000036639 antigens Human genes 0.000 description 13
- 108091007433 antigens Proteins 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 230000002401 inhibitory effect Effects 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- 238000010898 silica gel chromatography Methods 0.000 description 13
- 239000000427 antigen Substances 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 239000013058 crude material Substances 0.000 description 12
- 238000010348 incorporation Methods 0.000 description 12
- 239000002245 particle Substances 0.000 description 12
- 230000003612 virological effect Effects 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 239000002552 dosage form Substances 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- 229960003301 nivolumab Drugs 0.000 description 11
- 235000018102 proteins Nutrition 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 10
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 10
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 10
- 0 [1*]c1nn2c(c1[2*])-c1c([3*])c(=O)c([W])c([4*])n1C([5*])([6*])C2([7*])[8*] Chemical compound [1*]c1nn2c(c1[2*])-c1c([3*])c(=O)c([W])c([4*])n1C([5*])([6*])C2([7*])[8*] 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 10
- 239000012634 fragment Substances 0.000 description 10
- 239000000546 pharmaceutical excipient Substances 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 9
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 9
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 230000002458 infectious effect Effects 0.000 description 9
- 238000001802 infusion Methods 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 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 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 241000700605 Viruses Species 0.000 description 8
- 230000001684 chronic effect Effects 0.000 description 8
- 230000000139 costimulatory effect Effects 0.000 description 8
- 229940126546 immune checkpoint molecule Drugs 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 229960002621 pembrolizumab Drugs 0.000 description 7
- 229920001223 polyethylene glycol Polymers 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- 239000003643 water by type Substances 0.000 description 7
- JWGGWIXEKHQBDD-AWEZNQCLSA-N (8R)-8-tert-butyl-3-chloro-4-(3-methoxypropoxy)-12-oxo-5,6,9-triazatricyclo[7.4.0.02,6]trideca-1(13),2,4,10-tetraene-11-carboxylic acid Chemical compound CC(C)(C)[C@@H]1CN2C(=C(C(=N2)OCCCOC)Cl)C3=CC(=O)C(=CN13)C(=O)O JWGGWIXEKHQBDD-AWEZNQCLSA-N 0.000 description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
- 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 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 description 6
- 102000017578 LAG3 Human genes 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000002648 combination therapy Methods 0.000 description 6
- 230000007423 decrease Effects 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 230000028327 secretion Effects 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- JJRIMJFYFUGNFG-AWEZNQCLSA-N (8R)-3-bromo-8-tert-butyl-4-(3-methoxypropoxy)-12-oxo-5,6,9-triazatricyclo[7.4.0.02,6]trideca-1(13),2,4,10-tetraene-11-carboxylic acid Chemical compound BrC=1C(=NN2C=1C=1N([C@@H](C2)C(C)(C)C)C=C(C(C=1)=O)C(=O)O)OCCCOC JJRIMJFYFUGNFG-AWEZNQCLSA-N 0.000 description 5
- BMOFPZWOKBFSAG-INIZCTEOSA-N (8R)-8-tert-butyl-3-chloro-12-oxo-4-phenyl-5,6,9-triazatricyclo[7.4.0.02,6]trideca-1(13),2,4,10-tetraene-11-carboxylic acid Chemical compound C(C)(C)(C)[C@H]1N2C(C=3N(C1)N=C(C=3Cl)C1=CC=CC=C1)=CC(C(=C2)C(=O)O)=O BMOFPZWOKBFSAG-INIZCTEOSA-N 0.000 description 5
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 5
- LESBDKYPFZDBSQ-UHFFFAOYSA-N 8-tert-butyl-12-oxo-4-propan-2-yl-5,6,9-triazatricyclo[7.4.0.02,6]trideca-1(13),2,4,10-tetraene-11-carboxylic acid Chemical compound C(C)(C)(C)C1N2C(C=3N(C1)N=C(C3)C(C)C)=CC(C(=C2)C(=O)O)=O LESBDKYPFZDBSQ-UHFFFAOYSA-N 0.000 description 5
- 229940125565 BMS-986016 Drugs 0.000 description 5
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 5
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 229930006000 Sucrose Natural products 0.000 description 5
- 229940126547 T-cell immunoglobulin mucin-3 Drugs 0.000 description 5
- 230000000840 anti-viral effect Effects 0.000 description 5
- 239000003963 antioxidant agent Substances 0.000 description 5
- 235000006708 antioxidants Nutrition 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- FRMYTPFETKDTCJ-JTQLQIEISA-N ethyl 4-chloro-2-[(2R)-3,3-dimethyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butyl]-5-oxo-1H-pyrazole-3-carboxylate Chemical compound C(C)(C)(C)OC(=O)N[C@@H](CN1N=C(C(=C1C(=O)OCC)Cl)O)C(C)(C)C FRMYTPFETKDTCJ-JTQLQIEISA-N 0.000 description 5
- 239000008273 gelatin Substances 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- 235000011187 glycerol Nutrition 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 239000002674 ointment Substances 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000007921 spray Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000005720 sucrose Substances 0.000 description 5
- 239000000829 suppository Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 230000029812 viral genome replication Effects 0.000 description 5
- UWXKKIOZOHPSHF-SFHVURJKSA-N (8R)-12-oxo-4-phenyl-8-propan-2-yl-5,6,9-triazatricyclo[7.4.0.02,6]trideca-1(13),2,4,10-tetraene-11-carboxylic acid Chemical compound C(C)(C)[C@H]1N2C(C=3N(C1)N=C(C=3)C1=CC=CC=C1)=CC(C(=C2)C(=O)O)=O UWXKKIOZOHPSHF-SFHVURJKSA-N 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- 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 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 241000416162 Astragalus gummifer Species 0.000 description 4
- 102100024263 CD160 antigen Human genes 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 101000761938 Homo sapiens CD160 antigen Proteins 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- 102100025390 Integrin beta-2 Human genes 0.000 description 4
- 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 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 229920001615 Tragacanth Polymers 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 229960000980 entecavir Drugs 0.000 description 4
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 4
- WAQNXHXSLXNOCQ-UHFFFAOYSA-N ethyl 3-(3-methoxypropoxy)-1H-pyrazole-5-carboxylate Chemical compound COCCCOC1=NNC(=C1)C(=O)OCC WAQNXHXSLXNOCQ-UHFFFAOYSA-N 0.000 description 4
- QYLBMBGRWHJTKV-AWEZNQCLSA-N ethyl 4-chloro-2-[(2R)-3,3-dimethyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butyl]-5-(3-methoxypropoxy)pyrazole-3-carboxylate Chemical compound C(C)(C)(C)OC(=O)N[C@@H](CN1N=C(C(=C1C(=O)OCC)Cl)OCCCOC)C(C)(C)C QYLBMBGRWHJTKV-AWEZNQCLSA-N 0.000 description 4
- YNAWQPKFEXKLOC-KRWDZBQOSA-N ethyl 5-[tert-butyl(dimethyl)silyl]oxy-2-[(2R)-3,3-dimethyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butyl]pyrazole-3-carboxylate Chemical compound C(C)(C)(C)OC(=O)N[C@@H](CN1N=C(C=C1C(=O)OCC)O[Si](C)(C)C(C)(C)C)C(C)(C)C YNAWQPKFEXKLOC-KRWDZBQOSA-N 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 238000007429 general method Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 229960005386 ipilimumab Drugs 0.000 description 4
- 230000000155 isotopic effect Effects 0.000 description 4
- 239000008101 lactose 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
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 4
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 125000004043 oxo group Chemical group O=* 0.000 description 4
- 239000006072 paste Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000004808 supercritical fluid chromatography Methods 0.000 description 4
- 230000002459 sustained effect Effects 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 235000012222 talc Nutrition 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- 229960004556 tenofovir Drugs 0.000 description 4
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 210000002845 virion Anatomy 0.000 description 4
- 239000001993 wax Substances 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- HQUYDMGPGDLNJM-LBPRGKRZSA-N (2R)-2-(benzylamino)-3-methylbutan-1-ol Chemical compound CC(C)[C@H](CO)NCC1=CC=CC=C1 HQUYDMGPGDLNJM-LBPRGKRZSA-N 0.000 description 3
- HPECSOGEXTXMKH-QFIPXVFZSA-N (2R)-2-[benzyl-[(3-phenyl-1H-pyrazol-5-yl)methyl]amino]-3-methylbutan-1-ol Chemical compound C(C1=CC=CC=C1)N([C@@H](CO)C(C)C)CC1=CC(=NN1)C1=CC=CC=C1 HPECSOGEXTXMKH-QFIPXVFZSA-N 0.000 description 3
- WXWHSMOSLBLXQH-HNNXBMFYSA-N (6R)-2-phenyl-6-propan-2-yl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine Chemical compound C(C)(C)[C@H]1NCC=2N(C1)N=C(C=2)C1=CC=CC=C1 WXWHSMOSLBLXQH-HNNXBMFYSA-N 0.000 description 3
- MBUVEMONURMHMV-QFIPXVFZSA-N (6R)-5-benzyl-2-phenyl-6-propan-2-yl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine Chemical compound C(C1=CC=CC=C1)N1CC=2N(C[C@H]1C(C)C)N=C(C2)C2=CC=CC=C2 MBUVEMONURMHMV-QFIPXVFZSA-N 0.000 description 3
- RSQBMJAUTIGWCS-NSHDSACASA-N (6R)-6-tert-butyl-3-chloro-2-(3-methoxypropoxy)-6,7-dihydropyrazolo[1,5-a]pyrazine Chemical compound C(C)(C)(C)[C@H]1N=CC=2N(C1)N=C(C=2Cl)OCCCOC RSQBMJAUTIGWCS-NSHDSACASA-N 0.000 description 3
- BZBZMNQHYCSMTM-HNNXBMFYSA-N (8R)-3-chloro-12-oxo-4-phenyl-8-propan-2-yl-5,6,9-triazatricyclo[7.4.0.02,6]trideca-1(13),2,4,10-tetraene-11-carboxylic acid Chemical compound CC(C)[C@H](CN(C1=C2Cl)N=C2C2=CC=CC=C2)N(C=C2C(O)=O)C1=CC2=O BZBZMNQHYCSMTM-HNNXBMFYSA-N 0.000 description 3
- KUWYOCXBJJOAOW-KRWDZBQOSA-N (8R)-8-tert-butyl-3-chloro-4-(2-methoxyphenyl)-12-oxo-5,6,9-triazatricyclo[7.4.0.02,6]trideca-1(13),2,4,10-tetraene-11-carboxylic acid Chemical compound CC(C)(C)[C@H](CN(C1=C2Cl)N=C2C(C=CC=C2)=C2OC)N(C=C2C(O)=O)C1=CC2=O KUWYOCXBJJOAOW-KRWDZBQOSA-N 0.000 description 3
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- HFBSYWTWFCBRLW-UHFFFAOYSA-N 1-[5-(hydroxymethyl)-3-propan-2-ylpyrazol-1-yl]-3,3-dimethylbutan-2-ol Chemical compound OCC1=CC(=NN1CC(C(C)(C)C)O)C(C)C HFBSYWTWFCBRLW-UHFFFAOYSA-N 0.000 description 3
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 3
- 102100027207 CD27 antigen Human genes 0.000 description 3
- 101150013553 CD40 gene Proteins 0.000 description 3
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- 108020004638 Circular DNA Proteins 0.000 description 3
- 102000013816 Cytotoxic T-lymphocyte antigen 4 Human genes 0.000 description 3
- 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 3
- 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 3
- 238000002965 ELISA Methods 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 3
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 3
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 description 3
- 101150030213 Lag3 gene Proteins 0.000 description 3
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 3
- 240000007472 Leucaena leucocephala Species 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 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 3
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 229960001997 adefovir Drugs 0.000 description 3
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 3
- 235000010419 agar Nutrition 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 235000012216 bentonite Nutrition 0.000 description 3
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- FNASCUBBFNCFQO-VURMDHGXSA-N ethyl (2z)-2-(ethoxymethylidene)-3-oxobutanoate Chemical compound CCO\C=C(\C(C)=O)C(=O)OCC FNASCUBBFNCFQO-VURMDHGXSA-N 0.000 description 3
- HETWCEMAVJEYNF-FQEVSTJZSA-N ethyl (8R)-12-oxo-4-phenyl-8-propan-2-yl-5,6,9-triazatricyclo[7.4.0.02,6]trideca-1(13),2,4,10-tetraene-11-carboxylate Chemical compound C(C)(C)[C@H]1N2C(C=3N(C1)N=C(C=3)C1=CC=CC=C1)=CC(C(=C2)C(=O)OCC)=O HETWCEMAVJEYNF-FQEVSTJZSA-N 0.000 description 3
- KNSUKESWNUOGAS-INIZCTEOSA-N ethyl (8R)-8-tert-butyl-3-chloro-4-(3-methoxypropoxy)-12-oxo-5,6,9-triazatricyclo[7.4.0.02,6]trideca-1(13),2,4,10-tetraene-11-carboxylate Chemical compound CCOC(=O)C1=CN2[C@@H](CN3C(=C(C(=N3)OCCCOC)Cl)C2=CC1=O)C(C)(C)C KNSUKESWNUOGAS-INIZCTEOSA-N 0.000 description 3
- LLOSPRFJHZZUCI-WMCAAGNKSA-N ethyl (8R)-8-tert-butyl-3-chloro-4-(3-methoxypropoxy)-12-oxo-5,6,9-triazatricyclo[7.4.0.02,6]trideca-2,4,10-triene-11-carboxylate Chemical compound CCOC(=O)C1=CN2[C@@H](CN3C(=C(C(=N3)OCCCOC)Cl)C2CC1=O)C(C)(C)C LLOSPRFJHZZUCI-WMCAAGNKSA-N 0.000 description 3
- FZZUVZARIBESPX-UHFFFAOYSA-N ethyl 2-(3,3-dimethyl-2-oxobutyl)-5-propan-2-ylpyrazole-3-carboxylate Chemical compound CC(C(CN1N=C(C=C1C(=O)OCC)C(C)C)=O)(C)C FZZUVZARIBESPX-UHFFFAOYSA-N 0.000 description 3
- PSXUMORLZYSVAJ-INIZCTEOSA-N ethyl 2-[(2R)-3,3-dimethyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butyl]-5-(3-methoxypropoxy)pyrazole-3-carboxylate Chemical compound C(C)(C)(C)OC(=O)N[C@@H](CN1N=C(C=C1C(=O)OCC)OCCCOC)C(C)(C)C PSXUMORLZYSVAJ-INIZCTEOSA-N 0.000 description 3
- USEBOUUNVVHUNQ-UHFFFAOYSA-N ethyl 3-[tert-butyl(dimethyl)silyl]oxy-1h-pyrazole-5-carboxylate Chemical compound CCOC(=O)C=1C=C(O[Si](C)(C)C(C)(C)C)NN=1 USEBOUUNVVHUNQ-UHFFFAOYSA-N 0.000 description 3
- IMDQQJVFFFCMON-UHFFFAOYSA-N ethyl 4-chloro-3-(3-methoxypropoxy)-1H-pyrazole-5-carboxylate Chemical compound ClC=1C(=NNC=1C(=O)OCC)OCCCOC IMDQQJVFFFCMON-UHFFFAOYSA-N 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 238000001640 fractional crystallisation Methods 0.000 description 3
- 108020001507 fusion proteins Proteins 0.000 description 3
- 102000037865 fusion proteins Human genes 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000002519 immonomodulatory effect Effects 0.000 description 3
- 239000003701 inert diluent Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 229960001627 lamivudine Drugs 0.000 description 3
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 3
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- RLRGETOSWKYBHX-CLFYSBASSA-N methyl (z)-4-hydroxy-2-oxo-4-phenylbut-3-enoate Chemical compound COC(=O)C(=O)\C=C(/O)C1=CC=CC=C1 RLRGETOSWKYBHX-CLFYSBASSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 229950010773 pidilizumab Drugs 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 150000003141 primary amines Chemical class 0.000 description 3
- 230000002285 radioactive effect Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 229960005311 telbivudine Drugs 0.000 description 3
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 description 3
- QQFVJWUVBPWAKN-AWEZNQCLSA-N tert-butyl N-[(2R)-1-[4-chloro-5-(hydroxymethyl)-3-(3-methoxypropoxy)pyrazol-1-yl]-3,3-dimethylbutan-2-yl]carbamate Chemical compound CC(C)(C)[C@H](CN1C(=C(C(=N1)OCCCOC)Cl)CO)NC(=O)OC(C)(C)C QQFVJWUVBPWAKN-AWEZNQCLSA-N 0.000 description 3
- PAZJLYSNAWZKNB-AWEZNQCLSA-N tert-butyl N-[(2R)-1-[4-chloro-5-formyl-3-(3-methoxypropoxy)pyrazol-1-yl]-3,3-dimethylbutan-2-yl]carbamate Chemical compound CC(C)(C)[C@H](CN1C(=C(C(=N1)OCCCOC)Cl)C=O)NC(=O)OC(C)(C)C PAZJLYSNAWZKNB-AWEZNQCLSA-N 0.000 description 3
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 2
- BORMSYZIYOPVOL-HNNXBMFYSA-N (6R)-2-phenyl-6-propan-2-yl-6,7-dihydropyrazolo[1,5-a]pyrazine Chemical compound CC(C)[C@@H]1CN2C(=CC(=N2)C3=CC=CC=C3)C=N1 BORMSYZIYOPVOL-HNNXBMFYSA-N 0.000 description 2
- WECGBGSPFLIIMT-INIZCTEOSA-N (8R)-8-tert-butyl-4-(3-methoxypropoxy)-12-oxo-5,6,9-triazatricyclo[7.4.0.02,6]trideca-1(13),2,4,10-tetraene-11-carboxylic acid Chemical compound CC(C)(C)[C@H](CN(C1=C2)N=C2OCCCOC)N(C=C2C(O)=O)C1=CC2=O WECGBGSPFLIIMT-INIZCTEOSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 2
- RXWKTWPLCOMMQW-UHFFFAOYSA-N 1-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-propan-2-ylpyrazol-1-yl]-3,3-dimethylbutan-2-ol Chemical compound [Si](C)(C)(C(C)(C)C)OCC1=CC(=NN1CC(C(C)(C)C)O)C(C)C RXWKTWPLCOMMQW-UHFFFAOYSA-N 0.000 description 2
- SYFBAWIMDCIXLQ-UHFFFAOYSA-N 1-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-propan-2-ylpyrazol-1-yl]-3,3-dimethylbutan-2-one Chemical compound [Si](C)(C)(C(C)(C)C)OCC1=CC(=NN1CC(C(C)(C)C)=O)C(C)C SYFBAWIMDCIXLQ-UHFFFAOYSA-N 0.000 description 2
- SAIRZMWXVJEBMO-UHFFFAOYSA-N 1-bromo-3,3-dimethylbutan-2-one Chemical compound CC(C)(C)C(=O)CBr SAIRZMWXVJEBMO-UHFFFAOYSA-N 0.000 description 2
- CEVMYGZHEJSOHZ-UHFFFAOYSA-N 1-bromo-3-methoxypropane Chemical compound COCCCBr CEVMYGZHEJSOHZ-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 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 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- 102100038078 CD276 antigen Human genes 0.000 description 2
- 101710185679 CD276 antigen Proteins 0.000 description 2
- 102100035793 CD83 antigen Human genes 0.000 description 2
- 229940045513 CTLA4 antagonist Drugs 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 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 2
- 108020004414 DNA Proteins 0.000 description 2
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 2
- 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 2
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 2
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 2
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 2
- 241000206672 Gelidium Species 0.000 description 2
- 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 2
- 241000711549 Hepacivirus C Species 0.000 description 2
- 101710083479 Hepatitis A virus cellular receptor 2 homolog Proteins 0.000 description 2
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 description 2
- 101000946856 Homo sapiens CD83 antigen Proteins 0.000 description 2
- 101001068133 Homo sapiens Hepatitis A virus cellular receptor 2 Proteins 0.000 description 2
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 2
- 101000971538 Homo sapiens Killer cell lectin-like receptor subfamily F member 1 Proteins 0.000 description 2
- 101001138062 Homo sapiens Leukocyte-associated immunoglobulin-like receptor 1 Proteins 0.000 description 2
- 101001109503 Homo sapiens NKG2-C type II integral membrane protein Proteins 0.000 description 2
- 101000633784 Homo sapiens SLAM family member 7 Proteins 0.000 description 2
- 101000914496 Homo sapiens T-cell antigen CD7 Proteins 0.000 description 2
- 101000831007 Homo sapiens T-cell immunoreceptor with Ig and ITIM domains Proteins 0.000 description 2
- 101000934346 Homo sapiens T-cell surface antigen CD2 Proteins 0.000 description 2
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 2
- 101000795169 Homo sapiens Tumor necrosis factor receptor superfamily member 13C Proteins 0.000 description 2
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 2
- 101000666896 Homo sapiens V-type immunoglobulin domain-containing suppressor of T-cell activation Proteins 0.000 description 2
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 2
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 2
- 108010078049 Interferon alpha-2 Proteins 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 102100021458 Killer cell lectin-like receptor subfamily F member 1 Human genes 0.000 description 2
- 102100020943 Leukocyte-associated immunoglobulin-like receptor 1 Human genes 0.000 description 2
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 108010061593 Member 14 Tumor Necrosis Factor Receptors Proteins 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 102100022683 NKG2-C type II integral membrane protein Human genes 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 229910020889 NaBH3 Inorganic materials 0.000 description 2
- 108700026244 Open Reading Frames Proteins 0.000 description 2
- 208000037581 Persistent Infection Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 2
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 2
- 102100029198 SLAM family member 7 Human genes 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102100027208 T-cell antigen CD7 Human genes 0.000 description 2
- 102100024834 T-cell immunoreceptor with Ig and ITIM domains Human genes 0.000 description 2
- 102100025237 T-cell surface antigen CD2 Human genes 0.000 description 2
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 102100029690 Tumor necrosis factor receptor superfamily member 13C Human genes 0.000 description 2
- 102100028785 Tumor necrosis factor receptor superfamily member 14 Human genes 0.000 description 2
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 2
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 2
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 2
- 102100038282 V-type immunoglobulin domain-containing suppressor of T-cell activation Human genes 0.000 description 2
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 2
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 229960004748 abacavir Drugs 0.000 description 2
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 2
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 2
- 229960004150 aciclovir Drugs 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 229950007936 apricitabine Drugs 0.000 description 2
- RYMCFYKJDVMSIR-RNFRBKRXSA-N apricitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1S[C@H](CO)OC1 RYMCFYKJDVMSIR-RNFRBKRXSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 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
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229960000724 cidofovir Drugs 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- 229960005319 delavirdine Drugs 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 150000001975 deuterium Chemical group 0.000 description 2
- 229960002656 didanosine Drugs 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 229950009791 durvalumab Drugs 0.000 description 2
- 229960003804 efavirenz Drugs 0.000 description 2
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 2
- 238000000132 electrospray ionisation Methods 0.000 description 2
- 229960000366 emtricitabine Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- VTQMVFCOKDKVEZ-AWEZNQCLSA-N ethyl 4-bromo-2-[(2R)-3,3-dimethyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butyl]-5-(3-methoxypropoxy)pyrazole-3-carboxylate Chemical compound CCOC(=O)C1=C(C(=NN1C[C@@H](C(C)(C)C)NC(=O)OC(C)(C)C)OCCCOC)Br VTQMVFCOKDKVEZ-AWEZNQCLSA-N 0.000 description 2
- ILTUMWMASHHTOQ-UHFFFAOYSA-N ethyl 5-propan-2-yl-1h-pyrazole-3-carboxylate Chemical compound CCOC(=O)C=1C=C(C(C)C)NN=1 ILTUMWMASHHTOQ-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 2
- 229940093471 ethyl oleate Drugs 0.000 description 2
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 2
- 229960002049 etravirine Drugs 0.000 description 2
- PYGWGZALEOIKDF-UHFFFAOYSA-N etravirine Chemical compound CC1=CC(C#N)=CC(C)=C1OC1=NC(NC=2C=CC(=CC=2)C#N)=NC(N)=C1Br PYGWGZALEOIKDF-UHFFFAOYSA-N 0.000 description 2
- 229960004396 famciclovir Drugs 0.000 description 2
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- IJJVMEJXYNJXOJ-UHFFFAOYSA-N fluquinconazole Chemical compound C=1C=C(Cl)C=C(Cl)C=1N1C(=O)C2=CC(F)=CC=C2N=C1N1C=NC=N1 IJJVMEJXYNJXOJ-UHFFFAOYSA-N 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 229960002963 ganciclovir Drugs 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 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
- 210000002865 immune cell Anatomy 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229940047124 interferons Drugs 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 229960002510 mandelic acid Drugs 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- ROXAFVODFXYSFO-UHFFFAOYSA-N methyl 3-phenyl-1h-pyrazole-5-carboxylate Chemical compound N1C(C(=O)OC)=CC(C=2C=CC=CC=2)=N1 ROXAFVODFXYSFO-UHFFFAOYSA-N 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- 238000000465 moulding Methods 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
- 229960000689 nevirapine Drugs 0.000 description 2
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 2
- 239000012457 nonaqueous media Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Chemical group 0.000 description 2
- 108010044644 pegfilgrastim Proteins 0.000 description 2
- 239000002304 perfume Substances 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 229960005141 piperazine Drugs 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000010839 reverse transcription Methods 0.000 description 2
- 229960000329 ribavirin Drugs 0.000 description 2
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000002603 single-photon emission computed tomography Methods 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- JJICLMJFIKGAAU-UHFFFAOYSA-M sodium;2-amino-9-(1,3-dihydroxypropan-2-yloxymethyl)purin-6-olate Chemical compound [Na+].NC1=NC([O-])=C2N=CN(COC(CO)CO)C2=N1 JJICLMJFIKGAAU-UHFFFAOYSA-M 0.000 description 2
- RMLUKZWYIKEASN-UHFFFAOYSA-M sodium;2-amino-9-(2-hydroxyethoxymethyl)purin-6-olate Chemical compound [Na+].O=C1[N-]C(N)=NC2=C1N=CN2COCCO RMLUKZWYIKEASN-UHFFFAOYSA-M 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 229960001203 stavudine Drugs 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000011593 sulfur Chemical group 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- QKSQWQOAUQFORH-VAWYXSNFSA-N tert-butyl (ne)-n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)\N=N\C(=O)OC(C)(C)C QKSQWQOAUQFORH-VAWYXSNFSA-N 0.000 description 2
- FQYFESVIGXIYBU-UHFFFAOYSA-N tert-butyl N-[1-[5-(hydroxymethyl)-3-propan-2-ylpyrazol-1-yl]-3,3-dimethylbutan-2-yl]carbamate Chemical compound OCC1=CC(=NN1CC(C(C)(C)C)NC(OC(C)(C)C)=O)C(C)C FQYFESVIGXIYBU-UHFFFAOYSA-N 0.000 description 2
- AZHJHZWFJVBGIL-QMMMGPOBSA-N tert-butyl n-[(2r)-1-hydroxy-3,3-dimethylbutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](CO)C(C)(C)C AZHJHZWFJVBGIL-QMMMGPOBSA-N 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 229940044616 toll-like receptor 7 agonist Drugs 0.000 description 2
- 229940044655 toll-like receptor 9 agonist Drugs 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 229940093257 valacyclovir Drugs 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 230000009265 virologic response Effects 0.000 description 2
- 239000011534 wash buffer Substances 0.000 description 2
- 229960000523 zalcitabine Drugs 0.000 description 2
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- NWYYWIJOWOLJNR-YFKPBYRVSA-N (2r)-2-amino-3-methylbutan-1-ol Chemical compound CC(C)[C@@H](N)CO NWYYWIJOWOLJNR-YFKPBYRVSA-N 0.000 description 1
- OBETXYAYXDNJHR-SSDOTTSWSA-M (2r)-2-ethylhexanoate Chemical compound CCCC[C@@H](CC)C([O-])=O OBETXYAYXDNJHR-SSDOTTSWSA-M 0.000 description 1
- DNISEZBAYYIQFB-PHDIDXHHSA-N (2r,3r)-2,3-diacetyloxybutanedioic acid Chemical compound CC(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(C)=O DNISEZBAYYIQFB-PHDIDXHHSA-N 0.000 description 1
- GBZLWWCCIFQAGF-LBPRGKRZSA-N (6R)-3,5-dichloro-2-phenyl-6-propan-2-yl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine Chemical compound ClC=1C(=NN2C1CN([C@@H](C2)C(C)C)Cl)C2=CC=CC=C2 GBZLWWCCIFQAGF-LBPRGKRZSA-N 0.000 description 1
- FVWFQMKEZRTZRB-LBPRGKRZSA-N (6R)-3-chloro-2-phenyl-6-propan-2-yl-6,7-dihydropyrazolo[1,5-a]pyrazine Chemical compound ClC=1C(=NN2C1C=N[C@@H](C2)C(C)C)C2=CC=CC=C2 FVWFQMKEZRTZRB-LBPRGKRZSA-N 0.000 description 1
- FBQOPWXORWBLBJ-HNNXBMFYSA-N (6R)-5-chloro-2-phenyl-6-propan-2-yl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine Chemical compound ClN1CC=2N(C[C@H]1C(C)C)N=C(C2)C2=CC=CC=C2 FBQOPWXORWBLBJ-HNNXBMFYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-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
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JBYHSSAVUBIJMK-UHFFFAOYSA-N 1,4-oxathiane Chemical compound C1CSCCO1 JBYHSSAVUBIJMK-UHFFFAOYSA-N 0.000 description 1
- DWPLEOPKBWNPQV-UHFFFAOYSA-N 1-(2-methoxyphenyl)ethanone Chemical compound COC1=CC=CC=C1C(C)=O DWPLEOPKBWNPQV-UHFFFAOYSA-N 0.000 description 1
- DFPYXQYWILNVAU-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1.C1=CC=C2N(O)N=NC2=C1 DFPYXQYWILNVAU-UHFFFAOYSA-N 0.000 description 1
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 1
- IWWLVWWEZSOTJH-UHFFFAOYSA-N 2,3-dihydroxy-4-(4-methylbenzoyl)oxy-4-oxobutanoic acid Chemical compound CC1=CC=C(C(=O)OC(=O)C(O)C(O)C(O)=O)C=C1 IWWLVWWEZSOTJH-UHFFFAOYSA-N 0.000 description 1
- UKHJNJFJCGBKSF-UHFFFAOYSA-N 2,5-diazabicyclo[2.2.1]heptane Chemical compound C1NC2CNC1C2 UKHJNJFJCGBKSF-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- JNODDICFTDYODH-UHFFFAOYSA-N 2-hydroxytetrahydrofuran Chemical compound OC1CCCO1 JNODDICFTDYODH-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- DIQOUXNTSMWQSA-UHFFFAOYSA-N 2-oxa-5-azabicyclo[2.2.1]heptane Chemical compound C1OC2CNC1C2 DIQOUXNTSMWQSA-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- LKDJYZBKCVSODK-UHFFFAOYSA-N 3,8-diazabicyclo[3.2.1]octane Chemical compound C1NCC2CCC1N2 LKDJYZBKCVSODK-UHFFFAOYSA-N 0.000 description 1
- UUBZROKNETVXIK-UHFFFAOYSA-N 3-(4,6-dichloro-2-ethoxycarbonyl-1h-indol-3-yl)propanoic acid Chemical compound ClC1=CC(Cl)=C2C(CCC(O)=O)=C(C(=O)OCC)NC2=C1 UUBZROKNETVXIK-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-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
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- MNILDQSRDHCFJG-UHFFFAOYSA-N 3-oxa-8-azabicyclo[3.2.1]octane Chemical compound C1OCC2CCC1N2 MNILDQSRDHCFJG-UHFFFAOYSA-N 0.000 description 1
- AWABRMSZZMDOEI-UHFFFAOYSA-N 3-phenyl-1h-pyrazole-5-carbaldehyde Chemical compound N1C(C=O)=CC(C=2C=CC=CC=2)=N1 AWABRMSZZMDOEI-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
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 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 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- DGGKXQQCVPAUEA-UHFFFAOYSA-N 8-azabicyclo[3.2.1]octane Chemical compound C1CCC2CCC1N2 DGGKXQQCVPAUEA-UHFFFAOYSA-N 0.000 description 1
- POOPWPIOIMBTOH-UHFFFAOYSA-N 8-oxa-3-azabicyclo[3.2.1]octane Chemical compound C1NCC2CCC1O2 POOPWPIOIMBTOH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KVBWNKARENNBHA-AYLQFLAKSA-N C.CC(=O)c1cn2c(cc1=O)-c1c(Cl)c(-c3ccccc3)nn1C[C@H]2C(C)C.CC(=O)c1cn2c(cc1=O)-c1cc(-c3ccccc3)nn1C[C@H]2C(C)C.COc1ccccc1-c1nn2c(c1Cl)-c1cc(=O)c(C(C)=O)cn1[C@H](C(C)(C)C)C2 Chemical compound C.CC(=O)c1cn2c(cc1=O)-c1c(Cl)c(-c3ccccc3)nn1C[C@H]2C(C)C.CC(=O)c1cn2c(cc1=O)-c1cc(-c3ccccc3)nn1C[C@H]2C(C)C.COc1ccccc1-c1nn2c(c1Cl)-c1cc(=O)c(C(C)=O)cn1[C@H](C(C)(C)C)C2 KVBWNKARENNBHA-AYLQFLAKSA-N 0.000 description 1
- LPPKNVMONYBJLB-KBBJAELYSA-N CC(=O)c1cn2c(cc1=O)-c1c(Cl)c(-c3ccccc3)nn1C[C@H]2C(C)(C)C.CC(=O)c1cn2c(cc1=O)-c1cc(C(C)C)nn1CC2C(C)(C)C.COCCCOc1cc2n(n1)C[C@@H](C(C)(C)C)n1cc(C(C)=O)c(=O)cc1-2.COCCCOc1nn2c(c1Br)-c1cc(=O)c(C(C)=O)cn1[C@H](C(C)(C)C)C2.COCCCOc1nn2c(c1Cl)-c1cc(=O)c(C(C)=O)cn1[C@H](C(C)(C)C)C2 Chemical compound CC(=O)c1cn2c(cc1=O)-c1c(Cl)c(-c3ccccc3)nn1C[C@H]2C(C)(C)C.CC(=O)c1cn2c(cc1=O)-c1cc(C(C)C)nn1CC2C(C)(C)C.COCCCOc1cc2n(n1)C[C@@H](C(C)(C)C)n1cc(C(C)=O)c(=O)cc1-2.COCCCOc1nn2c(c1Br)-c1cc(=O)c(C(C)=O)cn1[C@H](C(C)(C)C)C2.COCCCOc1nn2c(c1Cl)-c1cc(=O)c(C(C)=O)cn1[C@H](C(C)(C)C)C2 LPPKNVMONYBJLB-KBBJAELYSA-N 0.000 description 1
- VUDWKVMOMRVBJD-IBGZPJMESA-N CC(C)(C)[C@@H]1Cn2nc(-c3ccccc3)cc2-c2cc(=O)c(C(=O)O)cn21 Chemical compound CC(C)(C)[C@@H]1Cn2nc(-c3ccccc3)cc2-c2cc(=O)c(C(=O)O)cn21 VUDWKVMOMRVBJD-IBGZPJMESA-N 0.000 description 1
- UQVGVKFWOOQLTB-UFRHTXTISA-N CC(C)[C@@H]1Cn2nc(-c3ccccc3)c(Cl)c2C=N1.CC(C)[C@H]1C=Cc2cc(-c3ccccc3)nn2C1 Chemical compound CC(C)[C@@H]1Cn2nc(-c3ccccc3)c(Cl)c2C=N1.CC(C)[C@H]1C=Cc2cc(-c3ccccc3)nn2C1 UQVGVKFWOOQLTB-UFRHTXTISA-N 0.000 description 1
- GLNNXAAVMCAOKX-QUYCAJJTSA-N CC(C)[C@@H]1Cn2nc(-c3ccccc3)c(Cl)c2CN1Cl.CC(C)[C@@H]1Cn2nc(-c3ccccc3)cc2CN1Cl Chemical compound CC(C)[C@@H]1Cn2nc(-c3ccccc3)c(Cl)c2CN1Cl.CC(C)[C@@H]1Cn2nc(-c3ccccc3)cc2CN1Cl GLNNXAAVMCAOKX-QUYCAJJTSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 101710091045 Envelope protein Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 241000700739 Hepadnaviridae Species 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 1
- 101000955999 Homo sapiens V-set domain-containing T-cell activation inhibitor 1 Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 108010043766 IRX 2 Proteins 0.000 description 1
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 1
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 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
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- ZKGNPQKYVKXMGJ-UHFFFAOYSA-N N,N-dimethylacetamide Chemical compound CN(C)C(C)=O.CN(C)C(C)=O ZKGNPQKYVKXMGJ-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-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
- 229910002651 NO3 Inorganic materials 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000012270 PD-1 inhibitor Substances 0.000 description 1
- 239000012668 PD-1-inhibitor Substances 0.000 description 1
- 239000012271 PD-L1 inhibitor Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 101710094000 Programmed cell death 1 ligand 1 Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 101710188315 Protein X Proteins 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 229910006024 SO2Cl2 Inorganic materials 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 108091027967 Small hairpin RNA Proteins 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 102100038929 V-set domain-containing T-cell activation inhibitor 1 Human genes 0.000 description 1
- 206010058874 Viraemia Diseases 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- 101710086987 X protein Proteins 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
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000033289 adaptive immune response Effects 0.000 description 1
- 238000011374 additional therapy Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001341 alkaline earth metal compounds Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- DCBDOYDVQJVXOH-UHFFFAOYSA-N azane;1h-indole Chemical compound N.C1=CC=C2NC=CC2=C1 DCBDOYDVQJVXOH-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 102000023732 binding proteins Human genes 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 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
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 229940043430 calcium compound Drugs 0.000 description 1
- 150000001674 calcium compounds Chemical class 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229940124765 capsid inhibitor Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 150000005827 chlorofluoro hydrocarbons Chemical class 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000003181 co-melting Methods 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 125000004122 cyclic group Chemical group 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000005860 defense response to virus Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 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
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- OLAMWIPURJGSKE-UHFFFAOYSA-N et2o diethylether Chemical compound CCOCC.CCOCC OLAMWIPURJGSKE-UHFFFAOYSA-N 0.000 description 1
- LHWWETDBWVTKJO-UHFFFAOYSA-N et3n triethylamine Chemical compound CCN(CC)CC.CCN(CC)CC LHWWETDBWVTKJO-UHFFFAOYSA-N 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethanedisulfonate group Chemical group C(CS(=O)(=O)[O-])S(=O)(=O)[O-] AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 229940052303 ethers for general anesthesia Drugs 0.000 description 1
- WZXYVBRQIXLVIO-WMCAAGNKSA-N ethyl (8R)-3-bromo-8-tert-butyl-4-(3-methoxypropoxy)-12-oxo-5,6,9-triazatricyclo[7.4.0.02,6]trideca-2,4,10-triene-11-carboxylate Chemical compound CCOC(=O)C1=CN2[C@@H](CN3C(=C(C(=N3)OCCCOC)Br)C2CC1=O)C(C)(C)C WZXYVBRQIXLVIO-WMCAAGNKSA-N 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229960001731 gluceptate Drugs 0.000 description 1
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000027700 hepatic dysfunction Diseases 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 230000001553 hepatotropic effect Effects 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- JHCKVPVXWBVGDI-UHFFFAOYSA-N hydrazine;dihydrate Chemical compound O.O.NN JHCKVPVXWBVGDI-UHFFFAOYSA-N 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000008629 immune suppression Effects 0.000 description 1
- 230000006058 immune tolerance Effects 0.000 description 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000003259 immunoinhibitory effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 229960003521 interferon alfa-2a Drugs 0.000 description 1
- 229960003507 interferon alfa-2b Drugs 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- SYJRVVFAAIUVDH-UHFFFAOYSA-N ipa isopropanol Chemical compound CC(C)O.CC(C)O SYJRVVFAAIUVDH-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- LLYKPZOWCPVRPD-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine;n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=CC=N1 LLYKPZOWCPVRPD-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 229940071846 neulasta Drugs 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 229960003347 obinutuzumab Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OIPZNTLJVJGRCI-UHFFFAOYSA-M octadecanoyloxyaluminum;dihydrate Chemical compound O.O.CCCCCCCCCCCCCCCCCC(=O)O[Al] OIPZNTLJVJGRCI-UHFFFAOYSA-M 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 229940121655 pd-1 inhibitor Drugs 0.000 description 1
- 229940121656 pd-l1 inhibitor Drugs 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- HQQSBEDKMRHYME-UHFFFAOYSA-N pefloxacin mesylate Chemical compound [H+].CS([O-])(=O)=O.C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 HQQSBEDKMRHYME-UHFFFAOYSA-N 0.000 description 1
- 229960001373 pegfilgrastim Drugs 0.000 description 1
- 108010092853 peginterferon alfa-2a Proteins 0.000 description 1
- 108010092851 peginterferon alfa-2b Proteins 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- 230000015843 photosynthesis, light reaction Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229960000688 pomalidomide Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- WHYQCQRHPQBZHM-UHFFFAOYSA-N pyrazole-1-carboxylic acid Chemical class OC(=O)N1C=CC=N1 WHYQCQRHPQBZHM-UHFFFAOYSA-N 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229940120975 revlimid Drugs 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 description 1
- 239000012723 sample buffer Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229940100996 sodium bisulfate Drugs 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- MIXCUJKCXRNYFM-UHFFFAOYSA-M sodium;diiodomethanesulfonate;n-propyl-n-[2-(2,4,6-trichlorophenoxy)ethyl]imidazole-1-carboxamide Chemical compound [Na+].[O-]S(=O)(=O)C(I)I.C1=CN=CN1C(=O)N(CCC)CCOC1=C(Cl)C=C(Cl)C=C1Cl MIXCUJKCXRNYFM-UHFFFAOYSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940071103 sulfosalicylate Drugs 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JJXOIFHXNBFRNV-UHFFFAOYSA-N tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C.CC(C)(C)OC(=O)OC(=O)OC(C)(C)C JJXOIFHXNBFRNV-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229940034915 thalomid Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229950007217 tremelimumab Drugs 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 238000010518 undesired secondary reaction Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000008299 viral mechanism Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 235000016804 zinc Nutrition 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- 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
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Definitions
- the present invention relates to novel fused tricyclic pyrazolo-dihydro-pyrazinyl pyridone compounds that are inhibitors of hepatitis virus replication, and are thus useful to treat viral infections, and particularly hepatitis B virus (HBV).
- HBV hepatitis B virus
- the invention provides novel fused tricyclic pyrazolo-dihydro-pyrazinyl pyridone compounds as disclosed herein, pharmaceutical compositions containing such compounds, and methods of using these compounds and compositions in the treatment and prevention of HBV infections.
- HBV hepatitis B virus
- HCC hepatocellular carcinoma
- HBV belongs to the family of Hepadnaviridae, a group of small hepatotropic DNA viruses that replicate through the reverse transcription of an RNA intermediate.
- the 3.2-kb HBV genome in viral particles is in a circular, partially double-stranded DNA conformation (relaxed circular DNA or rcDNA).
- the HBV genome consists of four overlapping open reading frames (ORFs), which encode for the core, polymerase (Pol), envelope, and X proteins.
- rcDNA is transcriptionally inert and must be converted into covalently closed circular DNA (cccDNA) in the nucleus of infected cells before viral RNAs can be transcribed.
- Covalently closed circular DNA is the only template for HBV transcription and, because HBV RNA templates genomic reverse transcription, its persistence is required for persistent infection.
- the envelope of HBV comprises a mixture of surface antigen proteins (HBsAg).
- the HBsAg coat is a mixture of three overlapping proteins: all three share a common region, which corresponds to the smallest of the three proteins (SHBsAg).
- the mixture consists mostly of SHBsAg, but also includes Medium HBsAg, which comprises SHBsAg plus an additional polypeptide segment, and Large HBsAg, which comprises M HBsAg plus another added polypeptide segment.
- the S, M and L HBsAg proteins also assemble into a subviral particle knows as the 22-nm particle, which is not infectious but contains the same proteins that envelope the infectious virus particles.
- these subviral, non-infectious particles have been used as a vaccine, since they contain the same antigenic surface proteins as the infectious HBV virion, and thus elicit antibodies that recognize the infectious agent.
- these subviral particles greatly outnumber infectious virions, and are believed to protect the infectious virions from the immune system of the infected host. By sheer numbers, they may act as decoys, distracting immune responses from the infectious virus particles, but in addition they are reported to suppress the function of immune cells (monocytes, dendritic cells and natural killer cells) and may thus impair the immune response to HBV. Because these subviral particles protect infectious HBV from the host immune system, reducing the level of subviral particles has been recognized as a viable therapeutic approach. See, e.g., WO2015/113990.
- HBsAg hepatitis B surface antigen
- HBV viral DNA polymerase
- entecavir nucleoside/nucleotide inhibitors of the viral DNA polymerase
- tenofovir nucleoside/nucleotide inhibitors of the viral DNA polymerase
- these therapies cannot eradicate the intrahepatic HBV cccDNA pool in chronic hepatitis B patients or limit the transcription of HBsAg from the pre-existing cccDNA, nor do they affect the secretion of synthesized HBsAg into patients' blood to counteract the host innate immune response.
- these HBV treatments are in most cases life-long therapies, and discontinuation often leads to virological relapse.
- the invention provides compounds that reduce serum HbsAg levels and are believed to operate by suppression of the secretion of the 22 nm subviral particles containing HBsAg. These compounds are useful to treat HBV infections and to reduce the incidence of serious liver disorders caused by HBV infections. They also exhibit improved properties relative to compounds having similar biological activity, such as improved solubility in buffered aqueous solution and lower predicted propensity for certain adverse effects.
- the present invention provides novel compounds that inhibit secretion of HBsAg from cells infected with hepatitis B virus and thereby reduce viral load and viral replication in patients having chronic HBV infection.
- the compounds of the invention are suitable for treatment of patients with HBV, including chronic HBV (cHBV).
- Some of the compounds of the invention in addition to being highly effective at suppression of HBsAg levels, also exhibit improved safety relative to similar compounds known in the art, such as reduced inhibition of sodium ion channels that can be indicative of potential cardiotoxicity, reduced drug-drug interactions, and lower risk of time-dependent cytochrome (CYP) inhibition.
- CYP time-dependent cytochrome
- the invention also provides pharmaceutical compositions containing the novel compounds as well as methods to use the compounds and compositions to inhibit hepatitis B virus replication, and to treat disease conditions associated with or caused by HBV. Further objects of this invention are described in the following description and the examples. Thus the compounds of the invention are suitable for treatment of patients with HBV, including chronic HBV.
- the invention provides compounds of Formula (I):
- R 1 is —C 1 -C 8 -alkyl; —(C 0 -C 8 -alkylene)-(C 1 -C 8 -alkoxy) x , or —(C 0 -C 8 -alkylene)-(C 3 -C 8 -cycloalkyl); each of which is optionally substituted with one or two groups selected from halo, —OR 10 , ⁇ O, —CN, —NR 10 2 , —COOR 10 , —CONR 10 2 , and —(C 0 -C 8 -alkylene)-aryl;
- a 5-6 membered aryl or heteroaryl group wherein the 5-6 membered aryl or heteroaryl group of R 1 is independently substituted by one or more groups selected from the group consisting of —H, —CN, —(C 0 -C 8 -alkylene)-(—OR 10 ) x , and halo;
- heterocyclic or heteroaryl group containing N, O or S as a ring member; wherein the heterocyclic or heteroaryl ring is optionally substituted with up to three groups selected from —R 10 , —OR 10 , —NR 10 2 , -halo, —CN, —COOR 10 , —CONR 10 2 , and ⁇ O;
- x represents the number groups which replace a hydrogen on the group to which it is attached
- R 2 is H, C 1 -C 8 -alkyl, halo, —CN; or taken together with R 1 to form a 5-7 membered heterocyclic or heteroaryl containing N, O or S as a ring member; wherein the heterocyclic or heteroaryl ring is optionally substituted with up to three groups selected from —R 10 , —OR 10 , —NR 10 2 , -halo, —CN, —COOR 10 , —CONR 10 2 , and ⁇ O;
- R 3 is H, hydroxyl, halo or C 1 -C 8 -alkyl
- each R 4 , R 5 , R 6 , R 7 , or R 8 is independently —H, —C 1 -C 8 -alkyl, —C 1 -C 8 -haloalkyl, —CN, —C 1 -C 8 -alkoxy, —C 3 -C 8 cycloalkyl, aryl, or a 5- or 6-membered heteroaryl containing up to three heteroatoms selected from N, O and S as ring members; where each —C 1 -C 8 -alkyl, —C 3 -C 8 cycloalkyl, aryl or a 5- or 6-membered heteroaryl is optionally substituted with up to three groups selected from —OR 10 , —NR 10 2 , -halo, —CN and —SO 2 R 9 ; or R 5 taken together with R 7 or R 6 taken together with R 8 form a 5-7 membered heterocyclic or heteroaryl group containing N, O or S as
- W is —COOR 9 , —C(O)NH—SO 2 R 10 , —C(O)NH—SO 2 NR 10 2 , -5-tetrazolyl, or -1,2,4-oxadiazol-3-yl-5(4H)-one;
- R 9 is H or C 1 -C 8 alkyl; the C 1 -C 8 alkyl optionally substituted with one or two groups selected from halo, —OR 10 , ⁇ O, —CN, —NR 10 2 , —COOR 10 , and —CONR 10 2 ;
- R 10 is independently selected at each occurrence from —H, —C 1 -C 8 alkyl and aryl, each of —C 1 -C 8 alkyl and aryl optionally substituted with one to three groups selected from halo, —OH, —C 1 -C 8 alkoxy, ⁇ O, —CN, —NH 2 , —NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl) 2 , and -cyclopropyl; and two R 10 groups directly attached to the same atom, which may be C or N, can optionally be taken together to form a 3-6 membered ring that can optionally contain a heteroatom selected from N, O and S as a ring member, and can be substituted by up to two groups selected from —OH, ⁇ O, —C 1 -C 8 alkyl, and —C 1 -C 8 alkoxy;
- the invention also includes methods of making these compounds, pharmaceutical compositions containing these compounds, methods to use these compounds and compositions to inhibit hepatitis B virus replication, and to treat disease conditions associated with or caused by HBV, pharmaceutical combinations comprising these compounds, and methods to use the compounds in the manufacture of a medicament. Further objects of this invention are described in the following description and the examples.
- the term “subject” refers to an animal.
- the animal is a mammal.
- a subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
- the subject is a human.
- a “patient” as used herein refers to a human subject.
- the term “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
- treating refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
- treating refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
- treating or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
- “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
- Optionally substituted means the group referred to can be substituted at one or more positions by any one or any combination of the radicals listed thereafter.
- the number, placement and selection of substituents is understood to encompass only those substitutions that a skilled chemist would expect to be reasonably stable; thus ‘oxo’ would not be a substituent on an aryl or heteroaryl ring, for example, and a single carbon atom would not have three hydroxy or amino substituents.
- optional substituents are typically up to four groups selected from halo, oxo, CN, amino, hydroxy, —C 1-3 alkyl, —OR*, —NR* 2 , —SR*, —SO 2 R*, —COOR*, and —CONR* 2 , where each R* is independently H or C 1-3 alkyl.
- Aryl refers to a phenyl or naphthyl group unless otherwise specified.
- Aryl groups unless otherwise specified may be optionally substituted with up to four groups selected from halo, CN, amino, hydroxy, C 1-3 alkyl, —OR*, —NR* 2 , —SR*, —SO 2 R*, —COOR*, and —CONR* 2 , where each R* is independently H or C 1-3 alkyl.
- Halo or “halogen”, as used herein, may be fluorine, chlorine, bromine or iodine.
- C 1-6 alkyl or “C 1 -C 6 alkyl”, as used herein, denotes straight chain or branched alkyl having 1-6 carbon atoms. If a different number of carbon atoms is specified, such as C 4 or C 3 , then the definition is to be amended accordingly, such as “C 1-4 alkyl” will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
- C 1-6 alkylene or “C 1 -C 6 alkylene”, as used herein, denotes straight chain or branched alkyl having 1-6 carbon atoms and two open valences for connection to two other groups. If a different number of carbon atoms is specified, such as C 4 or C 3 , then the definition is to be amended accordingly, such as “C 1-4 alkylene” will represent methylene (—CH 2 —), ethylene (—CH 2 CH 2 —), straight chain or branched propylene (—CH 2 CH 2 CH 2 — or —CH 2 —CHMe-CH 2 —), and the like.
- C 1-6 alkoxy denotes straight chain or branched alkoxy (—O-Alkyl) having 1-6 carbon atoms. If a different number of carbon atoms is specified, such as C 4 or C 3 , then the definition is to be amended accordingly, such as “C 1-4 alkoxy” will represent methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
- C 1-4 Haloalkyl or “C 1 -C 4 haloalkyl” as used herein, denotes straight chain or branched alkyl having 1-4 carbon atoms wherein at least one hydrogen has been replaced with a halogen.
- the number of halogen replacements can be from one up to the number of hydrogen atoms on the unsubstituted alkyl group. If a different number of carbon atoms is specified, such as C or C 3 , then the definition is to be amended accordingly.
- C 1-4 haloalkyl will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl that have at least one hydrogen substituted with halogen, such as where the halogen is fluorine: CF 3 CF 2 —, (CF 3 ) 2 CH—, CH 3 —CF 2 —, CF 3 CF 2 —, CF 3 , CF 2 H—, CF 3 CF 2 CH(CF 3 )— or CF 3 CF 2 CF 2 CF 2 —.
- C 3-8 cycloalkyl refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. If a different number of carbon atoms is specified, such as C 3 -C 6 , then the definition is to be amended accordingly.
- “4- to 8-Membered heterocyclyl”, “5- to 6-membered heterocyclyl”, “3- to 10-membered heterocyclyl”, “3- to 14-membered heterocyclyl”, “4- to 14-membered heterocyclyl” and “5- to 14-membered heterocyclyl”, refers, respectively, to 4- to 8-membered, 5- to 6-membered, 3- to 10-membered, 3- to 14-membered, 4- to 14-membered and 5- to 14-membered heterocyclic rings; unless otherwise specified, such rings contain 1 to 7, 1 to 5, or 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur as ring members, and the rings may be saturated, or partially saturated but not aromatic.
- heterocyclic group can be attached to another group at a nitrogen or a carbon atom.
- heterocyclyl includes single ring groups, fused ring groups and bridged groups. Examples of such heterocyclyl include, but are not limited to pyrrolidine, piperidine, piperazine, pyrrolidinone, morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, 1,4-dioxane, 1,4-oxathiane, 8-aza-bicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane, 3-Oxa-8-aza-bicyclo[3.2.1]octane, 8-Oxa-3-aza-bicyclo[3.2.1]octane, 2-Oxa-5-aza-bicyclo[2.2.1]heptane, 2,5-Diaza-bicyclo[
- heterocyclic groups have 1-2 heteroatoms selected from N, O and S as ring members, and 4-7 ring atoms, and are optionally substituted with up to four groups selected from halo, oxo, CN, amino, hydroxy, C 1-3 alkyl, —OR*, —NR* 2 , —SR*, —SO 2 R*, —COOR*, and —CONR* 2 , where each R* is independently H or C 1-3 alkyl.
- heterocyclic groups containing a sulfur atom are optionally substituted with one or two oxo groups on the sulfur.
- 4-6 membered cyclic ether refers to a 4 to 6 membered ring comprising one oxygen atom as a ring member. Examples include oxetane, tetrahydrofuran and tetrahydropyran.
- Heteroaryl is a completely unsaturated (aromatic) ring.
- the term “heteroaryl” refers to a 5-14 membered monocyclic- or bicyclic- or tricyclic-aromatic ring system, having 1 to 8 heteroatoms selected from N, O or S.
- the heteroaryl is a 5-10 membered ring or ring system (e.g., 5-7 membered monocyclic group or an 8-10 membered bicyclic group), often a 5-6 membered ring containing up to four heteroatoms selected from N, O and S, though often a heteroaryl ring contains no more than one divalent O or S in the ring.
- Typical heteroaryl groups include furan, isothiazole, thiadiazole, oxadiazole, indazole, indole, quinoline, 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-(1,2,4-triazolyl), 4- or 5-(1,2, 3-triazolyl), tetrazolyl, triazine, pyrimidine, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl.
- Heteroaryl groups are optionally substituted with up to four groups selected from halo, CN, amino, hydroxy, C 1-3 alkyl, —OR*, —NR* 2 , —SR*, —SO 2 R*, —COOR*, and —CONR* 2 , where each R* is independently H or C 1-3 alkyl.
- hydroxy or “hydroxyl” refers to the group —OH.
- R 1 is —C 1 -C 8 -alkyl; —(C 0 -C 8 -alkylene)-(C 1 -C 8 -alkoxy) x , or —(C 0 -C 8 -alkylene)-(C 3 -C 8 -cycloalkyl); each of which is optionally substituted with one or two groups selected from halo, —OR 10 , ⁇ O, —CN, —NR 10 2 , —COOR 10 , —CONR 10 2 , and —(C 0 -C 8 -alkylene)-aryl;
- a 5-6 membered aryl or heteroaryl group wherein the 5-6 membered aryl or heteroaryl group of R 1 is independently substituted by one or more groups selected from the group consisting of —H, —CN, —(C 0 -C 8 -alkylene)-(—OR 10 ) x , and halo;
- heterocyclic or heteroaryl group containing N, O or S as a ring member; wherein the heterocyclic or heteroaryl ring is optionally substituted with up to three groups selected from —R 10 , —OR 10 , —NR 10 2 , -halo, —CN, —COOR 10 , —CONR 10 2 , and ⁇ O;
- x represents the number groups which replace a hydrogen on the group to which it is attached
- R 2 is H, C 1 -C 8 -alkyl, halo, —CN; or taken together with R 1 to form a 5-7 membered heterocyclic or heteroaryl containing N, O or S as a ring member; wherein the heterocyclic or heteroaryl ring is optionally substituted with up to three groups selected from —R 10 , —OR 10 , —NR 10 2 , -halo, —CN, —COOR 10 , —CONR 10 2 , and ⁇ O;
- R 3 is H, hydroxyl, halo or C 1 -C 8 -alkyl
- each R 4 , R 5 , R 6 , R 7 , or R 8 is independently —H, —C 1 -C 8 -alkyl, —C 1 -C 8 -haloalkyl, —CN, —C 1 -C 8 -alkoxy, —C 3 -C 8 cycloalkyl, aryl, or a 5- or 6-membered heteroaryl containing up to three heteroatoms selected from N, O and S as ring members; where each —C 1 -C 8 -alkyl, —C 3 -C 8 cycloalkyl, aryl or a 5- or 6-membered heteroaryl is optionally substituted with up to three groups selected from —OR 10 , —NR 10 2 , -halo, —CN and —SO 2 R 9 ; or R 5 taken together with R 7 or R 6 taken together with R 8 form a 5-7 membered heterocyclic or heteroaryl group containing N, O or S as
- W is —COOR 9 , —C(O)NH—SO 2 R 10 , —C(O)NH—SO 2 NR 10 2 , -5-tetrazolyl, or -1,2,4-oxadiazol-3-yl-5(4H)-one;
- R 9 is H or C 1 -C 8 alkyl; the C 1 -C 8 alkyl optionally substituted with one or two groups selected from halo, —OR 10 , ⁇ O, —CN, —NR 10 2 , —COOR 10 , and —CONR 10 2 ;
- R 10 is independently selected at each occurrence from —H, —C 1 -C 8 alkyl and aryl, each of —C 1 -C 8 alkyl and aryl optionally substituted with one to three groups selected from halo, —OH, —C 1 -C 8 alkoxy, ⁇ O, —CN, —NH 2 , —NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl) 2 , and -cyclopropyl; and two R 10 groups directly attached to the same atom, which may be C or N, can optionally be taken together to form a 3-6 membered ring that can optionally contain a heteroatom selected from N, O and S as a ring member, and can be substituted by up to two groups selected from —OH, ⁇ O, —C 1 -C 8 alkyl, and —C 1 -C 8 alkoxy;
- R 1 is a 5-6 membered aryl group; wherein the 5-6 membered aryl group of R 1 is independently substituted by one or more groups selected from the group consisting of —H or —OR 10 .
- R 1 is phenyl; or a pharmaceutically acceptable salt thereof.
- a pharmaceutical composition comprising a compound of any of the preceding embodiments admixed with at least one pharmaceutically acceptable carrier.
- a method to treat a subject having a hepatitis B infection which comprises administering to the subject a compound of any of embodiments 1-17 or a pharmaceutical composition of embodiment 18.
- a method to inhibit replication of hepatitis B virus which comprises contacting the hepatitis B virus, either in vitro or in vivo, with a compound according to any one of embodiments 1-17.
- a pharmaceutical combination comprising a compound of any of embodiments 1-17 and at least one additional therapeutic agent.
- Another embodiment of the invention provides a compound as described above, or a pharmaceutically acceptable salt thereof, for use as a medicament.
- the medicament is for treatment of a subject having an HBV infection.
- the subject is a human diagnosed with chronic HBV.
- this medicament is for the treatment or prevention of a viral disease and/or infection in a human being, including where the virus involved is HBV.
- composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
- the composition comprises at least two pharmaceutically acceptable carriers and/or excipients.
- the pharmaceutical composition according to this invention further comprises a therapeutically effective amount of at least one other antiviral agent.
- the other antiviral agent is one useful to treat HBV. Suitable additional therapeutic agents are described herein.
- the invention also provides the use of a pharmaceutical composition as described hereinabove for the treatment of a HBV infection in a human being having or at risk of having the infection.
- the subject for treatment has been diagnosed as having a chronic HBV infection.
- the invention also provides the use of a pharmaceutical composition as described hereinabove for the treatment of HBV infection in a human being having or at risk of having the disease.
- Another aspect of the invention involves a method of treating or preventing a hepatitis B viral disease and/or infection in a human being by administering to the human being an antivirally effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a composition comprising a compound as described above, alone or in combination with at least one other antiviral agent, administered together or separately.
- An additional aspect of this invention refers to an article of manufacture comprising a composition of the invention that is effective to treat a hepatitis B viral disease and/or infection; and packaging material comprising a label which indicates that the composition can be used to treat disease and/or infection by a hepatitis B virus; wherein the composition comprises a compound of formula (I) according to this invention or a pharmaceutically acceptable salt thereof.
- Still another aspect of this invention relates to a method of inhibiting the replication of HBV, comprising exposing the virus to an effective amount of the compound of formula (I), or a salt thereof, under conditions where replication of the virus is inhibited.
- This method can be practiced in vitro or in vivo.
- a compound of formula (I), or a salt thereof to inhibit the replication of HBV either in vitro or in vivo, or to reduce the amount of HBsAg present in a subject infected with HBV.
- the compound of Formula (I) can be a compound according to any of embodiments 1-17 described above.
- the compound of Formula (I) is co-administered with or used in combination with at least one additional therapeutic agent selected from: an interferon or peginterferon, an HBV polymerase inhibitor, a viral entry inhibitor, a viral maturation inhibitor, a capsid assembly inhibitor, an HBV core modulator, a reverse transcriptase inhibitor, a TLR-agonist, or an immunomodulator.
- the compound of Formula (I) may be prepared for simultaneous or sequential use in combination with an additional therapeutic agent; or the compound of Formula (I) may be combined into a pharmaceutical combination comprising a compound of Formula (I) and at least one additional therapeutic agent.
- Some particular therapeutic agents that may be used in combination with the compounds of the invention include immunomodulators described herein, interferon alfa 2a, interferon alfa-2b, pegylated interferon alfa-2a, pegylated interferon alfa-2b, TLR-7 and TLR-9 agonists, entecavir, tenofovir, cidofovir, telbivudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, apricitabine, atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, adefovir, efavirenz, nevirapine, delavirdine, and etravirine.
- Suitable core modulators are disclosed in WO2013/096744; suitable HBV capsid inhibitors are described in US2015
- additional agents may be combined with the compounds of this invention to create a single pharmaceutical dosage form.
- these additional agents may be separately administered to the patient as part of a multiple dosage form, for example, using a kit.
- Such additional agents may be administered to the patient prior to, concurrently with, or following the administration of a compound of the invention, or a pharmaceutically acceptable salt thereof.
- these additional therapeutic agents may be administered separately from and optionally by different routes of administration and on different dosing schedules from the compound of the invention, provided the compound of the invention and the additional therapeutic agent are used concurrently for treatment of an HBV infection or a disorder caused or complicated by an HBV infection.
- the dose range of the compounds of the invention applicable per day is usually from 0.01 to 100 mg/kg of body weight, preferably from 0.1 to 50 mg/kg of body weight.
- the total daily dosage is between 1 and 25 mg, and may be administered in a single dose or in divided doses at different times to maintain a suitable plasma concentration.
- Each dosage unit may conveniently contain from 5% to 95% active compound (w/w).
- Preferably such preparations contain from 20% to 80% active compound which may be admixed with one or more pharmaceutically acceptable carriers or excipients.
- the actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the combination will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.
- composition of this invention comprises a combination of a compound of the invention and one or more additional therapeutic or prophylactic agent
- both the compound and the additional agent may be used at lower dosages than would be used typically for the individual compound when used as a single-agent treatment.
- each component may be present at dosage levels of between about 10 to 100%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen.
- the compounds of the invention may be used in combination with other therapeutic agents, just as combinations of therapeutic agents are currently used for the treatment of hepatitis C virus (HCV) infections.
- a compound of the invention may be used in combination with a different anti-HBV therapeutic agent such as a nucleoside or an immunomodulatory agent.
- anti-HBV therapeutic agent such as a nucleoside or an immunomodulatory agent.
- Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologicals) that are effective to inhibit the formation and/or replication of a virus in a human being, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a human being.
- Such agents can be selected from entecavir, tenofovir, cidofovir, telbivudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, apricitabine, atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, adefovir, efavirenz, nevirapine, delavirdine, and etravirine, and immunomodulators described herein including interferons and pegylated interferons, TLR-7 agonists, and TLR-9 agonists.
- HBV treatments including immunomodulatory agents, such as interferon- ⁇ and pegylated interferon- ⁇ , and oral nucleoside/nucleotide analogues (NAs), including lamivudine, adefovir, telbivudine, entecavir and tenofovir, are known to suppress but not eliminate HBV. J. Antimicrob. Chemother. 2011, vol. 66(12), 2715-25, and thus those therapeutics may be used in combination with a compound of the invention.
- immunomodulatory agents such as interferon- ⁇ and pegylated interferon- ⁇
- NAs nucleoside/nucleotide analogues
- the compounds of the invention contain one or more chiral centers. These compounds may be made and used as single isomers or as mixtures of isomers. Methods for separating the isomers, including diastereomers and enantiomers, are known in the art, and examples of suitable methods are described herein.
- the compounds of the invention are used as a single substantially pure isomer, meaning at least 90% of a sample of the compound is the specified isomer and less than 10% of the sample is any other isomer or mixture of isomers. Preferably, at least 95% of the sample is a single isomer.
- a suitable isomer is within the ordinary level of skill, as one isomer will typically be more active in the in vivo or in vitro assay described herein for measuring HBV activity, and will be the preferred isomer. Where in vitro activity differences between isomers are relatively small, e.g. less than about a factor of 4, a preferred isomer may be selected based on activity level against viral replication in cell culture, using methods such as those described herein: the isomer having a lower MIC (minimum inhibitory concentration) or EC-50 is preferred.
- MIC minimum inhibitory concentration
- the compounds of the invention may be synthesized by the general synthetic routes illustrated below, specific examples of which are described in more detail in the Examples. Additional guidance for synthesis of the compounds of Formula (I) and synthetic intermediates useful for these syntheses are disclosed in published PCT applications WO2015/113990 and WO2015/173164.
- Scheme 1 illustrates a general method useful to make compounds of the invention, as demonstrated in the Examples herein.
- a variety of pyrazole-2-carboxylates starting materials are known in the art.
- the carboxylate can be reduced to an alcohol using methods known in the art, and the alcohol can be protected with a protecting group such as known silyl ethers (e.g., TBS).
- the indole nitrogen can be alkylated with a suitable alph-haloketone to introduce the group containing R 6 .
- Reductive amination is one method to introduce nitrogen at the carbonyl center.
- the protected alcohol at C2 of the indole/azaindole can be deprotected and oxidized to an aldehyde oxidation state, at which point it cyclizes with the primary amine to form the new 6-membered ring substituted with R 6 .
- the imine of the new ring is then annulated to form an additional fused ring by a method known in the art, using (Z)-ethyl 2-(ethoxymethylene)-3-oxobutanoate.
- the new ring is then oxidized to provide the pyridone ring shown in Formula (I). Methods useful in preparing these compounds are disclosed in published PCT applications WO2015/113990 and WO2015/173164.
- enantiomers of these compounds can be separated by chiral HPLC and similar known methods. While one enantiomer of compounds of this formula is typically more active than the other enantiomer, both isomers exhibit activity one HBsAg as demonstrated herein.
- an enantiomerically pure compounds of Formula (I) can be synthesized using an enantiomerically pure amino alcohol derivative as shown in Scheme 2.
- an optical isomer or “a stereoisomer” refers to any of the various stereoisomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom.
- the term “chiral” refers to molecules which have the property of non-superimposability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other.
- a 1:1 mixture of a pair of enantiomers is a “racemic” mixture.
- the term is used to designate a racemic mixture where appropriate.
- “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
- the absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R—S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
- Resolved compounds whose absolute configuration is unknown can be designated (+) or ( ⁇ ) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
- Certain compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
- the compounds can be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
- the present invention is meant to include all such possible stereoisomers, including racemic mixtures, diasteriomeric mixtures and optically pure forms.
- Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a di-substituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
- Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers or diastereomers, for example, by chromatography and/or fractional crystallization.
- any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
- a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O, O′-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
- Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
- HPLC high pressure liquid chromatography
- the compounds of the present invention can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
- the compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms.
- solvate refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules.
- solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like.
- hydrate refers to the complex where the solvent molecule is water.
- the compounds of the present invention including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.
- salt refers to an acid addition or base addition salt of a compound of the present invention.
- Salts include in particular “pharmaceutically acceptable salts”.
- pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable.
- the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
- Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen
- Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
- Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
- Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
- Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
- the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
- Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
- Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
- the pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods.
- such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
- a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
- Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
- use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
- any formula given herein is intended to represent unlabelled forms as well as isotopically labelled forms of the compounds of the present invention having up to three atoms with non-natural isotope distributions, e.g., sites that are enriched in deuterium or 13 C or 15 N.
- Isotopically labelled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number other than the natural-abundance mass distribution.
- isotopes that can be usefully over-incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S 36 Cl, 125 I respectively.
- the invention includes various isotopically labelled compounds of the present invention, for example those into which radioactive isotopes, such as 3 H and 14 C, or those in which non-radioactive isotopes, such as 2 H and 13 C are present at levels substantially above normal isotope distribution.
- Such isotopically labelled compounds are useful in metabolic studies (with 14 C, for example), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
- PET positron emission tomography
- SPECT single-photon emission computed tomography
- an 18 F labelled compound of the present invention may be particularly desirable for PET or SPECT studies.
- Isotopically-labelled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labelled reagent in place of the non-labelled reagent typically employed. Labelled samples may be useful with quite low isotope incorporation, such as where a radiolabel is used to detect trace amounts of the compound.
- isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
- a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
- solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 -DMSO.
- Compounds of the present invention that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers.
- These co-crystals may be prepared from compounds of the present invention by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of the present invention with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed.
- Suitable co-crystal formers include those described in WO 2004/078163. Hence the invention further provides co-crystals comprising a compound of the present invention.
- the compounds of the invention can be administered by known methods, including oral, parenteral, inhalation, and the like.
- the compound of the invention is administered orally, as a pill, lozenge, troche, capsule, solution, or suspension.
- a compound of the invention is administered by injection or infusion. Infusion is typically performed intravenously, often over a period of time between about 15 minutes and 4 hours.
- a compound of the invention is administered intranasally or by inhalation; inhalation methods are particularly useful for treatment of respiratory infections.
- Compounds of the present invention exhibit oral bioavailability, so oral administration is sometimes preferred.
- a compound of the present invention is used in combination with a second therapeutic agent, which may be an antiviral agent, such as those named herein.
- combination is meant either a fixed combination in one dosage unit form, as separate dosage forms suitable for use together either simultaneously or sequentially, or as a kit of parts for the combined administration where a compound of the present invention and a combination partner may be administered independently at the same time or separately within time intervals that especially allow that the combination partners show a cooperative, e.g., synergistic, effect, or any combination thereof.
- the second antiviral agent may be administered in combination with the compounds of the present inventions wherein the second antiviral agent is administered prior to, simultaneously, or after the compound or compounds of the present invention.
- a compound of the invention may be formulated with a second agent into the same dosage form.
- An example of a dosage form containing a compound of the invention and a second agent is a tablet or a capsule.
- a combination of a compound of the invention and a second antiviral agent may provide synergistic activity.
- the compound of the invention and second antiviral agent may be administered together, separate but simultaneously, or sequentially.
- an “effective amount” of a compound is that amount necessary or sufficient to treat or prevent a viral infection and/or a disease or condition described herein.
- an effective amount of a compound of Formula I is an amount sufficient to treat viral infection in a subject.
- an effective amount is an amount sufficient to treat HBV in a subject in need of such treatment.
- the effective amount can vary depending on such factors as the size and weight of the subject, the type of illness, or the particular compound of the invention. For example, the choice of the compound of the invention can affect what constitutes an “effective amount.”
- One of ordinary skill in the art would be able to study the factors contained herein and make the determination regarding the effective amount of the compounds of the invention without undue experimentation.
- the regimen of administration can affect what constitutes an effective amount.
- the compound of the invention can be administered to the subject either prior to or after the onset of a viral infection. Further, several divided dosages, as well as staggered dosages, can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection. Further, the dosages of the compound(s) of the invention can be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
- Compounds of the invention may be used in the treatment of states, disorders or diseases as described herein, or for the manufacture of pharmaceutical compositions for use in the treatment of these diseases.
- the invention provides methods of use of compounds of the present invention in the treatment of these diseases or for preparation of pharmaceutical compositions having compounds of the present invention for the treatment of these diseases.
- pharmaceutical composition includes preparations suitable for administration to mammals, e.g., humans.
- the compounds of the present invention can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of at least one compound of Formula (I) or any subgenus thereof as active ingredient in combination with a pharmaceutically acceptable carrier, or optionally two or more pharmaceutically acceptable carriers.
- phrases “pharmaceutically acceptable carrier” is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present invention to mammals.
- the carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
- Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
- materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'
- wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
- antioxidants examples include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, ⁇ -tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
- water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
- oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin
- Formulations of the present invention include those suitable for oral, nasal, inhalation, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
- the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
- Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
- the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
- Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, for example, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
- a compound of the present invention may also be administered as a bolus, electuary or paste.
- the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol and glycerol monostea
- compositions may also comprise buffering agents.
- Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
- a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
- Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
- compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
- These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
- embedding compositions that can be used include polymeric substances and waxes.
- the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
- Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and e
- the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
- Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
- suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
- Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
- Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
- the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
- the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
- Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
- Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
- dosage forms can be made by dissolving or dispersing the compound in the proper medium.
- Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
- Ophthalmic formulations are also contemplated as being within the scope of this invention.
- compositions of this invention suitable for parenteral administration may comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable carriers such as sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
- pharmaceutically acceptable carriers such as sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
- aqueous and nonaqueous carriers examples include water, ethanol, glycol ethers, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
- suitable aqueous and nonaqueous carriers include water, ethanol, glycol ethers, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
- Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
- compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
- the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
- Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
- the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc., administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories.
- parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
- Intravenous infusion is sometimes a preferred method of delivery for compounds of the invention. Infusion may be used to deliver a single daily dose or multiple doses.
- a compound of the invention is administered by infusion over an interval between 15 minutes and 4 hours, typically between 0.5 and 3 hours. Such infusion may be used once per day, twice per day or up to three times per day.
- systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
- These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
- the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
- Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
- the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
- a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
- the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
- a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, intravenous and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kg per day, and still more preferably from about 0.1 to about 20 mg per kg per day. An effective amount is that amount which prevents or treats a viral infection, such as HBV.
- Treatment with a compound or composition described herein may be repeated daily for a period sufficient to reduce or substantially eliminate an HBV infection or viral load. For example, treatment may be continued for a week, or two weeks, or 3-4 weeks, or 4-8 weeks, or 8-12 weeks, 2-6 months, or longer, e.g., until viral load or other measure of infection shows a substantial reduction in viral load or viral activity or other signs or symptoms of HBV infection.
- the skilled treating physician can readily determine a suitable duration of treatment.
- the effective daily dose of the active compound may be administered as a single dose per day, or as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
- Compounds delivered orally or by inhalation are commonly administered in one to four doses per day.
- Compounds delivered by injection are typically administered once per day, or once every other day.
- Compounds delivered by infusion are typically administered in one to three doses per day.
- the doses may be administered at intervals of about 4 hours, about 6 hours, about 8 hours or about 12 hours.
- methods of using the compounds of the invention include administering the compound as a pharmaceutical composition, wherein at least one compound of the invention is admixed with a pharmaceutically acceptable carrier prior to administration.
- the compounds and compositions described herein can be used or administered in combination with one or more therapeutic agents that act as immunomodulators, e.g., an activator of a costimulatory molecule, or an inhibitor of an immune-inhibitory molecule, or a vaccine.
- the Programmed Death 1 (PD-1) protein is an inhibitory member of the extended CD28/CTLA4 family of T cell regulators (Okazaki et al. (2002) Curr. Opin. Immunol. 14: 391779-82; Bennett et al. (2003) J. Immunol. 170:711-8).
- PD-1 is expressed on activated B cells, T cells, and monocytes.
- PD-1 is an immune-inhibitory protein that negatively regulates TCR signals (Ishida, Y.
- PD-1 and PD-L1 can act as an immune checkpoint, which can lead to, e.g., a decrease in infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and/or immune evasion by cancerous or infected cells (Dong et al. (2003) J. Mol. Med. 81:281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314; Konishi et al. (2004) Clin. Cancer Res.
- Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2; the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66).
- Immunomodulation can be achieved by binding to either the immune-inhibitory protein (e.g., PD-1) or to binding proteins that modulate the inhibitory protein (e.g., PD-L1, PD-L2).
- the combination therapies of the invention include an immunomodulator that is an inhibitor or antagonist of an inhibitory molecule of an immune checkpoint molecule.
- the immunomodulator binds to a protein that naturally inhibits the immuno-inhibitory checkpoint molecule.
- these immunomodulators can enhance the antiviral response, and thus enhance efficacy relative to treatment with the antiviral compound alone.
- Immune checkpoints refers to a group of molecules on the cell surface of CD4 and CD8 T cells. These molecules can effectively serve as “brakes” to down-modulate or inhibit an adaptive immune response. Immune checkpoint molecules include, but are not limited to, Programmed Death 1 (PD-1), Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD137, CD40, and LAG3, which directly inhibit immune cells.
- PD-1 Programmed Death 1
- CTL-4 Cytotoxic T-Lymphocyte Antigen 4
- B7H1, B7H4, OX-40 CD137, CD40, and LAG3, which directly inhibit immune cells.
- Immunotherapeutic agents which can act as immune checkpoint inhibitors useful in the methods of the present invention, include, but are not limited to, inhibitors of PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFR beta.
- Inhibition of an inhibitory molecule can be performed by inhibition at the DNA, RNA or protein level.
- an inhibitory nucleic acid e.g., a dsRNA, siRNA or shRNA
- the inhibitor of an inhibitory signal is a polypeptide, e.g., a soluble ligand, or an antibody or antigen-binding fragment thereof, that binds to the inhibitory molecule.
- the immunomodulator can be administered concurrently with, prior to, or subsequent to, one or more compounds of the invention, and optionally one or more additional therapies or therapeutic agents.
- the therapeutic agents in the combination can be administered in any order. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. It will further be appreciated that the therapeutic agents utilized in this combination may be administered together in a single composition or administered separately in different compositions. In general, it is expected that each of the therapeutic agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
- the antiviral compounds described herein are administered in combination with one or more immunomodulators that are inhibitors of PD-1, PD-L1 and/or PD-L2.
- Each such inhibitor may be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or an oligopeptide. Examples of such immunomodulators are known in the art.
- the immunomodulator is an anti-PD-1 antibody chosen from MDX-1106, Merck 3475 or CT-011.
- the immunomodulator is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence).
- an immunoadhesin e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence).
- the immunomodulator is a PD-1 inhibitor such as AMP-224.
- the immunomodulator is a PD-L1 inhibitor such as anti-PD-LI antibody.
- the immunomodulator is an anti-PD-L1 binding antagonist chosen from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105.
- MDX-1105 also known as BMS-936559, is an anti-PD-LI antibody described in WO2007/005874.
- Antibody YW243.55.S70 is an anti-PD-LI described in WO 2010/077634.
- the immunomodulator is nivolumab (CAS Registry Number: 946414-94-4).
- Alternative names for nivolumab include MDX-1106, MDX-1106-04, ONO-4538, or BMS-936558.
- Nivolumab is a fully human IgG4 monoclonal antibody which specifically blocks PD-1.
- Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD-1 are disclosed in U.S. Pat. No. 8,008,449, EP2161336 and WO2006/121168.
- the immunomodulator is an anti-PD-1 antibody pembrolizumab.
- Pembrolizumab also referred to as lambrolizumab, MK-3475, MK03475, SCH-900475 or KEYTRUDA®; Merck
- MK-3475 a humanized IgG4 monoclonal antibody that binds to PD-1.
- SCH-900475 or KEYTRUDA® a humanized anti-PD-1 antibodies.
- Pembrolizumab and other humanized anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, U.S. Pat. No. 8,354,509, WO2009/114335, and WO2013/079174.
- the immunomodulator is pidilizumab (CT-011; Cure Tech), a humanized IgG1k monoclonal antibody that binds to PD1.
- pidilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in WO2009/101611.
- anti-PD1 antibodies useful as immunomodulators for use in the methods disclosed herein include AMP 514 (Amplimmune), and anti-PD1 antibodies disclosed in U.S. Pat. No. 8,609,089, US 2010028330, and/or US 20120114649.
- the anti-PD-L1 antibody is MSB0010718C.
- MSB0010718C also referred to as A09-246-2; Merck Serono
- A09-246-2 Merck Serono
- the immunomodulator is MDPL3280A (Genentech/Roche), a human Fc optimized IgG1 monoclonal antibody that binds to PD-L1.
- MDPL3280A and other human monoclonal antibodies to PD-L1 are disclosed in U.S. Pat. No. 7,943,743 and U.S Publication No.: 20120039906.
- Other anti-PD-L1 binding agents useful as immunomodulators for methods of the invention include YW243.55.S70 (see WO2010/077634), MDX-1105 (also referred to as BMS-936559), and anti-PD-L1 binding agents disclosed in WO2007/005874.
- the immunomodulator is AMP-224 (B7-DCIg; Amplimmune; e.g., disclosed in WO2010/027827 and WO2011/066342), is a PD-L2 Fc fusion soluble receptor that blocks the interaction between PD1 and B7-H1.
- the immunomodulator is an anti-LAG-3 antibody such as BMS-986016.
- BMS-986016 (also referred to as BMS986016) is a monoclonal antibody that binds to LAG-3.
- BMS-986016 and other humanized anti-LAG-3 antibodies are disclosed in US 2011/0150892, WO2010/019570, and WO2014/008218
- the combination therapies disclosed herein include a modulator of a costimulatory molecule or an inhibitory molecule, e.g., a co-inhibitory ligand or receptor.
- the costimulatory modulator, e.g., agonist, of a costimulatory molecule is chosen from an agonist (e.g., an agonistic antibody or antigen-binding fragment thereof, or soluble fusion) of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand.
- an agonist e.g., an agonistic antibody or antigen-binding fragment thereof, or soluble fusion
- the combination therapies disclosed herein include an immunomodulator that is a costimulatory molecule, e.g., an agonist associated with a positive signal that includes a costimulatory domain of CD28, CD27, ICOS and/or GITR.
- an immunomodulator that is a costimulatory molecule, e.g., an agonist associated with a positive signal that includes a costimulatory domain of CD28, CD27, ICOS and/or GITR.
- Exemplary GITR agonists include, e.g., GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as, a GITR fusion protein described in U.S. Pat. No. 6,111,090, European Patent No.: 090505B1, U.S. Pat. No. 8,586,023, PCT Publication Nos.: WO 2010/003118 and 2011/090754, or an anti-GITR antibody described, e.g., in U.S. Pat. No. 7,025,962, European Patent No.: 1947183B1, U.S. Pat. Nos.
- the immunomodulator used is a soluble ligand (e.g., a CTLA-4-Ig), or an antibody or antibody fragment that binds to PD-L1, PD-L2 or CTLA4.
- the anti-PD-1 antibody molecule can be administered in combination with an anti-CTLA-4 antibody, e.g., ipilimumab, for example.
- anti-CTLA4 antibodies include tremelimumab (IgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675,206); and ipilimumab (CTLA-4 antibody, also known as MDX-010, CAS No. 477202-00-9).
- an anti-PD-1 antibody molecule is administered after treatment with a compound of the invention as described herein.
- an anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-LAG-3 antibody or an antigen-binding fragment thereof.
- the anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-TIM-3 antibody or antigen-binding fragment thereof.
- the anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-LAG-3 antibody and an anti-TIM-3 antibody, or antigen-binding fragments thereof.
- the combination of antibodies recited herein can be administered separately, e.g., as separate antibodies, or linked, e.g., as a bispecific or trispecific antibody molecule.
- a bispecific antibody that includes an anti-PD-1 or PD-L1 antibody molecule and an anti-TIM-3 or anti-LAG-3 antibody, or antigen-binding fragment thereof, is administered.
- the combination of antibodies recited herein is used to treat a cancer, e.g., a cancer as described herein (e.g., a solid tumor).
- a cancer e.g., a cancer as described herein (e.g., a solid tumor).
- the efficacy of the aforesaid combinations can be tested in animal models known in the art. For example, the animal models to test the synergistic effect of anti-PD-1 and anti-LAG-3 are described, e.g., in Woo et al. (2012) Cancer Res. 72(4):917-27).
- immunomodulators that can be used in the combination therapies include, but are not limited to, e.g., afutuzumab (available from Roche®); pegfilgrastim (Neulasta®); lenalidomide (CC-5013, Revlimid®); thalidomide (Thalomid®), actimid (CC4047); and cytokines, e.g., IL-21 or IRX-2 (mixture of human cytokines including interleukin 1, interleukin 2, and interferon ⁇ , CAS 951209-71-5, available from IRX Therapeutics).
- afutuzumab available from Roche®
- pegfilgrastim Nema®
- lenalidomide CC-5013, Revlimid®
- Thalomid® thalidomide
- actimid CC4047
- cytokines e.g., IL-21 or IRX-2 (mixture of human cytokines including interleukin 1, interle
- Exemplary doses of such immunomodulators that can be used in combination with the antiviral compounds of the invention include a dose of anti-PD-1 antibody molecule of about 1 to 10 mg/kg, e.g., 3 mg/kg, and a dose of an anti-CTLA-4 antibody, e.g., ipilimumab, of about 3 mg/kg.
- Examples of embodiments of the methods of using the antiviral compounds of the invention in combination with an immunomodulator include these, which may be used along with a compound of Formula I or any subgenus or species thereof that is disclosed herein:
- a method to treat a viral infection in a subject comprising administering to the subject a compound of Formula (I) as described herein, and an immunomodulator.
- the activator of the costimulatory molecule is an agonist of one or more of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 and CD83 ligand.
- inhibitor of the immune checkpoint molecule is chosen from PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and TGFR beta.
- any of embodiments i-vii wherein the antibody or antigen-binding fragment thereof is altered, e.g., mutated, to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function.
- immunomodulator is an anti-PD-L1 antibody chosen from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105.
- the immunomodulator is an anti-PD-1 antibody molecule administered by injection (e.g., subcutaneously or intravenously) at a dose of about 1 to 30 mg/kg, e.g., about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 5 mg/kg, or about 3 mg/kg., e.g., once a week to once every 2, 3, or 4 weeks.
- xvi. The method of embodiment xv, wherein the anti-PD-1 antibody molecule, e.g., nivolumab, is administered intravenously at a dose from about 1 mg/kg to 3 mg/kg, e.g., about 1 mg/kg, 2 mg/kg or 3 mg/kg, every two weeks.
- the anti-PD-1 antibody molecule e.g., nivolumab
- xvii The method of embodiment xv, wherein the anti-PD-1 antibody molecule, e.g., nivolumab, is administered intravenously at a dose of about 2 mg/kg at 3-week intervals.
- the anti-PD-1 antibody molecule e.g., nivolumab
- LiHMDS Lithium bis(trimethylsilyl)amide Me methyl
- a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention is designated a “protecting group,” unless the context indicates otherwise.
- the protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as e.g., Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627 pp. (URL: http://www.science-of-synthesis.com (Electronic Version, 48 Volumes)); J. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973, in T. W. Greene and P. G. M.
- Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known per se.
- salts of compounds of the present invention having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g., the sodium salt of 2-ethyl hexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used.
- metal compounds such as alkali metal salts of suitable organic carboxylic acids, e.g., the sodium salt of 2-ethyl hexanoic acid
- organic alkali metal or alkaline earth metal compounds such as the corresponding hydroxides, carbonates or hydrogen carbonates
- Acid addition salts of compounds of the present invention are obtained in customary manner, e.g., by treating the compounds with an acid or a suitable anion exchange reagent.
- Internal salts of compounds of the present invention containing acid and basic salt-forming groups, e.g., a free carboxy group and a free amino group, may be formed, e.g., by the neutralization of salts, such as acid addition salts, to the isoelectric point, e.g., with weak bases, or by treatment with ion exchangers.
- Salts can be converted in customary manner into the free compounds; metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.
- diastereoisomers can be separated in a manner known per se into the individual isomers; diastereoisomers can be separated, for example, by partitioning between polyphasic solvent mixtures, recrystallization and/or chromatographic separation, for example over silica gel or by, e.g., medium pressure liquid chromatography over a reversed phase column, and racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisomers so obtainable, for example by means of fractional crystallization, or by chromatography over optically active column materials.
- Intermediates and final products can be worked up and/or purified according to standard methods, e.g., using chromatographic methods, distribution methods, (re-) crystallization, and the like.
- the invention is illustrated by the following examples, which should not be construed as limiting.
- the assays used to demonstrate the efficacy of compounds of Formula (I) in these assays are generally regarded as predictive of efficacy in subjects.
- Mass spectra were run on UHPLC-MS systems using electrospray ionization. These were WATERS Acquity Single Quard Detector. [M+H] + refers to mono-isotopic molecular weights.
- NMR spectra were run on open access Varian 400 or Varian 500 NMR spectrometers. Spectra were measured at 298K and were referenced using the solvent peak. Chemical shifts for 1 H NMR are reported in parts per million (ppm).
- Step 3 (R)-ethyl 1-(2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyl)-4-chloro-3-(3-methoxypropoxy)-1H-pyrazole-5-carboxylate [1.1c]
- Step 4 (R)-tert-butyl (1-(4-chloro-5-(hydroxymethyl)-3-(3-methoxypropoxy)-1H-pyrazol-1-yl)-3,3-dimethylbutan-2-yl)carbamate [1.1d]
- Step 5 (R)-tert-butyl (1-(4-chloro-5-formyl-3-(3-methoxypropoxy)-1H-pyrazol-1-yl)-3,3-dimethylbutan-2-yl)carbamate [1.1e]
- Step 6 (R)-6-(tert-butyl)-3-chloro-2-(3-methoxypropoxy)-6,7-dihydropyrazolo[1,5-a]pyrazine [1.f]
- Step 7 (6R)-ethyl 6-(tert-butyl)-1-chloro-2-(3-methoxypropoxy)-10-oxo-6,10,11,11a-tetrahydro-5H-pyrazolo[1,5-a]pyrido[2,1-c]pyrazine-9-carboxylate [1.1g]
- Step 8 (R)-ethyl 6-(tert-butyl)-1-chloro-2-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrazolo[1,5-a]pyrido[2,1-c]pyrazine-9-carboxylate [1.h]
- Step 9 (R)-6-(tert-butyl)-1-chloro-2-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrazolo[1,5-a]pyrido[2,1-c]pyrazine-9-carboxylic Acid [1.1]
- Step 1 Ethyl (R)-1-(2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyl)-3-(3-methoxypropoxy)-1H-pyrazole-5-carboxylate [1.3a]
- Step 2 (R)-ethyl 4-bromo-1-(2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyl)-3-(3-methoxypropoxy)-1H-pyrazole-5-carboxylate [1.3b]
- Step 3 (R)-1-bromo-6-(tert-butyl)-2-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrazolo[1,5-a]pyrido[2,1-c]pyrazine-9-carboxylic Acid [1.3]
- Step 1 ethyl 1-(3,3-dimethyl-2-oxobutyl)-3-isopropyl-1H-pyrazole-5-carboxylate
- Step 3 1-(5-(((tert-butyldimethylsilyl)oxy)methyl)-3-isopropyl-1H-pyrazol-1-yl)-3,3-dimethylbutan-2-ol [2.1c]
- Step 4 (6R)-ethyl 1-bromo-6-(tert-butyl)-2-(3-methoxypropoxy)-10-oxo-6,10,11,11a-tetrahydro-5H-pyrazolo[1,5-a]pyrido[2,1-c]pyrazine-9-carboxylate [2.1d]
- Step 5 Tert-butyl (1-(5-(hydroxymethyl)-3-isopropyl-1H-pyrazol-1-yl)-3,3-dimethylbutan-2-yl)carbamate [2.1e]
- Step 6 6-(tert-butyl)-2-isopropyl-10-oxo-6,10-dihydro-5H-pyrazolo[1,5-a]pyrido[2,1-c]pyrazine-9-carboxylic Acid [2.1]
- Step 3 (R)-6-(tert-butyl)-1-chloro-10-oxo-2-phenyl-5,6-dihydro-10H-pyrazolo[1,5-a]pyrido[2,1-c]pyrazine-9-carboxylic Acid [3.1]
- Step 2 (R)-2-(benzyl((3-phenyl-1H-pyrazol-5-yl)methyl)amino)-3-methylbutan-1-ol [3.3b]
- Step 3 (R)-5-benzyl-6-isopropyl-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine [3.3c]
- Step 4 (R)-6-isopropyl-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine [3.3d]
- Step 5 (R)-5-chloro-6-isopropyl-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine [3.3e-I] and (R)-3,5-dichloro-6-isopropyl-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine [3.3e-II]
- Step 6 (R)-6-isopropyl-2-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine [3.3f-I] and (R)-3-chloro-6-isopropyl-2-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine [3.3f-II]
- Step 7 (R)-ethyl 6-isopropyl-10-oxo-2-phenyl-6,10-dihydro-5H-pyrazolo[1,5-a]pyrido[2,1-c]pyrazine-9-carboxylate [3.3g]
- Step 8 (R)-6-isopropyl-10-oxo-2-phenyl-6,10-dihydro-5H-pyrazolo[1,5-a]pyrido[2,1-c]pyrazine-9-carboxylic Acid [3.3]
- HepG2-Clone42 a Tet-inducible HBV-expressing cell line with a stably integrated 1.3mer copy of the HBV ayw strain, was generated based on the Tet-inducible HepAD38 cell line with slight modifications.
- HepG2-Clone42 cells were cultured in DMEM/F-12+GlutamaxTM (Life Technologies, Carlsbad, Calif., USA), supplemented with 10% fetal bovine serum (Life Technologies), G-418 (Corning, Manassas, Va., USA) at a final concentration of 0.5 mg/mL, and 5 ⁇ g/mL Doxycycline (Sigma, St. Louis, Mo., USA) and maintained in 5% CO 2 at 37° C.
- HepG2-Clone42 cells were seeded into black clear-bottom 96-well plates at a concentration of 6.0 ⁇ 10 4 cells/well. 24 hours post-seeding, the cells were treated with 200 ⁇ l/well of media containing five-fold serial dilutions of compounds in DMSO. DMSO alone was used as the no drug control. The final DMSO concentration in all wells was 0.5%.
- the HBsAg ELISA kit (Alpha Diagnostic International, San Antonio, Tex., USE, Catalog #4110) was used to determine the level (semi-quantitative) of secreted HBV sAg.
- the HBSAg ELISA assay was performed following the manufacturer's protocol as described.
- Step 1 Pipet 100 ⁇ L each of compound or DMSO treated samples into HBsAg ELISA plates. Seal plates and incubate at room temp for 60 minutes.
- Step 2 Aspirate samples and wash three times with Wash Buffer. Dispense 100 ⁇ L of antibody-HRP conjugate to each well. Incubate at room temp for 30 minutes.
- Step 3 Aspirate samples and wash three times with Wash Buffer. Add 100 ⁇ L of TMB Substrate to all wells and incubate 15 minutes at room temp.
- Step 4 Dispense 100 ⁇ L of Stop Solution to each well. Measure absorbance of ELISA plate at 450 nm.
- Dose-response curves were generated and the EC 50 value was defined as the compound concentration at which HBsAg secretion was reduced 50% compared to the DMSO control.
- X C is the absorbance signal from compound-treated well
- M B is average absorbance signal (background signal) for column 12 (no cells+HBsAg ELISA sample buffer)
- M D is average absorbance signal from DMSO-treated wells. Then calculate EC 50 values by non-linear regression using a four parameter curve logistic equation.
- +++ means ⁇ 1 nm; ++ means ⁇ 1 nm and ⁇ 10 nm and + means >10 nm.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Virology (AREA)
- Zoology (AREA)
- Communicable Diseases (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Agronomy & Crop Science (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Dentistry (AREA)
- Wood Science & Technology (AREA)
- Environmental Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
-
- as described herein, along with pharmaceutically acceptable salts, pharmaceutical compositions and pharmaceutical combinations containing such compounds, as well as methods to use these compounds, salts and compositions for treating viral infections, particularly infections caused by hepatitis B virus (HBV), and for reducing the occurrence of serious conditions associated with HBV.
Description
- This application is a continuation of U.S. patent application Ser. No. 16/986,527, filed Jun. 19, 2020, which is a National Stage Entry of PCT/IB2018/060295, filed Dec. 19, 2018, which claims the benefit of priority to U.S. Ser. No. 62/608,458, filed Dec. 20, 2017, the contents of each of which is incorporated herein by reference.
- The present invention relates to novel fused tricyclic pyrazolo-dihydro-pyrazinyl pyridone compounds that are inhibitors of hepatitis virus replication, and are thus useful to treat viral infections, and particularly hepatitis B virus (HBV). The invention provides novel fused tricyclic pyrazolo-dihydro-pyrazinyl pyridone compounds as disclosed herein, pharmaceutical compositions containing such compounds, and methods of using these compounds and compositions in the treatment and prevention of HBV infections.
- Globally, over 400 million people are chronically infected with hepatitis B virus (HBV), and more than 12 million reside in the United States alone. Of those chronically infected patients, up to 40 percent will eventually develop complications of liver failure from cirrhosis or development of hepatocellular carcinoma (HCC). HBV belongs to the family of Hepadnaviridae, a group of small hepatotropic DNA viruses that replicate through the reverse transcription of an RNA intermediate. The 3.2-kb HBV genome in viral particles is in a circular, partially double-stranded DNA conformation (relaxed circular DNA or rcDNA). The HBV genome consists of four overlapping open reading frames (ORFs), which encode for the core, polymerase (Pol), envelope, and X proteins. rcDNA is transcriptionally inert and must be converted into covalently closed circular DNA (cccDNA) in the nucleus of infected cells before viral RNAs can be transcribed. Covalently closed circular DNA is the only template for HBV transcription and, because HBV RNA templates genomic reverse transcription, its persistence is required for persistent infection.
- The envelope of HBV comprises a mixture of surface antigen proteins (HBsAg). The HBsAg coat is a mixture of three overlapping proteins: all three share a common region, which corresponds to the smallest of the three proteins (SHBsAg). The mixture consists mostly of SHBsAg, but also includes Medium HBsAg, which comprises SHBsAg plus an additional polypeptide segment, and Large HBsAg, which comprises M HBsAg plus another added polypeptide segment. In addition to forming the infectious virion particle, the S, M and L HBsAg proteins also assemble into a subviral particle knows as the 22-nm particle, which is not infectious but contains the same proteins that envelope the infectious virus particles. Indeed, these subviral, non-infectious particles have been used as a vaccine, since they contain the same antigenic surface proteins as the infectious HBV virion, and thus elicit antibodies that recognize the infectious agent. Interestingly, these subviral particles greatly outnumber infectious virions, and are believed to protect the infectious virions from the immune system of the infected host. By sheer numbers, they may act as decoys, distracting immune responses from the infectious virus particles, but in addition they are reported to suppress the function of immune cells (monocytes, dendritic cells and natural killer cells) and may thus impair the immune response to HBV. Because these subviral particles protect infectious HBV from the host immune system, reducing the level of subviral particles has been recognized as a viable therapeutic approach. See, e.g., WO2015/113990.
- One of the key diagnostic symptoms of chronic HBV is the high serum levels of the hepatitis B surface antigen (HBsAg). Clinical data in recent years suggest that sustained virologic response is often associated with on-treatment HBsAg decline during the early phase of the treatment as early as week 8, while sustained exposure to HBsAg and other viral antigens may lead to HBV-specific immune-tolerance and T-cell exhaustion. Chronic HB patients who experienced larger and faster decreases in serum HBsAg levels during treatment achieved significantly higher rate (˜40%) of sustained virologic response as defined by sustained viral control post treatment.
- Current treatment options for HBV include interferon therapies and nucleoside/nucleotide inhibitors of the viral DNA polymerase, such as entecavir and tenofovir. These focus on reduction in the level of viremia and toleration of hepatic dysfunction, and may have adverse side-effects and also select for drug-resistant virus variants during long term therapy. More importantly, these therapies cannot eradicate the intrahepatic HBV cccDNA pool in chronic hepatitis B patients or limit the transcription of HBsAg from the pre-existing cccDNA, nor do they affect the secretion of synthesized HBsAg into patients' blood to counteract the host innate immune response. As a result, these HBV treatments are in most cases life-long therapies, and discontinuation often leads to virological relapse.
- Accordingly, there remains a need for more effective treatments for HBV, including therapeutics that reduce serum levels of HBsAg and for treating chronic HBV infections (cHBV). The invention provides compounds that reduce serum HbsAg levels and are believed to operate by suppression of the secretion of the 22 nm subviral particles containing HBsAg. These compounds are useful to treat HBV infections and to reduce the incidence of serious liver disorders caused by HBV infections. They also exhibit improved properties relative to compounds having similar biological activity, such as improved solubility in buffered aqueous solution and lower predicted propensity for certain adverse effects.
- The present invention provides novel compounds that inhibit secretion of HBsAg from cells infected with hepatitis B virus and thereby reduce viral load and viral replication in patients having chronic HBV infection. Thus the compounds of the invention are suitable for treatment of patients with HBV, including chronic HBV (cHBV). Some of the compounds of the invention, in addition to being highly effective at suppression of HBsAg levels, also exhibit improved safety relative to similar compounds known in the art, such as reduced inhibition of sodium ion channels that can be indicative of potential cardiotoxicity, reduced drug-drug interactions, and lower risk of time-dependent cytochrome (CYP) inhibition. Thus the compounds of the invention are suitable for treatment of patients with HBV. The invention also provides pharmaceutical compositions containing the novel compounds as well as methods to use the compounds and compositions to inhibit hepatitis B virus replication, and to treat disease conditions associated with or caused by HBV. Further objects of this invention are described in the following description and the examples. Thus the compounds of the invention are suitable for treatment of patients with HBV, including chronic HBV.
- In one aspect, the invention provides compounds of Formula (I):
- A compound of formula (I):
- a stereoisomer thereof or a pharmaceutically acceptable salt thereof; wherein:
- R1 is —C1-C8-alkyl; —(C0-C8-alkylene)-(C1-C8-alkoxy)x, or —(C0-C8-alkylene)-(C3-C8-cycloalkyl); each of which is optionally substituted with one or two groups selected from halo, —OR10, ═O, —CN, —NR10 2, —COOR10, —CONR10 2, and —(C0-C8-alkylene)-aryl;
- a 5-6 membered aryl or heteroaryl group; wherein the 5-6 membered aryl or heteroaryl group of R1 is independently substituted by one or more groups selected from the group consisting of —H, —CN, —(C0-C8-alkylene)-(—OR10)x, and halo;
- or taken together with R2 to form a 5-7 membered heterocyclic or heteroaryl group containing N, O or S as a ring member; wherein the heterocyclic or heteroaryl ring is optionally substituted with up to three groups selected from —R10, —OR10, —NR10 2, -halo, —CN, —COOR10, —CONR10 2, and ═O;
- x represents the number groups which replace a hydrogen on the group to which it is attached;
- R2 is H, C1-C8-alkyl, halo, —CN; or taken together with R1 to form a 5-7 membered heterocyclic or heteroaryl containing N, O or S as a ring member; wherein the heterocyclic or heteroaryl ring is optionally substituted with up to three groups selected from —R10, —OR10, —NR10 2, -halo, —CN, —COOR10, —CONR10 2, and ═O;
- R3 is H, hydroxyl, halo or C1-C8-alkyl
- each R4, R5, R6, R7, or R8 is independently —H, —C1-C8-alkyl, —C1-C8-haloalkyl, —CN, —C1-C8-alkoxy, —C3-C8 cycloalkyl, aryl, or a 5- or 6-membered heteroaryl containing up to three heteroatoms selected from N, O and S as ring members; where each —C1-C8-alkyl, —C3-C8 cycloalkyl, aryl or a 5- or 6-membered heteroaryl is optionally substituted with up to three groups selected from —OR10, —NR10 2, -halo, —CN and —SO2R9; or R5 taken together with R7 or R6 taken together with R8 form a 5-7 membered heterocyclic or heteroaryl group containing N, O or S as a ring member; wherein the heterocyclic or heteroaryl ring is optionally substituted with up to three groups selected from —R10, —OR10, —NR10 2, -halo, —CN, —COOR10, —CONR10 2, and ═O;
- W is —COOR9, —C(O)NH—SO2R10, —C(O)NH—SO2NR10 2, -5-tetrazolyl, or -1,2,4-oxadiazol-3-yl-5(4H)-one;
- R9 is H or C1-C8 alkyl; the C1-C8 alkyl optionally substituted with one or two groups selected from halo, —OR10, ═O, —CN, —NR10 2, —COOR10, and —CONR10 2;
- R10 is independently selected at each occurrence from —H, —C1-C8 alkyl and aryl, each of —C1-C8 alkyl and aryl optionally substituted with one to three groups selected from halo, —OH, —C1-C8 alkoxy, ═O, —CN, —NH2, —NH(C1-C8 alkyl), —N(C1-C8 alkyl)2, and -cyclopropyl; and two R10 groups directly attached to the same atom, which may be C or N, can optionally be taken together to form a 3-6 membered ring that can optionally contain a heteroatom selected from N, O and S as a ring member, and can be substituted by up to two groups selected from —OH, ═O, —C1-C8 alkyl, and —C1-C8 alkoxy;
- or a pharmaceutically acceptable salt thereof.
- The invention also includes methods of making these compounds, pharmaceutical compositions containing these compounds, methods to use these compounds and compositions to inhibit hepatitis B virus replication, and to treat disease conditions associated with or caused by HBV, pharmaceutical combinations comprising these compounds, and methods to use the compounds in the manufacture of a medicament. Further objects of this invention are described in the following description and the examples.
- For purposes of interpreting this specification, the following definitions will apply, and whenever appropriate, terms used in the singular will also include the plural.
- Terms used in the specification have the following meanings unless the context clearly indicates otherwise:
- As used herein, the term “subject” refers to an animal. In certain aspects, the animal is a mammal. A subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a human. A “patient” as used herein refers to a human subject.
- As used herein, the term “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
- As used herein, the term “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
- As used herein, the term “a,” “an,” “the” and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.
- All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.
- “Optionally substituted” means the group referred to can be substituted at one or more positions by any one or any combination of the radicals listed thereafter. The number, placement and selection of substituents is understood to encompass only those substitutions that a skilled chemist would expect to be reasonably stable; thus ‘oxo’ would not be a substituent on an aryl or heteroaryl ring, for example, and a single carbon atom would not have three hydroxy or amino substituents. Unless otherwise specified, optional substituents are typically up to four groups selected from halo, oxo, CN, amino, hydroxy, —C1-3alkyl, —OR*, —NR*2, —SR*, —SO2R*, —COOR*, and —CONR*2, where each R* is independently H or C1-3 alkyl.
- “Aryl” as used herein refers to a phenyl or naphthyl group unless otherwise specified.
- Aryl groups unless otherwise specified may be optionally substituted with up to four groups selected from halo, CN, amino, hydroxy, C1-3 alkyl, —OR*, —NR*2, —SR*, —SO2R*, —COOR*, and —CONR*2, where each R* is independently H or C1-3 alkyl.
- “Halo” or “halogen”, as used herein, may be fluorine, chlorine, bromine or iodine.
- “C1-6 alkyl” or “C1-C6 alkyl”, as used herein, denotes straight chain or branched alkyl having 1-6 carbon atoms. If a different number of carbon atoms is specified, such as C4 or C3, then the definition is to be amended accordingly, such as “C1-4 alkyl” will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
- “C1-6 alkylene” or “C1-C6 alkylene”, as used herein, denotes straight chain or branched alkyl having 1-6 carbon atoms and two open valences for connection to two other groups. If a different number of carbon atoms is specified, such as C4 or C3, then the definition is to be amended accordingly, such as “C1-4 alkylene” will represent methylene (—CH2—), ethylene (—CH2CH2—), straight chain or branched propylene (—CH2CH2CH2— or —CH2—CHMe-CH2—), and the like.
- “C1-6 alkoxy”, as used herein, denotes straight chain or branched alkoxy (—O-Alkyl) having 1-6 carbon atoms. If a different number of carbon atoms is specified, such as C4 or C3, then the definition is to be amended accordingly, such as “C1-4 alkoxy” will represent methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
- “C1-4 Haloalkyl” or “C1-C4 haloalkyl” as used herein, denotes straight chain or branched alkyl having 1-4 carbon atoms wherein at least one hydrogen has been replaced with a halogen. The number of halogen replacements can be from one up to the number of hydrogen atoms on the unsubstituted alkyl group. If a different number of carbon atoms is specified, such as C or C3, then the definition is to be amended accordingly. Thus “C1-4 haloalkyl” will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl that have at least one hydrogen substituted with halogen, such as where the halogen is fluorine: CF3CF2—, (CF3)2CH—, CH3—CF2—, CF3CF2—, CF3, CF2H—, CF3CF2CH(CF3)— or CF3CF2CF2CF2—.
- “C3-8 cycloalkyl” as used herein refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. If a different number of carbon atoms is specified, such as C3-C6, then the definition is to be amended accordingly.
- “4- to 8-Membered heterocyclyl”, “5- to 6-membered heterocyclyl”, “3- to 10-membered heterocyclyl”, “3- to 14-membered heterocyclyl”, “4- to 14-membered heterocyclyl” and “5- to 14-membered heterocyclyl”, refers, respectively, to 4- to 8-membered, 5- to 6-membered, 3- to 10-membered, 3- to 14-membered, 4- to 14-membered and 5- to 14-membered heterocyclic rings; unless otherwise specified, such rings contain 1 to 7, 1 to 5, or 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur as ring members, and the rings may be saturated, or partially saturated but not aromatic. The heterocyclic group can be attached to another group at a nitrogen or a carbon atom. The term “heterocyclyl” includes single ring groups, fused ring groups and bridged groups. Examples of such heterocyclyl include, but are not limited to pyrrolidine, piperidine, piperazine, pyrrolidinone, morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, 1,4-dioxane, 1,4-oxathiane, 8-aza-bicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane, 3-Oxa-8-aza-bicyclo[3.2.1]octane, 8-Oxa-3-aza-bicyclo[3.2.1]octane, 2-Oxa-5-aza-bicyclo[2.2.1]heptane, 2,5-Diaza-bicyclo[2.2.1]heptane, azetidine, ethylenedioxo, oxetane or thiazole. In certain embodiments, if not otherwise specified, heterocyclic groups have 1-2 heteroatoms selected from N, O and S as ring members, and 4-7 ring atoms, and are optionally substituted with up to four groups selected from halo, oxo, CN, amino, hydroxy, C1-3 alkyl, —OR*, —NR*2, —SR*, —SO2R*, —COOR*, and —CONR*2, where each R* is independently H or C1-3 alkyl. In particular, heterocyclic groups containing a sulfur atom are optionally substituted with one or two oxo groups on the sulfur.
- “4-6 membered cyclic ether” as used herein refers to a 4 to 6 membered ring comprising one oxygen atom as a ring member. Examples include oxetane, tetrahydrofuran and tetrahydropyran.
- “Heteroaryl” is a completely unsaturated (aromatic) ring. The term “heteroaryl” refers to a 5-14 membered monocyclic- or bicyclic- or tricyclic-aromatic ring system, having 1 to 8 heteroatoms selected from N, O or S. Typically, the heteroaryl is a 5-10 membered ring or ring system (e.g., 5-7 membered monocyclic group or an 8-10 membered bicyclic group), often a 5-6 membered ring containing up to four heteroatoms selected from N, O and S, though often a heteroaryl ring contains no more than one divalent O or S in the ring. Typical heteroaryl groups include furan, isothiazole, thiadiazole, oxadiazole, indazole, indole, quinoline, 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-(1,2,4-triazolyl), 4- or 5-(1,2, 3-triazolyl), tetrazolyl, triazine, pyrimidine, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl. Heteroaryl groups are optionally substituted with up to four groups selected from halo, CN, amino, hydroxy, C1-3 alkyl, —OR*, —NR*2, —SR*, —SO2R*, —COOR*, and —CONR*2, where each R* is independently H or C1-3 alkyl.
- The term “hydroxy” or “hydroxyl” refers to the group —OH.
- Various embodiments of the invention are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments.
- The following enumerated embodiments are representative of the invention:
- 1. A compound of formula (I):
- a stereoisomer thereof or a pharmaceutically acceptable salt thereof; wherein:
- R1 is —C1-C8-alkyl; —(C0-C8-alkylene)-(C1-C8-alkoxy)x, or —(C0-C8-alkylene)-(C3-C8-cycloalkyl); each of which is optionally substituted with one or two groups selected from halo, —OR10, ═O, —CN, —NR10 2, —COOR10, —CONR10 2, and —(C0-C8-alkylene)-aryl;
- a 5-6 membered aryl or heteroaryl group; wherein the 5-6 membered aryl or heteroaryl group of R1 is independently substituted by one or more groups selected from the group consisting of —H, —CN, —(C0-C8-alkylene)-(—OR10)x, and halo;
- or taken together with R2 to form a 5-7 membered heterocyclic or heteroaryl group containing N, O or S as a ring member; wherein the heterocyclic or heteroaryl ring is optionally substituted with up to three groups selected from —R10, —OR10, —NR10 2, -halo, —CN, —COOR10, —CONR10 2, and ═O;
- x represents the number groups which replace a hydrogen on the group to which it is attached;
- R2 is H, C1-C8-alkyl, halo, —CN; or taken together with R1 to form a 5-7 membered heterocyclic or heteroaryl containing N, O or S as a ring member; wherein the heterocyclic or heteroaryl ring is optionally substituted with up to three groups selected from —R10, —OR10, —NR10 2, -halo, —CN, —COOR10, —CONR10 2, and ═O;
- R3 is H, hydroxyl, halo or C1-C8-alkyl;
- each R4, R5, R6, R7, or R8 is independently —H, —C1-C8-alkyl, —C1-C8-haloalkyl, —CN, —C1-C8-alkoxy, —C3-C8 cycloalkyl, aryl, or a 5- or 6-membered heteroaryl containing up to three heteroatoms selected from N, O and S as ring members; where each —C1-C8-alkyl, —C3-C8 cycloalkyl, aryl or a 5- or 6-membered heteroaryl is optionally substituted with up to three groups selected from —OR10, —NR10 2, -halo, —CN and —SO2R9; or R5 taken together with R7 or R6 taken together with R8 form a 5-7 membered heterocyclic or heteroaryl group containing N, O or S as a ring member; wherein the heterocyclic or heteroaryl ring is optionally substituted with up to three groups selected from —R10, —OR10, —NR10 2, -halo, —CN, —COOR10, —CONR10 2, and ═O;
- W is —COOR9, —C(O)NH—SO2R10, —C(O)NH—SO2NR10 2, -5-tetrazolyl, or -1,2,4-oxadiazol-3-yl-5(4H)-one;
- R9 is H or C1-C8 alkyl; the C1-C8 alkyl optionally substituted with one or two groups selected from halo, —OR10, ═O, —CN, —NR10 2, —COOR10, and —CONR10 2;
- R10 is independently selected at each occurrence from —H, —C1-C8 alkyl and aryl, each of —C1-C8 alkyl and aryl optionally substituted with one to three groups selected from halo, —OH, —C1-C8 alkoxy, ═O, —CN, —NH2, —NH(C1-C8 alkyl), —N(C1-C8 alkyl)2, and -cyclopropyl; and two R10 groups directly attached to the same atom, which may be C or N, can optionally be taken together to form a 3-6 membered ring that can optionally contain a heteroatom selected from N, O and S as a ring member, and can be substituted by up to two groups selected from —OH, ═O, —C1-C8 alkyl, and —C1-C8 alkoxy;
- or a pharmaceutically acceptable salt thereof.
- 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R1 is —C1-C8-alkyl.
- 3. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R1 is —C1-C8-alkoxy; optionally substituted by one or more —OR10.
- 4. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R1 is a 5-6 membered aryl group; wherein the 5-6 membered aryl group of R1 is independently substituted by one or more groups selected from the group consisting of —H or —OR10.
- 5. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R2 is H or halo.
- 6. The compound according to any one of embodiments 1 to 5, wherein W is —COOR9; or a pharmaceutically acceptable salt thereof.
- 7. The compound of any of embodiments 1-6, wherein R4 is H; or a pharmaceutically acceptable salt thereof.
- 8. The compound of any of embodiments 1-7, wherein R5 is H; or a pharmaceutically acceptable salt thereof.
- 9. The compound of any of embodiments 1-8, wherein R7 is H; or a pharmaceutically acceptable salt thereof.
- 10. The compound of any of embodiments 1-9, wherein R8 is H; or a pharmaceutically acceptable salt thereof.
- 11. The compound of any of embodiments 1-10, wherein R6 is C1-C8 alkyl; or a pharmaceutically acceptable salt thereof.
- 12. The compound of any of embodiments 1-11, wherein R9 is H; or a pharmaceutically acceptable salt thereof.
- 13. The compound of any of embodiments 1-12, wherein R10 is —C1-C8-alkyl; or a pharmaceutically acceptable salt thereof.
- 14. The compound of any of embodiments 1-5, which is of the formula:
- or a pharmaceutically acceptable salt thereof.
- 15. A compound according to embodiment 14, wherein R1 is phenyl; or a pharmaceutically acceptable salt thereof.
- 16. A compound according to embodiment 14, wherein R9 is H; or a pharmaceutically acceptable salt thereof.
- 17. The compound of embodiment 1, which is selected from the compounds of the Examples in Table 1.
- 18. A pharmaceutical composition, comprising a compound of any of the preceding embodiments admixed with at least one pharmaceutically acceptable carrier.
- 19. A method to treat a subject having a hepatitis B infection, which comprises administering to the subject a compound of any of embodiments 1-17 or a pharmaceutical composition of embodiment 18.
- 20. The method of embodiment 19, wherein the compound of any one of claims 1-17 or the pharmaceutical composition of embodiment 18 is used in combination with an additional therapeutic agent selected from an interferon or peginterferon, an HBV polymerase inhibitor, a viral entry inhibitor, a viral maturation inhibitor, a capsid assembly inhibitor, an HBV core modulator, a reverse transcriptase inhibitor, a TLR-agonist, or an immunomodulator.
- 21. A method to inhibit replication of hepatitis B virus, which comprises contacting the hepatitis B virus, either in vitro or in vivo, with a compound according to any one of embodiments 1-17.
- 22. A pharmaceutical combination, comprising a compound of any of embodiments 1-17 and at least one additional therapeutic agent.
- 23. A compound according to any of embodiments 1-17 for use in therapy.
- 24. The compound according to embodiment 23 wherein the therapy is treatment of a bacterial infection.
- 25. Use of a compound according to any one of embodiments 1-17 in the manufacture of a medicament.
- Another embodiment of the invention provides a compound as described above, or a pharmaceutically acceptable salt thereof, for use as a medicament. In one aspect, the medicament is for treatment of a subject having an HBV infection. In a particular embodiment, the subject is a human diagnosed with chronic HBV.
- Also within the scope of this invention is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament; in some embodiments, this medicament is for the treatment or prevention of a viral disease and/or infection in a human being, including where the virus involved is HBV.
- Included within the scope of this invention is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Optionally, the composition comprises at least two pharmaceutically acceptable carriers and/or excipients.
- According to a further aspect of this embodiment the pharmaceutical composition according to this invention further comprises a therapeutically effective amount of at least one other antiviral agent. In another embodiment, the other antiviral agent is one useful to treat HBV. Suitable additional therapeutic agents are described herein.
- The invention also provides the use of a pharmaceutical composition as described hereinabove for the treatment of a HBV infection in a human being having or at risk of having the infection. In one embodiment, the subject for treatment has been diagnosed as having a chronic HBV infection.
- The invention also provides the use of a pharmaceutical composition as described hereinabove for the treatment of HBV infection in a human being having or at risk of having the disease.
- Another aspect of the invention involves a method of treating or preventing a hepatitis B viral disease and/or infection in a human being by administering to the human being an antivirally effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a composition comprising a compound as described above, alone or in combination with at least one other antiviral agent, administered together or separately.
- An additional aspect of this invention refers to an article of manufacture comprising a composition of the invention that is effective to treat a hepatitis B viral disease and/or infection; and packaging material comprising a label which indicates that the composition can be used to treat disease and/or infection by a hepatitis B virus; wherein the composition comprises a compound of formula (I) according to this invention or a pharmaceutically acceptable salt thereof.
- Still another aspect of this invention relates to a method of inhibiting the replication of HBV, comprising exposing the virus to an effective amount of the compound of formula (I), or a salt thereof, under conditions where replication of the virus is inhibited. This method can be practiced in vitro or in vivo.
- Further included in the scope of the invention is the use of a compound of formula (I), or a salt thereof, to inhibit the replication of HBV either in vitro or in vivo, or to reduce the amount of HBsAg present in a subject infected with HBV.
- In all of the embodiments referring to a compound of Formula (I), the compound of Formula (I) can be a compound according to any of embodiments 1-17 described above.
- In some embodiments, the compound of Formula (I) is co-administered with or used in combination with at least one additional therapeutic agent selected from: an interferon or peginterferon, an HBV polymerase inhibitor, a viral entry inhibitor, a viral maturation inhibitor, a capsid assembly inhibitor, an HBV core modulator, a reverse transcriptase inhibitor, a TLR-agonist, or an immunomodulator. Optionally, the compound of Formula (I) may be prepared for simultaneous or sequential use in combination with an additional therapeutic agent; or the compound of Formula (I) may be combined into a pharmaceutical combination comprising a compound of Formula (I) and at least one additional therapeutic agent. Some particular therapeutic agents that may be used in combination with the compounds of the invention include immunomodulators described herein, interferon alfa 2a, interferon alfa-2b, pegylated interferon alfa-2a, pegylated interferon alfa-2b, TLR-7 and TLR-9 agonists, entecavir, tenofovir, cidofovir, telbivudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, apricitabine, atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, adefovir, efavirenz, nevirapine, delavirdine, and etravirine. Suitable core modulators are disclosed in WO2013/096744; suitable HBV capsid inhibitors are described in US2015/0252057.
- These additional agents may be combined with the compounds of this invention to create a single pharmaceutical dosage form. Alternatively these additional agents may be separately administered to the patient as part of a multiple dosage form, for example, using a kit. Such additional agents may be administered to the patient prior to, concurrently with, or following the administration of a compound of the invention, or a pharmaceutically acceptable salt thereof. Alternatively, these additional therapeutic agents may be administered separately from and optionally by different routes of administration and on different dosing schedules from the compound of the invention, provided the compound of the invention and the additional therapeutic agent are used concurrently for treatment of an HBV infection or a disorder caused or complicated by an HBV infection.
- The dose range of the compounds of the invention applicable per day is usually from 0.01 to 100 mg/kg of body weight, preferably from 0.1 to 50 mg/kg of body weight. In some embodiments, the total daily dosage is between 1 and 25 mg, and may be administered in a single dose or in divided doses at different times to maintain a suitable plasma concentration. Each dosage unit may conveniently contain from 5% to 95% active compound (w/w). Preferably such preparations contain from 20% to 80% active compound which may be admixed with one or more pharmaceutically acceptable carriers or excipients.
- The actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the combination will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.
- When the composition of this invention comprises a combination of a compound of the invention and one or more additional therapeutic or prophylactic agent, both the compound and the additional agent may be used at lower dosages than would be used typically for the individual compound when used as a single-agent treatment. Thus in some embodiments, each component may be present at dosage levels of between about 10 to 100%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen.
- It is anticipated that the compounds of the invention may be used in combination with other therapeutic agents, just as combinations of therapeutic agents are currently used for the treatment of hepatitis C virus (HCV) infections. Thus a compound of the invention may be used in combination with a different anti-HBV therapeutic agent such as a nucleoside or an immunomodulatory agent. These combination therapies provide complementary mechanisms to suppress HBV and thus their use in combination should enhance efficacy and also reduce the frequency of resistance development.
- Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologicals) that are effective to inhibit the formation and/or replication of a virus in a human being, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a human being. Such agents can be selected from entecavir, tenofovir, cidofovir, telbivudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, apricitabine, atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, adefovir, efavirenz, nevirapine, delavirdine, and etravirine, and immunomodulators described herein including interferons and pegylated interferons, TLR-7 agonists, and TLR-9 agonists. Current HBV treatments including immunomodulatory agents, such as interferon-α and pegylated interferon-α, and oral nucleoside/nucleotide analogues (NAs), including lamivudine, adefovir, telbivudine, entecavir and tenofovir, are known to suppress but not eliminate HBV. J. Antimicrob. Chemother. 2011, vol. 66(12), 2715-25, and thus those therapeutics may be used in combination with a compound of the invention.
- Many compounds of the invention contain one or more chiral centers. These compounds may be made and used as single isomers or as mixtures of isomers. Methods for separating the isomers, including diastereomers and enantiomers, are known in the art, and examples of suitable methods are described herein. In certain embodiments, the compounds of the invention are used as a single substantially pure isomer, meaning at least 90% of a sample of the compound is the specified isomer and less than 10% of the sample is any other isomer or mixture of isomers. Preferably, at least 95% of the sample is a single isomer. Selection of a suitable isomer is within the ordinary level of skill, as one isomer will typically be more active in the in vivo or in vitro assay described herein for measuring HBV activity, and will be the preferred isomer. Where in vitro activity differences between isomers are relatively small, e.g. less than about a factor of 4, a preferred isomer may be selected based on activity level against viral replication in cell culture, using methods such as those described herein: the isomer having a lower MIC (minimum inhibitory concentration) or EC-50 is preferred.
- The compounds of the invention may be synthesized by the general synthetic routes illustrated below, specific examples of which are described in more detail in the Examples. Additional guidance for synthesis of the compounds of Formula (I) and synthetic intermediates useful for these syntheses are disclosed in published PCT applications WO2015/113990 and WO2015/173164.
- Scheme 1 illustrates a general method useful to make compounds of the invention, as demonstrated in the Examples herein. A variety of pyrazole-2-carboxylates starting materials are known in the art. The carboxylate can be reduced to an alcohol using methods known in the art, and the alcohol can be protected with a protecting group such as known silyl ethers (e.g., TBS). the indole nitrogen can be alkylated with a suitable alph-haloketone to introduce the group containing R6. Reductive amination is one method to introduce nitrogen at the carbonyl center. Once the primary amine is in place, the protected alcohol at C2 of the indole/azaindole can be deprotected and oxidized to an aldehyde oxidation state, at which point it cyclizes with the primary amine to form the new 6-membered ring substituted with R6.
- The imine of the new ring is then annulated to form an additional fused ring by a method known in the art, using (Z)-ethyl 2-(ethoxymethylene)-3-oxobutanoate. The new ring is then oxidized to provide the pyridone ring shown in Formula (I). Methods useful in preparing these compounds are disclosed in published PCT applications WO2015/113990 and WO2015/173164.
- In Scheme 1, enantiomers of these compounds can be separated by chiral HPLC and similar known methods. While one enantiomer of compounds of this formula is typically more active than the other enantiomer, both isomers exhibit activity one HBsAg as demonstrated herein. Alternatively, an enantiomerically pure compounds of Formula (I) can be synthesized using an enantiomerically pure amino alcohol derivative as shown in Scheme 2.
- Using these general methods, other known starting materials, and the examples herein, a person of ordinary skill can synthesize compounds of Formula (I).
- The term “an optical isomer” or “a stereoisomer” refers to any of the various stereoisomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. The term “chiral” refers to molecules which have the property of non-superimposability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R—S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (−) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
- Depending on the choice of the starting materials and procedures, the compounds can be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms. The present invention is meant to include all such possible stereoisomers, including racemic mixtures, diasteriomeric mixtures and optically pure forms. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a di-substituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
- Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers or diastereomers, for example, by chromatography and/or fractional crystallization.
- Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O, O′-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
- Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms. The term “solvate” refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term “hydrate” refers to the complex where the solvent molecule is water.
- The compounds of the present invention, including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.
- As used herein, the terms “salt” or “salts” refers to an acid addition or base addition salt of a compound of the present invention. “Salts” include in particular “pharmaceutically acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
- Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate salts.
- Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
- Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
- Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
- Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
- The pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
- Any formula given herein is intended to represent unlabelled forms as well as isotopically labelled forms of the compounds of the present invention having up to three atoms with non-natural isotope distributions, e.g., sites that are enriched in deuterium or 13C or 15N. Isotopically labelled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number other than the natural-abundance mass distribution. Examples of isotopes that can be usefully over-incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18F 31P, 32P, 35S 36Cl, 125I respectively. The invention includes various isotopically labelled compounds of the present invention, for example those into which radioactive isotopes, such as 3H and 14C, or those in which non-radioactive isotopes, such as 2H and 13C are present at levels substantially above normal isotope distribution. Such isotopically labelled compounds are useful in metabolic studies (with 14C, for example), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18F labelled compound of the present invention may be particularly desirable for PET or SPECT studies. Isotopically-labelled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labelled reagent in place of the non-labelled reagent typically employed. Labelled samples may be useful with quite low isotope incorporation, such as where a radiolabel is used to detect trace amounts of the compound.
- Further, more extensive or site-specific substitution with heavier isotopes, particularly deuterium (i.e., 2H or D), may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the present invention, and typically a sample of a compound having deuterium as a substituent has at least 50% deuterium incorporation at the labelled position(s). The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
- Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO.
- Compounds of the present invention that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of the present invention by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of the present invention with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed. Suitable co-crystal formers include those described in WO 2004/078163. Hence the invention further provides co-crystals comprising a compound of the present invention.
- All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.
- The compounds of the invention can be administered by known methods, including oral, parenteral, inhalation, and the like. In certain embodiments, the compound of the invention is administered orally, as a pill, lozenge, troche, capsule, solution, or suspension. In other embodiments, a compound of the invention is administered by injection or infusion. Infusion is typically performed intravenously, often over a period of time between about 15 minutes and 4 hours. In other embodiments, a compound of the invention is administered intranasally or by inhalation; inhalation methods are particularly useful for treatment of respiratory infections. Compounds of the present invention exhibit oral bioavailability, so oral administration is sometimes preferred.
- In certain embodiments of the present invention, a compound of the present invention is used in combination with a second therapeutic agent, which may be an antiviral agent, such as those named herein.
- By the term “combination”, is meant either a fixed combination in one dosage unit form, as separate dosage forms suitable for use together either simultaneously or sequentially, or as a kit of parts for the combined administration where a compound of the present invention and a combination partner may be administered independently at the same time or separately within time intervals that especially allow that the combination partners show a cooperative, e.g., synergistic, effect, or any combination thereof.
- The second antiviral agent may be administered in combination with the compounds of the present inventions wherein the second antiviral agent is administered prior to, simultaneously, or after the compound or compounds of the present invention. When simultaneous administration of a compound of the invention with a second agent is desired and the route of administration is the same, then a compound of the invention may be formulated with a second agent into the same dosage form. An example of a dosage form containing a compound of the invention and a second agent is a tablet or a capsule.
- In some embodiments, a combination of a compound of the invention and a second antiviral agent may provide synergistic activity. The compound of the invention and second antiviral agent may be administered together, separate but simultaneously, or sequentially.
- An “effective amount” of a compound is that amount necessary or sufficient to treat or prevent a viral infection and/or a disease or condition described herein. In an example, an effective amount of a compound of Formula I is an amount sufficient to treat viral infection in a subject. In another example, an effective amount is an amount sufficient to treat HBV in a subject in need of such treatment. The effective amount can vary depending on such factors as the size and weight of the subject, the type of illness, or the particular compound of the invention. For example, the choice of the compound of the invention can affect what constitutes an “effective amount.” One of ordinary skill in the art would be able to study the factors contained herein and make the determination regarding the effective amount of the compounds of the invention without undue experimentation.
- The regimen of administration can affect what constitutes an effective amount. The compound of the invention can be administered to the subject either prior to or after the onset of a viral infection. Further, several divided dosages, as well as staggered dosages, can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection. Further, the dosages of the compound(s) of the invention can be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
- Compounds of the invention may be used in the treatment of states, disorders or diseases as described herein, or for the manufacture of pharmaceutical compositions for use in the treatment of these diseases. The invention provides methods of use of compounds of the present invention in the treatment of these diseases or for preparation of pharmaceutical compositions having compounds of the present invention for the treatment of these diseases.
- The language “pharmaceutical composition” includes preparations suitable for administration to mammals, e.g., humans. When the compounds of the present invention are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of at least one compound of Formula (I) or any subgenus thereof as active ingredient in combination with a pharmaceutically acceptable carrier, or optionally two or more pharmaceutically acceptable carriers.
- The phrase “pharmaceutically acceptable carrier” is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present invention to mammals. The carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. Typically, pharmaceutically acceptable carriers are sterilized and/or substantially pyrogen-free.
- Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
- Examples of pharmaceutically acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
- Formulations of the present invention include those suitable for oral, nasal, inhalation, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
- Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
- Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, for example, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.
- In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; absorbents, such as kaolin and bentonite clay; lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
- A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
- Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
- Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
- Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
- Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
- The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
- Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
- Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
- Pharmaceutical compositions of this invention suitable for parenteral administration may comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable carriers such as sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
- Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, glycol ethers, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
- These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
- In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
- Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
- The preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc., administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories.
- The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Intravenous infusion is sometimes a preferred method of delivery for compounds of the invention. Infusion may be used to deliver a single daily dose or multiple doses. In some embodiments, a compound of the invention is administered by infusion over an interval between 15 minutes and 4 hours, typically between 0.5 and 3 hours. Such infusion may be used once per day, twice per day or up to three times per day.
- The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
- These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
- Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
- Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
- The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
- A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
- In general, a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, intravenous and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kg per day, and still more preferably from about 0.1 to about 20 mg per kg per day. An effective amount is that amount which prevents or treats a viral infection, such as HBV.
- Treatment with a compound or composition described herein may be repeated daily for a period sufficient to reduce or substantially eliminate an HBV infection or viral load. For example, treatment may be continued for a week, or two weeks, or 3-4 weeks, or 4-8 weeks, or 8-12 weeks, 2-6 months, or longer, e.g., until viral load or other measure of infection shows a substantial reduction in viral load or viral activity or other signs or symptoms of HBV infection. The skilled treating physician can readily determine a suitable duration of treatment.
- If desired, the effective daily dose of the active compound may be administered as a single dose per day, or as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Compounds delivered orally or by inhalation, are commonly administered in one to four doses per day. Compounds delivered by injection are typically administered once per day, or once every other day. Compounds delivered by infusion are typically administered in one to three doses per day. When multiple doses are administered within a day, the doses may be administered at intervals of about 4 hours, about 6 hours, about 8 hours or about 12 hours.
- While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical composition such as those described herein. Thus methods of using the compounds of the invention include administering the compound as a pharmaceutical composition, wherein at least one compound of the invention is admixed with a pharmaceutically acceptable carrier prior to administration.
- Use of Compounds of the Invention in Combination with Immunomodulators
- The compounds and compositions described herein can be used or administered in combination with one or more therapeutic agents that act as immunomodulators, e.g., an activator of a costimulatory molecule, or an inhibitor of an immune-inhibitory molecule, or a vaccine. The Programmed Death 1 (PD-1) protein is an inhibitory member of the extended CD28/CTLA4 family of T cell regulators (Okazaki et al. (2002) Curr. Opin. Immunol. 14: 391779-82; Bennett et al. (2003) J. Immunol. 170:711-8). PD-1 is expressed on activated B cells, T cells, and monocytes. PD-1 is an immune-inhibitory protein that negatively regulates TCR signals (Ishida, Y. et al. (1992) EMBO J. 11:3887-3895; Blank, C. et al. (Epub 2006 Dec. 29) Immunol. Immunother. 56(5):739-745), and is up-regulated in chronic infections. The interaction between PD-1 and PD-L1 can act as an immune checkpoint, which can lead to, e.g., a decrease in infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and/or immune evasion by cancerous or infected cells (Dong et al. (2003) J. Mol. Med. 81:281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100). Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2; the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66). Immunomodulation can be achieved by binding to either the immune-inhibitory protein (e.g., PD-1) or to binding proteins that modulate the inhibitory protein (e.g., PD-L1, PD-L2).
- In one embodiment, the combination therapies of the invention include an immunomodulator that is an inhibitor or antagonist of an inhibitory molecule of an immune checkpoint molecule. In another embodiment the immunomodulator binds to a protein that naturally inhibits the immuno-inhibitory checkpoint molecule. When used in combination with antiviral compounds, these immunomodulators can enhance the antiviral response, and thus enhance efficacy relative to treatment with the antiviral compound alone.
- The term “immune checkpoints” refers to a group of molecules on the cell surface of CD4 and CD8 T cells. These molecules can effectively serve as “brakes” to down-modulate or inhibit an adaptive immune response. Immune checkpoint molecules include, but are not limited to, Programmed Death 1 (PD-1), Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD137, CD40, and LAG3, which directly inhibit immune cells. Immunotherapeutic agents which can act as immune checkpoint inhibitors useful in the methods of the present invention, include, but are not limited to, inhibitors of PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFR beta. Inhibition of an inhibitory molecule can be performed by inhibition at the DNA, RNA or protein level. In some embodiments, an inhibitory nucleic acid (e.g., a dsRNA, siRNA or shRNA), can be used to inhibit expression of an inhibitory molecule. In other embodiments, the inhibitor of an inhibitory signal is a polypeptide, e.g., a soluble ligand, or an antibody or antigen-binding fragment thereof, that binds to the inhibitory molecule.
- By “in combination with,” it is not intended to imply that the therapy or the therapeutic agents must be administered at the same time and/or formulated for delivery together, although these methods of delivery are within the scope described herein. The immunomodulator can be administered concurrently with, prior to, or subsequent to, one or more compounds of the invention, and optionally one or more additional therapies or therapeutic agents. The therapeutic agents in the combination can be administered in any order. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. It will further be appreciated that the therapeutic agents utilized in this combination may be administered together in a single composition or administered separately in different compositions. In general, it is expected that each of the therapeutic agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
- In certain embodiments, the antiviral compounds described herein are administered in combination with one or more immunomodulators that are inhibitors of PD-1, PD-L1 and/or PD-L2. Each such inhibitor may be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or an oligopeptide. Examples of such immunomodulators are known in the art.
- In some embodiments, the immunomodulator is an anti-PD-1 antibody chosen from MDX-1106, Merck 3475 or CT-011.
- In some embodiments, the immunomodulator is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence).
- In some embodiments, the immunomodulator is a PD-1 inhibitor such as AMP-224.
- In some embodiments, the immunomodulator is a PD-L1 inhibitor such as anti-PD-LI antibody.
- In some embodiments, the immunomodulator is an anti-PD-L1 binding antagonist chosen from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105. MDX-1105, also known as BMS-936559, is an anti-PD-LI antibody described in WO2007/005874. Antibody YW243.55.S70 is an anti-PD-LI described in WO 2010/077634.
- In some embodiments, the immunomodulator is nivolumab (CAS Registry Number: 946414-94-4). Alternative names for nivolumab include MDX-1106, MDX-1106-04, ONO-4538, or BMS-936558. Nivolumab is a fully human IgG4 monoclonal antibody which specifically blocks PD-1. Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD-1 are disclosed in U.S. Pat. No. 8,008,449, EP2161336 and WO2006/121168.
- In some embodiments, the immunomodulator is an anti-PD-1 antibody pembrolizumab. Pembrolizumab (also referred to as lambrolizumab, MK-3475, MK03475, SCH-900475 or KEYTRUDA®; Merck) is a humanized IgG4 monoclonal antibody that binds to PD-1. Pembrolizumab and other humanized anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, U.S. Pat. No. 8,354,509, WO2009/114335, and WO2013/079174.
- In some embodiments, the immunomodulator is pidilizumab (CT-011; Cure Tech), a humanized IgG1k monoclonal antibody that binds to PD1. Pidilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in WO2009/101611.
- Other anti-PD1 antibodies useful as immunomodulators for use in the methods disclosed herein include AMP 514 (Amplimmune), and anti-PD1 antibodies disclosed in U.S. Pat. No. 8,609,089, US 2010028330, and/or US 20120114649. In some embodiments, the anti-PD-L1 antibody is MSB0010718C. MSB0010718C (also referred to as A09-246-2; Merck Serono) is a monoclonal antibody that binds to PD-L1.
- In some embodiments, the immunomodulator is MDPL3280A (Genentech/Roche), a human Fc optimized IgG1 monoclonal antibody that binds to PD-L1. MDPL3280A and other human monoclonal antibodies to PD-L1 are disclosed in U.S. Pat. No. 7,943,743 and U.S Publication No.: 20120039906. Other anti-PD-L1 binding agents useful as immunomodulators for methods of the invention include YW243.55.S70 (see WO2010/077634), MDX-1105 (also referred to as BMS-936559), and anti-PD-L1 binding agents disclosed in WO2007/005874.
- In some embodiments, the immunomodulator is AMP-224 (B7-DCIg; Amplimmune; e.g., disclosed in WO2010/027827 and WO2011/066342), is a PD-L2 Fc fusion soluble receptor that blocks the interaction between PD1 and B7-H1.
- In some embodiments, the immunomodulator is an anti-LAG-3 antibody such as BMS-986016. BMS-986016 (also referred to as BMS986016) is a monoclonal antibody that binds to LAG-3. BMS-986016 and other humanized anti-LAG-3 antibodies are disclosed in US 2011/0150892, WO2010/019570, and WO2014/008218
- In certain embodiments, the combination therapies disclosed herein include a modulator of a costimulatory molecule or an inhibitory molecule, e.g., a co-inhibitory ligand or receptor.
- In one embodiment, the costimulatory modulator, e.g., agonist, of a costimulatory molecule is chosen from an agonist (e.g., an agonistic antibody or antigen-binding fragment thereof, or soluble fusion) of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand.
- In another embodiment, the combination therapies disclosed herein include an immunomodulator that is a costimulatory molecule, e.g., an agonist associated with a positive signal that includes a costimulatory domain of CD28, CD27, ICOS and/or GITR.
- Exemplary GITR agonists include, e.g., GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as, a GITR fusion protein described in U.S. Pat. No. 6,111,090, European Patent No.: 090505B1, U.S. Pat. No. 8,586,023, PCT Publication Nos.: WO 2010/003118 and 2011/090754, or an anti-GITR antibody described, e.g., in U.S. Pat. No. 7,025,962, European Patent No.: 1947183B1, U.S. Pat. Nos. 7,812,135, 8,388,967, 8,591,886, European Patent No.: EP 1866339, PCT Publication No.: WO 2011/028683, PCT Publication No.: WO 2013/039954, PCT Publication No.: WO2005/007190, PCT Publication No.: WO 2007/133822, PCT Publication No.: WO2005/055808, PCT Publication No.: WO 99/40196, PCT Publication No.: WO 2001/03720, PCT Publication No.: WO99/20758, PCT Publication No.: WO2006/083289, PCT Publication No.: WO 2005/115451, U.S. Pat. No. 7,618,632, and PCT Publication No.: WO 2011/051726.
- In one embodiment, the immunomodulator used is a soluble ligand (e.g., a CTLA-4-Ig), or an antibody or antibody fragment that binds to PD-L1, PD-L2 or CTLA4. For example, the anti-PD-1 antibody molecule can be administered in combination with an anti-CTLA-4 antibody, e.g., ipilimumab, for example. Exemplary anti-CTLA4 antibodies include tremelimumab (IgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675,206); and ipilimumab (CTLA-4 antibody, also known as MDX-010, CAS No. 477202-00-9).
- In one embodiment, an anti-PD-1 antibody molecule is administered after treatment with a compound of the invention as described herein.
- In another embodiment, an anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-LAG-3 antibody or an antigen-binding fragment thereof. In another embodiment, the anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-TIM-3 antibody or antigen-binding fragment thereof. In yet other embodiments, the anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-LAG-3 antibody and an anti-TIM-3 antibody, or antigen-binding fragments thereof. The combination of antibodies recited herein can be administered separately, e.g., as separate antibodies, or linked, e.g., as a bispecific or trispecific antibody molecule. In one embodiment, a bispecific antibody that includes an anti-PD-1 or PD-L1 antibody molecule and an anti-TIM-3 or anti-LAG-3 antibody, or antigen-binding fragment thereof, is administered. In certain embodiments, the combination of antibodies recited herein is used to treat a cancer, e.g., a cancer as described herein (e.g., a solid tumor). The efficacy of the aforesaid combinations can be tested in animal models known in the art. For example, the animal models to test the synergistic effect of anti-PD-1 and anti-LAG-3 are described, e.g., in Woo et al. (2012) Cancer Res. 72(4):917-27).
- Exemplary immunomodulators that can be used in the combination therapies include, but are not limited to, e.g., afutuzumab (available from Roche®); pegfilgrastim (Neulasta®); lenalidomide (CC-5013, Revlimid®); thalidomide (Thalomid®), actimid (CC4047); and cytokines, e.g., IL-21 or IRX-2 (mixture of human cytokines including interleukin 1, interleukin 2, and interferon γ, CAS 951209-71-5, available from IRX Therapeutics).
- Exemplary doses of such immunomodulators that can be used in combination with the antiviral compounds of the invention include a dose of anti-PD-1 antibody molecule of about 1 to 10 mg/kg, e.g., 3 mg/kg, and a dose of an anti-CTLA-4 antibody, e.g., ipilimumab, of about 3 mg/kg.
- Examples of embodiments of the methods of using the antiviral compounds of the invention in combination with an immunomodulator include these, which may be used along with a compound of Formula I or any subgenus or species thereof that is disclosed herein:
- i. A method to treat a viral infection in a subject, comprising administering to the subject a compound of Formula (I) as described herein, and an immunomodulator.
- ii. The method of embodiment i, wherein the immunomodulator is an activator of a costimulatory molecule or an inhibitor of an immune checkpoint molecule.
- iii. The method of either of embodiments i and ii, wherein the activator of the costimulatory molecule is an agonist of one or more of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 and CD83 ligand.
- iv. The method of any of embodiments i-iii above, wherein the inhibitor of the immune checkpoint molecule is chosen from PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and TGFR beta.
- v. The method of any of any of embodiments i-iii, wherein the inhibitor of the immune checkpoint molecule is chosen from an inhibitor of PD-1, PD-L1, LAG-3, TIM-3 or CTLA4, or any combination thereof.
- vi. The method of any of embodiments i-v, wherein the inhibitor of the immune checkpoint molecule is a soluble ligand or an antibody or antigen-binding fragment thereof, that binds to the immune checkpoint molecule.
- vii. The method of any of embodiments i-vi, wherein the antibody or antigen-binding fragment thereof is from an IgG1 or IgG4 (e.g., human IgG1 or IgG4).
- viii. The method of any of embodiments i-vii, wherein the antibody or antigen-binding fragment thereof is altered, e.g., mutated, to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function.
- ix. The method of any of embodiments i-viii, wherein the antibody molecule is a bispecific or multispecific antibody molecule that has a first binding specificity to PD-1 or PD-L1 and a second binding specificity to TIM-3, LAG-3, or PD-L2.
- x. The method of any of embodiments i-ix, wherein the immunomodulator is an anti-PD-1 antibody chosen from nivolumab, pembrolizumab, or pidilizumab.
- xi. The method of any of embodiments i-x, wherein the immunomodulator is an anti-PD-L1 antibody chosen from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105.
- xii. The method of any of embodiments i-x, wherein the immunomodulator is an anti-LAG-3 antibody molecule.
- xiii. The method of embodiment xii, wherein the anti-LAG-3 antibody molecule is BMS-986016.
- xiv. The method of any of embodiments i-x, wherein the immunomodulator is an anti-PD-1 antibody molecule administered by injection (e.g., subcutaneously or intravenously) at a dose of about 1 to 30 mg/kg, e.g., about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 5 mg/kg, or about 3 mg/kg., e.g., once a week to once every 2, 3, or 4 weeks.
- xv. The method of embodiment xiv, wherein the anti-PD-1 antibody molecule is administered at a dose from about 10 to 20 mg/kg every other week.
- xvi. The method of embodiment xv, wherein the anti-PD-1 antibody molecule, e.g., nivolumab, is administered intravenously at a dose from about 1 mg/kg to 3 mg/kg, e.g., about 1 mg/kg, 2 mg/kg or 3 mg/kg, every two weeks.
- xvii. The method of embodiment xv, wherein the anti-PD-1 antibody molecule, e.g., nivolumab, is administered intravenously at a dose of about 2 mg/kg at 3-week intervals.
- The compounds as described herein may be synthesized by the general synthetic routes below, specific examples of which are described in more detail in the Examples.
- All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). General methods for synthesis of compounds of the invention are illustrated by the Examples below, the general method in Scheme 1, and by methods disclosed in published PCT applications WO2015/113990 and WO2015/173164.
- Ac acetyl
ACN acetonitrile
AcOEt/EtOAc ethyl acetate
AcOH acetic acid
aq aqueous
Bn benzyl
Bu butyl (nBu=n-butyl, tBu=tert-butyl) - DBU 1,8-Diazabicyclo[5.4.0]-undec-7-ene
Boc2O di-tert-butyl dicarbonate - DIAD Diisopropyl azodicarboxylate
- EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
EI Electrospray ionisation - EtOAc Ethyl acetate
- FA Formic acid
- h hour(s)
HCl Hydrochloric acid - H2O water
IPA isopropanol
L liter(s) - LiHMDS Lithium bis(trimethylsilyl)amide
Me methyl - mg milligram
min minute(s)
mL milliliter - Pd/C palladium on charcoal
PG protecting group
Ph phenyl
Ph3P triphenyl phosphine - Rf ratio of fronts
RP reverse phase
Rt Retention time
rt Room temperature - T3P® Propylphosphonic acid anhydride
TBAF Tetrabutylammonium fluoride
TBDMS t-Butyldimethylsilyl - TFA Trifluoroacetic acid
- TsCl toluene sulfonyl chloride
- Within the scope of this text, a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention is designated a “protecting group,” unless the context indicates otherwise. The protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as e.g., Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627 pp. (URL: http://www.science-of-synthesis.com (Electronic Version, 48 Volumes)); J. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in “Methoden der Organischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jeschkeit, “Aminosäuren, Peptide, Proteine” (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharide und Derivate” (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic of protecting groups is that they can be removed readily (i.e., without the occurrence of undesired secondary reactions) for example by solvolysis, reduction, photolysis or alternatively under physiological conditions (e.g., by enzymatic cleavage).
- Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known per se. For example, salts of compounds of the present invention having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g., the sodium salt of 2-ethyl hexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used. Acid addition salts of compounds of the present invention are obtained in customary manner, e.g., by treating the compounds with an acid or a suitable anion exchange reagent. Internal salts of compounds of the present invention containing acid and basic salt-forming groups, e.g., a free carboxy group and a free amino group, may be formed, e.g., by the neutralization of salts, such as acid addition salts, to the isoelectric point, e.g., with weak bases, or by treatment with ion exchangers.
- Salts can be converted in customary manner into the free compounds; metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.
- Mixtures of isomers obtainable according to the invention can be separated in a manner known per se into the individual isomers; diastereoisomers can be separated, for example, by partitioning between polyphasic solvent mixtures, recrystallization and/or chromatographic separation, for example over silica gel or by, e.g., medium pressure liquid chromatography over a reversed phase column, and racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisomers so obtainable, for example by means of fractional crystallization, or by chromatography over optically active column materials.
- Intermediates and final products can be worked up and/or purified according to standard methods, e.g., using chromatographic methods, distribution methods, (re-) crystallization, and the like.
- The invention is illustrated by the following examples, which should not be construed as limiting. The assays used to demonstrate the efficacy of compounds of Formula (I) in these assays are generally regarded as predictive of efficacy in subjects.
- Mass spectra were run on UHPLC-MS systems using electrospray ionization. These were WATERS Acquity Single Quard Detector. [M+H]+ refers to mono-isotopic molecular weights.
- Mass spectra were run on LC-MS systems with one of the following conditions:
- Waters Acquity UPLC-H class system equipped with SQD detector.
- Column: ACQUITY UPLC HSS C18 (50*2.1) mm, 1.8u.
- Column temperature: Ambient.
- Mobile Phase: A) 0.1% FA+5 mM Ammonium Acetate in Water.
- B) 0.1% FA in Acetonitrile.
- Gradient: 5-5% solvent B in 0.40 min, 5-35% solvent B in 0.80 min, 35-55% solvent B in 1.2 min, 55-100% solvent B in 2.5 min.
- Flow rate: 0.55 mL/min.
- Compounds were detected by a Waters Photodiode Array Detector.
- Waters LCMS system equipped with ZQ 2000 detector.
- Column: X-BRIDGE C18 (50*4.6) mm, 3.5u.
- Column temperature: Ambient.
- Mobile Phase: A) 0.1% NH3 in Water.
- B) 0.1% NH3 in Acetonitrile.
- Gradient: 5-95% solvent B in 5.00 min.
- Flow rate: 1.0 mL/min.
- Compounds were detected by a Waters Photodiode Array Detector.
- Waters ACQUITY UPLC system and equipped with a ZQ 2000 MS system.
- Column: Kinetex by Phenomenex, 2.6 um, 2.1×50 mm
- Column temperature: 50° C.
- Gradient: 2-88% (or 00-45%, or 65-95%) solvent B over a 1.29 min period
- Flow rate: 1.2 mL/min.
- Compounds were detected by a Waters Photodiode Array Detector.
- Chiral separations were done with the following columns:
-
- AD: ChiralPak AD-H, SFC 21×250 mm
- OD: ChiralPak OD-H, SFC 21×250 mm
- NMR spectra were run on open access Varian 400 or Varian 500 NMR spectrometers. Spectra were measured at 298K and were referenced using the solvent peak. Chemical shifts for 1H NMR are reported in parts per million (ppm).
-
-
- To a solution of ethyl 3-isopropyl-1H-pyrazole-5-carboxylate (7.7 g, 49.3 mmol) in DMF (Volume: 164 ml) was added cesium carbonate (16.07 g, 49.3 mmol). The reaction mixture was cooled down to 0° C. followed by slow addition of 1-bromo-3-methoxypropane (5.83 ml, 51.8 mmol). The reaction mixture was warmed up to room temperature and stirred for 16 h. After quenched with water, the reaction mixture was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, 0% to 50% EtOAc in heptane, to give ethyl 3-(3-methoxypropoxy)-1H-pyrazole-5-carboxylate (4.65 g, 41%). LCMS (m/z): 301 [M+H]+. 1H NMR (400 MHz, CDCl3): 6.23 (s, 1H), 4.38 (d, J=7.14 Hz, 1H), 4.33-4.41 (m, 1H), 4.21-4.30 (m, 2H), 3.51-3.58 (m, 2H), 3.36 (s, 3H), 2.05 (t, J=6.28 Hz, 2H), 1.38 (t, J=7.12 Hz, 3H).
-
- To a solution of ethyl 3-(3-methoxypropoxy)-1H-pyrazole-5-carboxylate (4.6 g, 20.15 mmol) in MeCN (40.3 mL) was added sulfuryl dichloride (24.18 mL of 1 M solution in DCM), 24.18 mmol) at 0° C. The reaction mixture was warmed up to room temperature and stirred for 16 h. The volatile materials were removed in vacuo. The crude product was diluted with EtOAc, which was washed with saturated NaHCO3 solution, water and brine. The organic layers were dried over anhydrous sodium sulfate, filtered off, and concentrated to give product 4.5 g (85% yield). The crude material was used in the next step with no further purification. LCMS (m/z): 263 [M+H]+.
-
- To a solution of ethyl 4-chloro-3-(3-methoxypropoxy)-1H-pyrazole-5-carboxylate (4.5 g, 17.13 mmol), triphenylphosphine (5.39 g, 20.56 mmol), (R)-tert-butyl (1-hydroxy-3,3-dimethylbutan-2-yl)carbamate (4.84 g, 22.27 mmol) in THF (57.1 mL) was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (4.73 g, 20.56 mmol) portionwise and the resulting mixture was stirred at room temperature for 16 hours. The volatile material was removed in vacuo. To the remaining material was added water and EtOAc. The phases were separated and the organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (EtOAc/heptane, 0-20%) to give product 7.45 g (94% yield). LCMS (m/z): 462 [M+H]+. 1H NMR (500 MHz, CDCl3): 6.20 (s, 1H), 4.64-4.52 (m, 1H), 4.39 (q, J=7.0 Hz, 2H), 4.36-4.28 (m, 2H), 3.81 (td, J=11.0, 3.8 Hz, 1H), 3.54 (td, J=6.3, 4.0 Hz, 3H), 3.35 (s, 3H), 2.10-1.99 (m, 2H), 1.47 (s, 9H), 1.42 (t, J=7.2 Hz, 3H), 0.99 (s, 9H).
-
- To a solution of (R)-ethyl 1-(2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyl)-4-chloro-3-(3-methoxypropoxy)-1H-pyrazole-5-carboxylate (7.45 g, 16.13 mmol) in Me-THF (38.4 mL) was added sodium borohydride (1.22 g, 32.3 mmol) at room temperature. After the reaction mixture was slowly warmed up to and heated at 60° C., MeOH (3.26 mL, 81 mmol) was added over 30 min. On completion of the addition, the mixture was heated at 70° C. for 90 min. Then the reaction mixture was cooled to 20° C. and quenched with sat. NH4Cl aq. (30 mL). After stirring for 1.5 h, the organic layer was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO4, filtered off, and concentrated to give crude product (6.7 g, 99%). The crude material was used for the next step without further purification. LCMS (m/z): 420 [M+H]+. 1H NMR (500 MHz, CDCl3): 6.24 (bs, 1H), 4.72 (m, 1H), 4.59 (m, 2H), 4.36 (m, 1H), 4.30 (m, 2H), 3.8 (m, 2H), 3.56 (m, 2H), 3.37 (s, 3H), 2.11-2.05 (m, 2H), 1.32 (s, 9H), 1.02 (s, 9H).
-
- To a solution of (R)-tert-butyl (1-(4-chloro-5-(hydroxymethyl)-3-(3-methoxypropoxy)-1H-pyrazol-1-yl)-3,3-dimethylbutan-2-yl)carbamate (850 mg, 2.024 mmol) in DCM (20.2 mL) was added Dess-Martin reagent (1.03 g, 2.429 mmol). The reaction mixture was stirred at room temperature for 16 h. After the solution of sodium thiosulfate and sodium bicarbonate (1:4, 20 mL) was added, the reaction mixture was stirred for 2 h and was extracted with EtOAc. The organic layers were washed with sat. aq. NaHCO3 solution, water, and brine. After dried over Na2SO4 and filtered off, the filtrate was concentrated in vacuo. The crude material was purified by silica gel column chromatography (EtOAc/heptane, 0% to 40%) to give product (637 mg, 75% yield). LCMS (m/z): 418 [M+H]+.
-
- TFA (1.8 mL) was added to a solution of (R)-tert-butyl (1-(4-chloro-5-formyl-3-(3-methoxypropoxy)-1H-pyrazol-1-yl)-3,3-dimethylbutan-2-yl)carbamate (220 mg, 0.526 mmol) in DCM (3.5 mL) at 0° C. After stirred at room temperature for 3 hs, the mixture was concentrated in vacuo. The crude material was used in the next step without further purification. LCMS (m/z): 300 [M+H]+.
-
- (Z)-ethyl 2-(ethoxymethylene)-3-oxobutanoate (93 μl, 0.507 mmol) was added to a solution of (R)-6-(tert-butyl)-3-chloro-2-(3-methoxypropoxy)-6,7-dihydropyrazolo[1,5-a]pyrazine (70 mg, 0.169 mmol) in EtOH (0.77 mL) and the mixture was heated at 85° C. for 16 hs. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography, (EtOAc/heptane, 0% to 100%) to give product (74 mg, 99% yield). LCMS (m/z): 440 [M+H]+.
-
- Chloranil (41.4 mg, 0.168 mmol) was added to a solution of (6R)-ethyl 6-(tert-butyl)-1-chloro-2-(3-methoxypropoxy)-10-oxo-6,10,11,11a-tetrahydro-5H-pyrazolo[1,5-a]pyrido[2,1-c]pyrazine-9-carboxylate (74 mg, 0.168 mmol) in DME (0.84 mL) and the reaction mixture was heated at 90° C. for 60 mins. After the volatile materials were removed in vacuo, the reaction mixture was diluted with EtOAc and washed with sat. NaHCO3 aq. solution, water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude material (73 mg, 99% yield) was used in the next step with no further purification. LCMS (m/z): 438 [M+H]+.
-
- To a solution of (R)-ethyl 6-(tert-butyl)-1-chloro-2-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrazolo[1,5-a]pyrido[2,1-c]pyrazine-9-carboxylate (73 mg, 0.167 mmol) in THF (0.33 mL) and MeOH (0.33 mL) was added LiOH (0.3 mL, 1.0 M in water, 0.3 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was acidified with 1.0 N HCl aq. solution (0.08 mL) and extracted with DCM. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by reverse phase HPLC. The pure fractions were collected and lyophilized to give product as its TFA salt form (9.8 mg, 11% yield). LCMS (m/z): 410 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.55 (s, 1H), 7.56 (s, 1H), 4.64 (d, J=14.19 Hz, 1H), 4.49 (dd, J=4.97, 14.19 Hz, 1H), 4.36 (t, J=6.38 Hz, 2H), 4.14 (d, J=4.73 Hz, 1H), 3.58 (t, J=6.15 Hz, 2H), 3.38 (s, 3H), 2.16-2.39 (bs, 1H), 2.02-2.16 (m, 2H), 0.91 (s, 9H).
-
- To a solution of ethyl 5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate (9.5 g, 60.8 mmol) in DCM and DMF (Volume: 125.5 ml, Ratio: 7:1) was added imidazole (6.21 g, 91 mmol) and TBDMSCl (10.09 g, 66.9 mmol) at 0° C. The reaction mixture was warmed up to room temperature and stirred for overnight. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered off, and dried in vacuo. The crude product was used for the next step without further purification. LCMS (m/z): 271 [M+H]+. 1H NMR (500 MHz, CDCl3): 6.16 (s, 1H), 4.37 (d, J=7.09 Hz, 2H), 1.38 (t, J=7.09 Hz, 3H), 0.98 (s, 9H), 0.27 (s, 6H).
-
- (E)-di-tert-butyl diazene-1,2-dicarboxylate (15.41 g, 66.9 mmol) was added to a stirred solution of TRIPHENYLPHOSPHINE (17.55 g, 66.9 mmol), ethyl 3-((tert-butyldimethylsilyl)oxy)-1H-pyrazole-5-carboxylate (14.54 g, 66.9 mmol), and (R)-tert-butyl (1-hydroxy-3,3-dimethylbutan-2-yl)carbamate (16.45 g, 60.8 mmol) in THF (Volume: 203 ml) at 0° C. The mixture was warmed up and stirred at room temperature for overnight. LCMS (m/z): 470 (MH+), 1.35 min. After quenched with water (300 mL), the reaction mixture was extracted with EtOAc (300 mL×2). The organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo. The crude white solid was triturated with DCM, EtOAc and heptane (1:1:8, 100 mL) and filtered off. The filtrate were concentrated to yield (R)-ethyl 1-(2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyl)-3-((tert-butyldimethylsilyl)oxy)-1H-pyrazole-5-carboxylate. The residue provided 14.5 g of triphenylphosphine oxide. The crude product was used in the next step without further purification. LCMS (m/z): 470 [M+H]+.
-
- To a solution of (R)-ethyl 1-(2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyl)-3-((tert-butyldimethylsilyl)oxy)-1H-pyrazole-5-carboxylate (28.6 g, 60.9 mmol) in MeCN (Volume: 203 ml) was added 1 M solution of SO2Cl2 in DCM (73.1 ml, 73.1 mmol) at 0° C. The reaction mixture was warmed up to room temperature and stirred for 1 h. The volatile materials were removed in vacuo. The crude product was diluted with EtOAc, which was washed with Na2CO3 solution, water and brine. The organic layers were dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo. The crude product was used in the next step without further purification (yield: >200%). LCMS (m/z): 390 [M+H]+.
-
- To a solution of (R)-ethyl 1-(2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyl)-4-chloro-3-hydroxy-1H-pyrazole-5-carboxylate (17 g, 43.6 mmol) in DMF (Volume: 145 ml) was added cesium carbonate (21.31 g, 65.4 mmol). The reaction mixture was cooled down to 0° C. followed by addition of 1-bromo-3-methoxypropane (5.89 ml, 52.3 mmol). The reaction mixture was warmed up to room temperature and stirred for 3 h. After quenched with water, the reaction mixture was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo. The crude product was purified by ISCO (0% to 20% EtOAc in heptane). The desired one came out around 20% EtOAc to yield (R)-ethyl 1-(2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyl)-4-chloro-3-hydroxy-1H-pyrazole-5-carboxylate (15.2 g, 75%). LCMS (m/z): 462 [M+H]+.
-
- Compound 1.2 was synthesized from compound 1.1a following the procedures described in example 1.1 step 3-8. LCMS (m/z): 376 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.52 (s, 1H), 6.91 (s, 1H), 6.10 (s, 1H), 4.68 (d, J=14.2 Hz, 1H), 4.51 (dd, J=14.3, 5.1 Hz, 1H), 4.28 (t, J=6.4 Hz, 2H), 4.13 (d, J=5.0 Hz, 1H), 3.57 (t, J=6.2 Hz, 2H), 3.38 (s, 3H), 2.07 (p, J=6.3 Hz, 2H), 0.92 (s, 9H).
-
-
- Compound 1.3a was synthesized from compound 1.1a following the procedures described in example 1.1 step 3. LCMS (m/z): 454,456 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.50 (s, 1H), 7.70 (s, 1H), 4.66 (d, J=14.2 Hz, 1H), 4.51 (dd, J=14.2, 5.1 Hz, 1H), 4.38 (t, J=6.4 Hz, 2H), 4.09 (d, J=5.0 Hz, 1H), 3.59 (td, J=6.2, 1.0 Hz, 2H), 3.39 (s, 3H), 2.10 (p, J=6.3 Hz, 2H), 0.91 (s, 9H).
-
- NBS (0.475 g, 2.67 mmol) was added to a solution of (R)-ethyl 1-(2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyl)-3-(3-methoxypropoxy)-1H-pyrazole-5-carboxylate (1.2 g, 2.81 mmol) in MeCN (9.36 mL) at 0° C. and the resulting mixture was stirred at 0° C. for 2 hs. The reaction solution was quenched with Na2CO3 solution, extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by silica gel column chromatography (EtOAc/heptane 20%) to give product (775 mg, 55% yield). LCMS (m/z): 506, 508 [M+H]+.
-
- Compound 1.3 was synthesized from compound 1.3b following the procedures described in example 1.1 step 4-8. LCMS (m/z): 454, 456 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.50 (s, 1H), 7.70 (s, 1H), 4.66 (d, J=14.2 Hz, 1H), 4.51 (dd, J=14.2, 5.1 Hz, 1H), 4.38 (t, J=6.4 Hz, 2H), 4.09 (d, J=5.0 Hz, 1H), 3.59 (td, J=6.2, 1.0 Hz, 2H), 3.39 (s, 3H), 2.10 (p, J=6.3 Hz, 2H), 0.91 (s, 9H).
-
-
- To a solution of ethyl 3-isopropyl-1H-pyrazole-5-carboxylate (1.5 g, 8.23 mmol) in DME (11.76 ml) was added 2,6-lutidine (1.246 ml, 10.70 mmol) and 1-bromo-3,3-dimethylbutan-2-one (1.164 ml, 8.64 mmol). The reaction mixture was heated at 150° C. for 2 hs in a microwave reactor. 1.0 ml of lutidine and 0.5 ml of bromopinacolone were added to the reaction mixture. The mixture was again heated at 100° C. in a microwave reactor for 6 hs. After cooled at rt, the reaction solution was added water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (EtOAc/heptane, 0% to 30%) to give product (1.15 g, 50% yield). LCMS (m/z): 281 [M+H]+. 1H NMR (400 MHz, CDCl3): 6.65 (s, 1H), 5.21 (s, 2H), 4.37 (q, J=7.1 Hz, 2H), 2.57 (hept, J=7.0 Hz, 1H), 1.37 (t, J=7.1 Hz, 3H), 1.29-1.19 (m, 15H).
-
- To a solution of ethyl 1-(3,3-dimethyl-2-oxobutyl)-3-isopropyl-1H-pyrazole-5-carboxylate (1.7 g, 6.06 mmol) in THF (16.17 ml) at 0° C. was added LiBH4 (0.396 g, 18.19 mmol) and the resulting mixture was stirred at room temperature for 5 hs. The reaction mixture was then placed in an ice/water bath and quenched by slow addition of sat. aq. NH4Cl solution. The mixture was then extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was used in the next step with no further purification. LCMS (m/z): 241 [M+H]+.
-
- To a solution of 1-(5-(hydroxymethyl)-3-isopropyl-1H-pyrazol-1-yl)-3,3-dimethylbutan-2-ol (1.45 g, 6.03 mmol) in DCM (57.5 ml) at 0° C. was added TEA (1.850 ml, 13.27 mmol) and TBDMSCl (1.091 g, 7.24 mmol). After stirred at rt for 24 hs, the mixture was diluted with Et2O and washed with sat. aq. NH4Cl solution. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/heptane, 0% to 100%) to give product (905 mg, 42.3% yield). LCMS (m/z): 355 [M+H]+. 1H NMR (400 MHz, CDCl3): 5.95 (s, 1H), 4.68-4.56 (m, 3H), 4.32 (dd, J=13.7, 1.8 Hz, 1H), 3.86 (dd, J=13.7, 10.0 Hz, 1H), 3.62 (dd, J=10.0, 1.8 Hz, 1H), 2.92 (hept, J=6.9 Hz, 1H), 1.23 (dd, J=6.9, 1.0 Hz, 6H), 1.00 (s, 9H), 0.89 (s, 9H), 0.07 (d, J=1.6 Hz, 6H).
-
- Compound 2.1d was synthesized from compound 2.1c following the procedures described in example 1.1 step 5. LCMS (m/z): 353 [M+H]+. 1H NMR (400 MHz, CDCl3): 5.98 (s, 1H), 5.23 (s, 2H), 4.52 (s, 2H), 2.94 (hept, J=7.1 Hz, 1H), 1.24 (d, J=7.1 Hz, 15H), 0.87 (s, 9H).
-
- To a solution of 1-(5-(((tert-butyldimethylsilyl)oxy)methyl)-3-isopropyl-1H-pyrazol-1-yl)-3,3-dimethylbutan-2-one (771 mg, 2.187 mmol) in MeOH (7.3 mL) was added NH4OAc (1686 mg, 21.87 mmol) and NaBH3CN (412 mg, 6.56 mmol). The resulting mixture was then stirred at rt for 16 hs. Another portion of NaBH3CN (412 mg, 6.56 mmol) was added and the mixture was stirred at rt for another 5 hs. The reaction was quenched by adding sat. aq. Na2CO3 solution and then extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was dissolved in DCM (5 mL). Boc-anhydride (1.523 ml, 6.56 mmol) and TEA (1 mL) were added to above solution. After stirred at rt for 1 h, the mixture was concentrated in vacuo and the crude material was purified by silica gel column chromatography, (EtOAc/heptane, 0% to 100%) to give product (624 mg, 84% yield). LCMS (m/z): 340 [M+H]+. 1H NMR (400 MHz, CDCl3): 6.08 (s, 1H), 4.61 (d, J=5.2 Hz, 2H), 4.45-4.36 (m, 2H), 3.98 (td, J=11.0, 4.4 Hz, 1H), 3.81 (s, 1H), 2.94 (dq, J=13.9, 7.1 Hz, 1H), 1.45 (s, 6H), 1.30-1.20 (m, 9H), 1.01 (s, 9H).
-
- Compound 2.1 was synthesized from compound 2.1e following the procedures described in example 1.1 step 5-9. LCMS (m/z): 330 [M+H]+. NMR (400 MHz, CDCl3) δ 8.5 (s, 1H), 6.93 (s, 1H), 6.51 (s, 1H), 4.85-4.78 (m, 1H), 4.60-4.50 (m, 1H), 4.12 (m, 1H), 3.02 (m, 1H), 1.3 (d, J=6.94 Hz, 6H), 0.86 (s, 9H).
-
-
- To a solution of acetophenone (5.0 g, 41.614 mmol) in DMF (35.0 mL) at 0° C. was added sodium hydride (1.99 g, 60% in mineral oil, 49.93 mmol) portionwise and the resulting mixture was stirred at 0° C. for 30 mins. Dimethyl oxalate (5.89 g, 49.93 mmol) was added at 0° C. and the mixture was stirred at rt for 1 hour and at 50° C. for 30 mins. The reaction was quenched by water and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulphate, filtered and concentrated. The crude material was purified by silica gel column chromatography, EtOAc/hexane 4%, to give product 2.0 g (19.45% yield). LCMS (m/z): 207.22; [M+H]+. 1H NMR (400 MHz, DMSO-d6): 14.98 (s, 1H), 8.12-8.05 (m, 2H), 7.72 (t, J=7.4 Hz, 1H), 7.59 (t, J=7.7 Hz, 2H), 7.14 (s, 1H), 3.87 (s, 3H).
-
- To a solution of methyl (Z)-4-hydroxy-2-oxo-4-phenylbut-3-enoate (1.80 g, 8.712 mmol) in ethanol (9 mL) at 0° C. was added hydrazine hydrate monohydrate (0.436 g, 8.712 mmol) dropwise followed by catalytic amount of acetic acid. The mixture was then stirred at 80° C. for 5 hours. After cooled at rt, the reaction mixture was quenched by adding ice water and then extracted with DCM. The combined organic layers were dried over sodium sulphate, filtered and concentrated. To the residue was added pentane and the precipitate was collected by filtration to give product 1.57 g (88.9% yield). LCMS (m/z): 203.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 14.08 (s, 1H), 7.86 (dd, J=23.9, 7.7 Hz, 2H), 7.45 (dt, J=21.5, 7.3 Hz, 2H), 7.42-7.29 (m, 1H), 7.22 (d, J=2.1 Hz, 1H), 3.85 (d, J=19.2 Hz, 3H).
-
- Compound 3.1 was synthesized from compound 3.1b following the procedures described in example 1.1 step 2-8. LCMS (m/z): 398.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 15.82 (s, 1H), 8.99 (s, 1H), 7.87 (d, J=7.5 Hz, 2H), 7.52 (dt, J=15.7, 7.2 Hz, 3H), 7.43 (s, 1H), 4.95 (d, J=14.0 Hz, 2H), 4.86 (d, J=13.7 Hz, 1H), 0.79 (s, 9H).
-
- Compound 3.2 was synthesized from 1-(2-methoxyphenyl)ethan-1-one following the procedures described in example 3.1 step 1-3. LCMS (m/z): 428.45 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 15.87 (s, 1H), 8.99 (s, 1H), 7.50 (t, J=7.9 Hz, 1H), 7.39-7.28 (m, 2H), 7.19 (d, J=8.5 Hz, 1H), 7.07 (t, J=7.4 Hz, 1H), 4.96-4.81 (m, 3H), 3.80 (s, 3H), 0.81 (s, 9H).
-
-
- To a solution of (R)-2-amino-3-methylbutan-1-ol (5.16 g, 50.0 mmol) in THF (20 mL) at rt was added (bromomethyl)benzene (1.71 g, 10 mmol) and the resultant solution was stirred at rt for 4 hours. The reaction mixture was then diluted with ethyl acetate, washed with water (20 ml×5), dried over MgSO4, and concentrated to afford product. The crude material was used in the next step with no further purification. LCMS (m/z): 194.3 [M+H]+.
-
- To a mixture of suspension of 3-phenyl-1H-pyrazole-5-carbaldehyde (0.35 g, 2.033 mmol) and (R)-2-(benzylamino)-3-methylbutan-1-ol (0.393 g, 2.033 mmol) in DCE (6 ml) was added sodium triacetoxyborohydride (1.120 g, 5.29 mmol) and the resultant mixture was stirred at rt for 3 hours. The mixture was then diluted with EtOAc and carefully added sat. NaHCO3 aq. solution until pH was about 7. The organic layer was separated, dried with MgSO4 and concentrated. The crude material was purified by silica gel column chromatography (EtOAc/heptane 10-60%) to give product 320 mg (45.0% yield). LCMS (m/z): 350.4 [M+H]+.
-
- To a solution of (R)-2-(benzyl((3-phenyl-1H-pyrazol-5-yl)methyl)amino)-3-methylbutan-1-ol (270 mg, 0.773 mmol) and triphenylphosphine (709 mg, 2.70 mmol) in THF (5 mL) was added DEAD (0.428 ml, 2.70 mmol) and the resulting mixture was stirred at rt for 3 hours. The mixture was then concentrated and the residue was purified by silica gel column chromatography (EtOAc/heptane, 10 to 60%) to give product 157 mg (61% yield). LCMS (m/z): 332.4 [M+H]+.
-
- A mixture of (R)-5-benzyl-6-isopropyl-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (160 mg, 0.483 mmol), Pd on carbon (103 mg, 10% on carbon, 0.965 mmol) and NH4COOH (122 mg, 1.931 mmol) in MeOH (3 ml) was heated at 75° C. for 1 hour. After cooled at rt, the mixture was filtered and the filtrate was concentrated to give product 126 mg (quantitative yield). LCMS (m/z): 242.3 [M+H]+.
-
- To a solution of (R)-6-isopropyl-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (114 mg, 0.472 mmol) in DCM (1.2 ml) and MeOH (0.25 ml) was added NCS (72.5 mg, 0.543 mmol) and the resulting mixture was stirred at rt for 3 hs. The mixture was then concentrated and the residue was used in the next step directly.
- 3.3e-I: LCMS (m/z): 276.4 [M+H]+.
- 3.3e-II: LCMS (m/z): 310.3 [M+H]+.
-
- The crude product from previous step was dissolved in DCM (5 mL) and then DBU (0.071 mL, 0.472 mmol) was added. After stirred at rt for 10 mins, the mixture was concentrated. The residue was purified by silica gel column chromatography (EtOAc/heptane, 0 to 70%) to give product 3.3f-I and 3.3f-II.
- 3.3f-I: 60 mg (53% yield). LCMS (m/z): 240.4 [M+H]+.
- 3.3f-II: 14 mg (11% yield). LCMS (m/z): 274.4 [M+H]+.
-
- A mixture of (R)-6-isopropyl-2-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine (30 mg, 0.125 mmol) and (Z)-ethyl 2-(ethoxymethylene)-3-oxobutanoate (70.0 mg, 0.376 mmol) in EtOH (0.7 mL) was heated at 110° C. for 16 hours. After cooled at rt, the mixture was concentrated in vacuo. The residue was dissolved in DME (0.5 mL) and p-chloranil (30.7 mg, 0.125 mmol) was added. The resulting mixture was heated at 110° C. for 2 hours. After cooled at rt, the mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (EtOAc/heptane, 20 to 100%) to give product 18 mg, 0.048 mmol, 38.2% yield) LCMS (m/z): 378.4 [M+H]+.
-
- A solution of LiOH in water (0.191 ml, 1.0 M, 0.191 mmol) was added to a solution of (R)-ethyl 6-isopropyl-10-oxo-2-phenyl-6,10-dihydro-5H-pyrazolo[1,5-a]pyrido[2,1-c]pyrazine-9-carboxylate (18 mg, 0.048 mmol) in THF (1.0 ml) and the resulting solution was stirred at rt for 2 hours. The mixture was then concentrated and acidified by adding 3.0 N HCl aq. solution to pH=4. The precipitate was collected by filtration and then washed with water to give product 8.0 mg (47% yield). LCMS (m/z): 350.4 [M+H]+. 1H NMR (400 MHz, CD3CN): 8.63 (s, 1H), 7.95-7.80 (m, 2H), 7.56-7.26 (m, 4H), 7.10 (s, 1H), 4.87-4.59 (m, 2H), 4.48 (dd, J=8.7, 4.0 Hz, 1H), 1.93-1.86 (m, 1H), 0.97 (d, J=6.7 Hz, 3H), 0.84 (d, J=6.8 Hz, 3H).
-
- Compound 3.4 was synthesized from compound 3.3f-II following the procedures described in example 3.3 step 7-8. LCMS (m/z): 384.5 [M+H]+. 1H NMR (400 MHz, CD3CN): 8.66 (s, 1H), 7.90 (t, J=6.7 Hz, 2H), 7.52 (t, J=7.1 Hz, 4H), 4.87-4.57 (m, 2H), 4.48 (d, J=9.0 Hz, 1H), 1.90-1.77 (m, 1H), 1.06-0.73 (m, 6H).
- HepG2-Clone42, a Tet-inducible HBV-expressing cell line with a stably integrated 1.3mer copy of the HBV ayw strain, was generated based on the Tet-inducible HepAD38 cell line with slight modifications. Ladner S K, et al., Antimicrobial Agents and Chemotherapy. 41(8):1715-1720 (1997). HepG2-Clone42 cells were cultured in DMEM/F-12+Glutamax™ (Life Technologies, Carlsbad, Calif., USA), supplemented with 10% fetal bovine serum (Life Technologies), G-418 (Corning, Manassas, Va., USA) at a final concentration of 0.5 mg/mL, and 5 μg/mL Doxycycline (Sigma, St. Louis, Mo., USA) and maintained in 5% CO2 at 37° C.
- HepG2-Clone42 cells were seeded into black clear-bottom 96-well plates at a concentration of 6.0×104 cells/well. 24 hours post-seeding, the cells were treated with 200 μl/well of media containing five-fold serial dilutions of compounds in DMSO. DMSO alone was used as the no drug control. The final DMSO concentration in all wells was 0.5%.
- The HBsAg ELISA kit (Alpha Diagnostic International, San Antonio, Tex., USE, Catalog #4110) was used to determine the level (semi-quantitative) of secreted HBV sAg. The HBSAg ELISA assay was performed following the manufacturer's protocol as described.
- Step 1. Pipet 100 μL each of compound or DMSO treated samples into HBsAg ELISA plates. Seal plates and incubate at room temp for 60 minutes.
- Step 2. Aspirate samples and wash three times with Wash Buffer. Dispense 100 μL of antibody-HRP conjugate to each well. Incubate at room temp for 30 minutes.
- Step 3. Aspirate samples and wash three times with Wash Buffer. Add 100 μL of TMB Substrate to all wells and incubate 15 minutes at room temp.
- Step 4. Dispense 100 μL of Stop Solution to each well. Measure absorbance of ELISA plate at 450 nm.
- Dose-response curves were generated and the EC50 value was defined as the compound concentration at which HBsAg secretion was reduced 50% compared to the DMSO control.
- EC50 values were determined as follows:
- Determine the percent of HBsAg secretion inhibition. Calculate the percent inhibition on of HBsAg secretion inhibition using the following equation:
-
(XC−MB)/(MD−MB) - where XC is the absorbance signal from compound-treated well; MB is average absorbance signal (background signal) for column 12 (no cells+HBsAg ELISA sample buffer) and MD is average absorbance signal from DMSO-treated wells. Then calculate EC50 values by non-linear regression using a four parameter curve logistic equation.
- The curve fit model employed is XLFit Dose Response One Site Model 204: y=(A+((B−A)/(1+(10{circumflex over ( )}((C−x)*D))))) where A is the minimum y value, B is the maximum y value, C is the log EC50 value, and D is the slope factor. +++ means <1 nm; ++ means ≥1 nm and ≤10 nm and + means >10 nm.
Claims (22)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/551,080 US20220105091A1 (en) | 2017-12-20 | 2021-12-14 | Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762608458P | 2017-12-20 | 2017-12-20 | |
PCT/IB2018/060295 WO2019123285A1 (en) | 2017-12-20 | 2018-12-19 | Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals |
US202016956527A | 2020-06-19 | 2020-06-19 | |
US17/551,080 US20220105091A1 (en) | 2017-12-20 | 2021-12-14 | Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2018/060295 Continuation WO2019123285A1 (en) | 2017-12-20 | 2018-12-19 | Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals |
US16/956,527 Continuation US11234977B2 (en) | 2017-12-20 | 2018-12-19 | Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals |
Publications (1)
Publication Number | Publication Date |
---|---|
US20220105091A1 true US20220105091A1 (en) | 2022-04-07 |
Family
ID=65269002
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/956,527 Active 2039-01-18 US11234977B2 (en) | 2017-12-20 | 2018-12-19 | Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals |
US17/551,080 Abandoned US20220105091A1 (en) | 2017-12-20 | 2021-12-14 | Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/956,527 Active 2039-01-18 US11234977B2 (en) | 2017-12-20 | 2018-12-19 | Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals |
Country Status (5)
Country | Link |
---|---|
US (2) | US11234977B2 (en) |
EP (1) | EP3728266A1 (en) |
JP (1) | JP2021507906A (en) |
CN (1) | CN111433210A (en) |
WO (1) | WO2019123285A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024077024A3 (en) * | 2022-10-04 | 2024-05-30 | Bluejay Therapeutics, Inc. | Indazole pyridone compounds and uses thereof |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10738035B2 (en) | 2015-05-13 | 2020-08-11 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
EP3426245B1 (en) | 2016-03-07 | 2022-12-14 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
KR102556744B1 (en) | 2017-08-28 | 2023-07-18 | 이난타 파마슈티칼스, 인코포레이티드 | Hepatitis B antivirals |
EP3728266A1 (en) * | 2017-12-20 | 2020-10-28 | Novartis AG | Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals |
US11058678B2 (en) | 2018-01-22 | 2021-07-13 | Enanta Pharmaceuticals, Inc. | Substituted heterocycles as antiviral agents |
US10729688B2 (en) | 2018-03-29 | 2020-08-04 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
CA3113235A1 (en) | 2018-09-21 | 2020-03-26 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
EP3856740A4 (en) | 2018-09-30 | 2021-12-15 | Sunshine Lake Pharma Co., Ltd. | Fused tetracyclic compounds and uses thereof in medicine |
EP3883570A4 (en) | 2018-11-21 | 2022-07-13 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
WO2020247444A1 (en) | 2019-06-03 | 2020-12-10 | Enanta Pharmaceuticals, Inc, | Hepatitis b antiviral agents |
WO2020247575A1 (en) | 2019-06-04 | 2020-12-10 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
US11760755B2 (en) | 2019-06-04 | 2023-09-19 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
US11738019B2 (en) | 2019-07-11 | 2023-08-29 | Enanta Pharmaceuticals, Inc. | Substituted heterocycles as antiviral agents |
CN112300161B (en) * | 2019-07-30 | 2021-10-29 | 上海挚盟医药科技有限公司 | Compound for treating and/or preventing hepatitis B virus infection and preparation method and application thereof |
WO2021055425A2 (en) | 2019-09-17 | 2021-03-25 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
WO2021188414A1 (en) | 2020-03-16 | 2021-09-23 | Enanta Pharmaceuticals, Inc. | Functionalized heterocyclic compounds as antiviral agents |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11234977B2 (en) * | 2017-12-20 | 2022-02-01 | Novartis Ag | Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals |
Family Cites Families (65)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3381783D1 (en) | 1982-03-03 | 1990-09-13 | Genentech Inc | HUMAN ANTITHROMBIN III, DNA SEQUENCES THEREFOR, EXPRESSION AND CLONING VECTORS CONTAINING SUCH SEQUENCES AND THEREFORE TRANSFORMED CELL CULTURES, METHOD FOR EXPRESSING HUMAN ANTITHROMBIN III AND THESE CONTAINERS. |
GB9514465D0 (en) | 1995-07-14 | 1995-09-13 | Glaxo Lab Sa | Chemical compounds |
DE69738749D1 (en) | 1996-08-16 | 2008-07-17 | Schering Corp | CELL SURFACE ANTIGEN FROM MAMMALS AND RELATED REAGENTS |
US6111090A (en) | 1996-08-16 | 2000-08-29 | Schering Corporation | Mammalian cell surface antigens; related reagents |
US6509173B1 (en) | 1997-10-21 | 2003-01-21 | Human Genome Sciences, Inc. | Human tumor necrosis factor receptor-like proteins TR11, TR11SV1, and TR11SV2 |
AU2591599A (en) | 1998-02-09 | 1999-08-23 | Genentech Inc. | Novel tumor necrosis factor receptor homolog and nucleic acids encoding the same |
IL147442A0 (en) | 1999-07-12 | 2002-08-14 | Genentech Inc | Promotion or inhibition of angiogenesis and cardiovscularization by tumor necrosis factor ligand/receptor homologs |
EP1576014B1 (en) | 2002-12-23 | 2011-06-29 | Wyeth LLC | Antibodies against pd-1 and uses thereof |
CA2514733A1 (en) | 2003-02-28 | 2004-09-16 | Transform Pharmaceuticals, Inc. | Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen |
US7618632B2 (en) | 2003-05-23 | 2009-11-17 | Wyeth | Method of treating or ameliorating an immune cell associated pathology using GITR ligand antibodies |
WO2005007190A1 (en) | 2003-07-11 | 2005-01-27 | Schering Corporation | Agonists or antagonists of the clucocorticoid-induced tumour necrosis factor receptor (gitr) or its ligand for the treatment of immune disorders, infections and cancer |
JP2007518399A (en) | 2003-12-02 | 2007-07-12 | ジェンザイム コーポレイション | Compositions and methods for diagnosing and treating lung cancer |
GB0409799D0 (en) | 2004-04-30 | 2004-06-09 | Isis Innovation | Method of generating improved immune response |
US20060002932A1 (en) | 2004-06-04 | 2006-01-05 | Duke University | Methods and compositions for enhancement of immunity by in vivo depletion of immunosuppressive cell activity |
PE20060607A1 (en) | 2004-10-26 | 2006-07-14 | Angeletti P Ist Richerche Bio | TETRACYCLIC INDEOL DERIVATIVES AS ANTIVIRAL AGENTS |
US7812135B2 (en) | 2005-03-25 | 2010-10-12 | Tolerrx, Inc. | GITR-binding antibodies |
KR101339628B1 (en) | 2005-05-09 | 2013-12-09 | 메다렉스, 인코포레이티드 | Human monoclonal antibodies to programmed death 1 (pd-1) and methods for treating cancer using anti-pd-1 antibodies alone or in combination with other immunotherapeutics |
KR101888321B1 (en) | 2005-07-01 | 2018-08-13 | 이. 알. 스퀴부 앤드 선즈, 엘.엘.씨. | Human monoclonal antibodies to programmed death ligand 1(pd-l1) |
EP1981969A4 (en) | 2006-01-19 | 2009-06-03 | Genzyme Corp | Gitr antibodies for the treatment of cancer |
PL2170959T3 (en) | 2007-06-18 | 2014-03-31 | Merck Sharp & Dohme | Antibodies to human programmed death receptor pd-1 |
CA2693677C (en) | 2007-07-12 | 2018-02-13 | Tolerx, Inc. | Combination therapies employing gitr binding molecules |
CA2702132A1 (en) | 2007-10-10 | 2009-04-16 | Novartis Ag | Spiropyrrolidines and their use against hcv and hiv infection |
CN101970499B (en) | 2008-02-11 | 2014-12-31 | 治疗科技公司 | Monoclonal antibodies for tumor treatment |
EP2262837A4 (en) | 2008-03-12 | 2011-04-06 | Merck Sharp & Dohme | Pd-1 binding proteins |
KR20110044992A (en) | 2008-07-02 | 2011-05-03 | 이머전트 프로덕트 디벨롭먼트 시애틀, 엘엘씨 | TVF-β antagonist multi-target binding protein |
AR072999A1 (en) | 2008-08-11 | 2010-10-06 | Medarex Inc | HUMAN ANTIBODIES THAT JOIN GEN 3 OF LYMPHOCYTARY ACTIVATION (LAG-3) AND THE USES OF THESE |
CA2735006A1 (en) | 2008-08-25 | 2010-03-11 | Amplimmune, Inc. | Pd-1 antagonists and methods of use thereof |
PL2350129T3 (en) | 2008-08-25 | 2015-12-31 | Amplimmune Inc | Compositions of pd-1 antagonists and methods of use |
US8586023B2 (en) | 2008-09-12 | 2013-11-19 | Mie University | Cell capable of expressing exogenous GITR ligand |
KR20210060670A (en) | 2008-12-09 | 2021-05-26 | 제넨테크, 인크. | Anti-pd-l1 antibodies and their use to enhance t-cell function |
WO2010089411A2 (en) | 2009-02-09 | 2010-08-12 | Universite De La Mediterranee | Pd-1 antibodies and pd-l1 antibodies and uses thereof |
WO2010098367A1 (en) | 2009-02-25 | 2010-09-02 | Banyu Pharmaceutical Co.,Ltd. | Pyrimidopyrimidoindazole derivative |
US8512690B2 (en) | 2009-04-10 | 2013-08-20 | Novartis Ag | Derivatised proline containing peptide compounds as protease inhibitors |
CA3067609A1 (en) | 2009-09-03 | 2011-03-10 | Merck Sharp & Dohme Corp. | Anti-gitr antibodies |
GB0919054D0 (en) | 2009-10-30 | 2009-12-16 | Isis Innovation | Treatment of obesity |
US20130017199A1 (en) | 2009-11-24 | 2013-01-17 | AMPLIMMUNE ,Inc. a corporation | Simultaneous inhibition of pd-l1/pd-l2 |
US20130089554A1 (en) | 2009-12-29 | 2013-04-11 | Emergent Product Development Seattle, Llc | RON Binding Constructs and Methods of Use Thereof |
WO2013039954A1 (en) | 2011-09-14 | 2013-03-21 | Sanofi | Anti-gitr antibodies |
CA2856895C (en) | 2011-11-28 | 2021-10-26 | Merck Patent Gmbh | Anti-pd-l1 antibodies and uses thereof |
EA037918B1 (en) | 2011-12-21 | 2021-06-07 | Новира Терапьютикс, Инк. | Hepatitis b antiviral agents |
AR091649A1 (en) | 2012-07-02 | 2015-02-18 | Bristol Myers Squibb Co | OPTIMIZATION OF ANTIBODIES THAT FIX THE LYMPHOCYTE ACTIVATION GEN 3 (LAG-3) AND ITS USES |
EP2970307B1 (en) * | 2013-03-13 | 2020-03-11 | Genentech, Inc. | Pyrazolo compounds and uses thereof |
CA2931329A1 (en) | 2014-01-30 | 2015-08-06 | F. Hoffmann-La Roche Ag | Novel dihydroquinolizinones for the treatment and prophylaxis of hepatitis b virus infection |
RS58384B1 (en) | 2014-03-07 | 2019-04-30 | Hoffmann La Roche | Novel 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection |
CN106459032B (en) * | 2014-05-13 | 2019-04-05 | 豪夫迈·罗氏有限公司 | Treat and prevent hepatitis b virus infected new dihydro Quinolizinone type |
CA2952541C (en) | 2014-08-14 | 2019-10-01 | F. Hoffmann-La Roche Ag | Pyridazones and triazinones for the treatment and prophylaxis of hepatitis b virus infection |
US9637485B2 (en) * | 2014-11-03 | 2017-05-02 | Hoffmann-La Roche Inc. | 6,7-dihydrobenzo[a]quinolizin-2-one derivatives for the treatment and prophylaxis of hepatitis B virus infection |
JP6435054B2 (en) * | 2015-02-11 | 2018-12-05 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Novel 2-oxo-6,7-dihydrobenzo [a] quinolidine-3-carboxylic acid derivatives for the treatment and prevention of hepatitis B virus infection |
WO2017016960A1 (en) | 2015-07-24 | 2017-02-02 | F. Hoffmann-La Roche Ag | Process for the preparation of (6s)-6-alkyl-10-alkoxy-9-(substituted alkoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid analogues |
WO2017016921A1 (en) | 2015-07-24 | 2017-02-02 | F. Hoffmann-La Roche Ag | New crystalline forms of (6s)-10-methoxy-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid |
WO2017017042A1 (en) | 2015-07-27 | 2017-02-02 | F. Hoffmann-La Roche Ag | Novel tetracyclic 4-oxo-pyridine-3-carboxylic acid derivatives for the treatment and prophylaxis of hepatitis b virus infection |
WO2017102648A1 (en) | 2015-12-15 | 2017-06-22 | F. Hoffmann-La Roche Ag | Combination therapy of an hbsag inhibitor and a nucleos(t)ide analogue |
WO2017108630A1 (en) | 2015-12-21 | 2017-06-29 | F. Hoffmann-La Roche Ag | Combination therapy of an hbsag inhibitor and an hbv capsid assembly inhibitor |
WO2017114812A1 (en) | 2015-12-29 | 2017-07-06 | F. Hoffmann-La Roche Ag | Combination therapy of an hbsag inhibitor and an interferon |
AU2017219216B2 (en) | 2016-02-19 | 2019-12-19 | Novartis Ag | Tetracyclic pyridone compounds as antivirals |
WO2017216686A1 (en) | 2016-06-16 | 2017-12-21 | Novartis Ag | 8,9-fused 2-oxo-6,7-dihydropyrido-isoquinoline compounds as antivirals |
WO2017216685A1 (en) | 2016-06-16 | 2017-12-21 | Novartis Ag | Pentacyclic pyridone compounds as antivirals |
TW201811788A (en) | 2016-09-09 | 2018-04-01 | 瑞士商諾華公司 | Polycyclic pyridone compounds as antivirals |
TW201819380A (en) | 2016-10-18 | 2018-06-01 | 瑞士商諾華公司 | Fused tetracyclic pyridone compounds as antivirals |
KR102522060B1 (en) * | 2016-11-07 | 2023-04-14 | 아뷰터스 바이오파마 코포레이션 | Substituted pyridinone-containing tricyclic compounds and methods of use thereof |
CN106928215B (en) | 2017-03-06 | 2019-03-22 | 河南春风医药科技有限公司 | A kind of preparation method of Quinolizinone type compounds |
CN106928245B (en) | 2017-03-06 | 2019-06-11 | 河南春风医药科技有限公司 | A kind of Quinolizinone type compounds and its preparation method and application |
AR111419A1 (en) | 2017-04-27 | 2019-07-10 | Novartis Ag | INDAZOL PIRIDONA FUSIONED COMPOUNDS AS ANTIVIRALS |
CN108530449B (en) * | 2017-05-22 | 2021-05-07 | 河南春风医药科技有限公司 | Compound for treating or preventing hepatitis B virus infection and preparation method and application thereof |
EP3883570A4 (en) * | 2018-11-21 | 2022-07-13 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
-
2018
- 2018-12-19 EP EP18842653.0A patent/EP3728266A1/en not_active Withdrawn
- 2018-12-19 US US16/956,527 patent/US11234977B2/en active Active
- 2018-12-19 JP JP2020534172A patent/JP2021507906A/en active Pending
- 2018-12-19 CN CN201880077996.2A patent/CN111433210A/en active Pending
- 2018-12-19 WO PCT/IB2018/060295 patent/WO2019123285A1/en unknown
-
2021
- 2021-12-14 US US17/551,080 patent/US20220105091A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11234977B2 (en) * | 2017-12-20 | 2022-02-01 | Novartis Ag | Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024077024A3 (en) * | 2022-10-04 | 2024-05-30 | Bluejay Therapeutics, Inc. | Indazole pyridone compounds and uses thereof |
Also Published As
Publication number | Publication date |
---|---|
JP2021507906A (en) | 2021-02-25 |
CN111433210A (en) | 2020-07-17 |
US11234977B2 (en) | 2022-02-01 |
EP3728266A1 (en) | 2020-10-28 |
US20210346377A1 (en) | 2021-11-11 |
WO2019123285A1 (en) | 2019-06-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11234977B2 (en) | Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals | |
US10093673B2 (en) | Tetracyclic pyridone compounds as antivirals | |
US10975078B2 (en) | Fused indazole pyridone compounds as antivirals | |
WO2018073753A1 (en) | Fused tetracyclic pyridone compounds as antivirals | |
WO2018047109A1 (en) | Polycyclic pyridone compounds as antivirals | |
US20200407365A1 (en) | Indole-2-carbonyl compounds and their use for the treatment of hepatitis b | |
WO2017216686A1 (en) | 8,9-fused 2-oxo-6,7-dihydropyrido-isoquinoline compounds as antivirals | |
WO2017216685A1 (en) | Pentacyclic pyridone compounds as antivirals | |
US20210079015A1 (en) | Novel dihydroisoxazole compounds and their use for the treatment of hepatitis b |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
AS | Assignment |
Owner name: NOVARTIS AG, SWITZERLAND Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH INC.;REEL/FRAME:059007/0866 Effective date: 20180207 Owner name: NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH INC., MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:FU, JIPING;HAN, WOOSEOK;JIN, XIANMING;AND OTHERS;SIGNING DATES FROM 20180105 TO 20180108;REEL/FRAME:059007/0848 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |