WO2016123905A1 - Novel phosphoramidates for treatment of hcv infection - Google Patents
Novel phosphoramidates for treatment of hcv infection Download PDFInfo
- Publication number
- WO2016123905A1 WO2016123905A1 PCT/CN2015/084044 CN2015084044W WO2016123905A1 WO 2016123905 A1 WO2016123905 A1 WO 2016123905A1 CN 2015084044 W CN2015084044 W CN 2015084044W WO 2016123905 A1 WO2016123905 A1 WO 2016123905A1
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- WO
- WIPO (PCT)
- Prior art keywords
- compound
- fluoro
- dihydropyrimidin
- phosphoryl
- dioxo
- Prior art date
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- 238000011282 treatment Methods 0.000 title claims description 7
- 208000015181 infectious disease Diseases 0.000 title abstract description 13
- 150000008298 phosphoramidates Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 130
- -1 compounds compound Chemical class 0.000 claims abstract description 59
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 17
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- 229940002612 prodrug Drugs 0.000 claims abstract description 3
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- 125000000217 alkyl group Chemical group 0.000 claims description 42
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- 239000012470 diluted sample Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- ROBXZHNBBCHEIQ-BYPYZUCNSA-N ethyl (2s)-2-aminopropanoate Chemical compound CCOC(=O)[C@H](C)N ROBXZHNBBCHEIQ-BYPYZUCNSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003870 intestinal permeability Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
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- 208000019423 liver disease Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- XJGVXQDUIWGIRW-UHFFFAOYSA-N loxapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2OC2=CC=C(Cl)C=C12 XJGVXQDUIWGIRW-UHFFFAOYSA-N 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 229940078552 o-xylene Drugs 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- UHHKSVZZTYJVEG-UHFFFAOYSA-N oxepane Chemical compound C1CCCOCC1 UHHKSVZZTYJVEG-UHFFFAOYSA-N 0.000 description 1
- ATYBXHSAIOKLMG-UHFFFAOYSA-N oxepin Chemical compound O1C=CC=CC=C1 ATYBXHSAIOKLMG-UHFFFAOYSA-N 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical group NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000005412 pyrazyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- 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 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000012899 standard injection Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JWCVYQRPINPYQJ-UHFFFAOYSA-N thiepane Chemical compound C1CCCSCC1 JWCVYQRPINPYQJ-UHFFFAOYSA-N 0.000 description 1
- BISQTCXKVNCDDA-UHFFFAOYSA-N thiepine Chemical compound S1C=CC=CC=C1 BISQTCXKVNCDDA-UHFFFAOYSA-N 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- HPINPCFOKNNWNW-UHFFFAOYSA-N thiete Chemical compound C1SC=C1 HPINPCFOKNNWNW-UHFFFAOYSA-N 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- JTQAPFZZCXWQNQ-UHFFFAOYSA-N thiirene Chemical compound S1C=C1 JTQAPFZZCXWQNQ-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 239000013026 undiluted sample Substances 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Definitions
- Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2 ⁇ 15% of the world's population.
- chronic liver disease such as cirrhosis and hepatocellular carcinoma
- According to the World Health Organization there are more than 200 million infected individuals worldwide, with at least 3 to 4 million people being infected each year. Once infected, about 20% of people clear the virus, but the rest can harbor HCV for the rest of their lives.
- Ten to twenty percent of chronically infected individuals eventually develop liver ⁇ destroying cirrhosis or cancer.
- the viral disease is transmitted parenterally by contaminated blood and blood products, contaminated needles, or sexually and vertically from infected mothers or carrier mothers to their offspring.
- Current treatments for HCV infection which are restricted to immunotherapy with recombinant interferon ⁇ alone or in combination with the nucleoside analog ribavirin, are of limited clinical benefit.
- the present invention provides compounds that promise to provide the much needed solution.
- the present invention provides compounds of Formula (I) shown below.
- R 1 is aryl or heteroaryl
- each of R 2 and R 3 is hydrogen, alkyl, or heteroaryl, provided that when one of R 2 and R 3 is hydrogen or alkyl, the other one must be heteroaryl; or
- R 2 and R 3 together with the nitrogen atom to which they are attached, form a 5 ⁇ to 7 ⁇ membered heterocyclic ring optionally having one or two more heteroatoms (in addition to the nitrogen atom to which R 2 and R 3 are attached) each of which is independently O, S, or NR 6 , wherein R 6 is hydrogen, alkyl, acyl, aryl, or heteroaryl; the heterocyclic ring is optionally substituted at its ring carbon atom (s) with alkyl, halo, or alkoxycarbony; or
- R 4 is hydrogen or alkyl
- R 5 is hydrogen or alkyl
- X is a bond, O, NH, or N ⁇ alkyl
- n 1, 2, 3, or 4.
- R 1 is aryl or heteroaryl.
- R 1 can be phenyl and optionally substituted with 1 ⁇ 3 substituents each of which is independently halo or alkyl.
- R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R 2 is H, and R 3 is heteroaryl.
- R 3 can be pyridinyl or isoquinolinyl. Specific examples of R 3 include
- R 2 and R 3 together with the nitrogen atom to which they are attached, form a 5 ⁇ or 6 ⁇ membered heterocyclic ring, optionally with one or two more ring hetero atoms (in addition to the nitrogen atom to which R 2 and R 3 are attached) each of which is independently O, S, or NR 6 , wherein R 6 is hydrogen, alkyl, or aryl; and the heterocyclic ring is optionally substituted at its ring carbon atom with one or more alkoxycarbonyl.
- the heterocyclic ring can be
- R 2 and R 3 together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl.
- the heteroaryl can be
- R 4 is methyl or ethyl.
- R 5 is methyl, ethyl or isopropyl.
- X is a bond, O, NH, or N ⁇ alkyl.
- the phosphorous atom is chiral and at least 90% (e.g., at least 97%) is of the S steoroisomer.
- n 1, 2, 3, or 4.
- the compounds of this invention are pharmaceutically acceptable salt of Formula (I) .
- salts include acetate, 4 ⁇ toluenesulfonate, hydrobromide, or hydrochloride salts.
- the present invention provides pharmaceutical compositions comprising at least a compound described above and a pharmaceutically acceptable medium.
- Such pharmaceutical compositions can be useful for the treatment of HCV infection in a human.
- the present invention provides a method for treating HCV infection, comprising administering to an HCV ⁇ infected human patient with a compound or a pharmaceutical composition of this invention. In some embodiments, the method further includes administering another antiviral agent that is different from the compounds of this invention.
- Yet still another aspect of the present invention relates to the use of a compound of this invention for the manufacture of a medicament for treating HCV infection.
- the compounds of this invention have unexpectedly shown advantages that are significant for making the compounds of this invention more ideal for clinical use. Such advantages include but are not limited to the abilities of forming pharmaceutically acceptable salts that improve the compounds’ water solubility and stabilities and exhibiting similar or even better pharmaceutical effect, therefore making pharmaceutical compositions containing the compounds of this invention more suitable for clinical use or therapeutic treatment.
- a or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound.
- a compound refers to one or more compounds or at least one compound.
- the terms “a” (or “an” ) , “one or more” , and “at least one” can be used interchangeably herein.
- P* means that the phosphorus atom is chiral and that it has a corresponding Cahn ⁇ Ingold ⁇ Prelog designation of “R” or “S” which have their accepted plain meanings.
- purified refers to the purity of a given compound.
- a compound is “purified” when the given compound is a major component of the composition, i.e., at least 50% w/w pure.
- purified embraces at least 50% w/w purity, at least 60% w/w purity, at least 70% purity, at least 80% purity, at least 85% purity, at least 90% purity, at least 92% purity, at least 94% purity, at least 96% purity, at least 97% purity, at least 98% purity, at least 99% purity, at least 99.5% purity, and at least 99.9% purity, wherein “substantially pure” embraces at least 97% purity, at least 98% purity, at least 99% purity, at least 99.5% purity, and at least 99.9% purity, wherein “substantially pure” embraces at least 97% purity, at least 98% purity, at least 99% purity, at least 99.5% purity, and at least 99.9% purity
- metabolite refers to a compound produced in vivo after administration to a subject in need thereof.
- substantially anhydrous means that a substance contains at most 10% by weight of water, preferably at most 1% by weight of water, more preferably at most 0.5% by weight of water, and most preferably at most 0.1% by weight of water.
- prodrug refers to a bioreversible derivative of a drug molecule that undergoes an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. Additional description can be found in, e.g., J. Rautio et al., Nat Rev Drug Discov., 2008 Mar; 7 (3) : 255 ⁇ 70, which is incorporated hereby by reference in its entirety.
- a solvent or anti ⁇ solvent (as used in reactions, crystallization, etc. or lattice and/or adsorbed solvents) includes at least one of a C 1 to C 8 alcohol, a C 2 to C 8 ether, a C 3 to C 7 ketone, a C 3 to C 7 ester, a C 1 to C 2 chlorocarbon, a C 2 to C 7 nitrile, a miscellaneous solvent, a C 5 to C 12 saturated hydrocarbon, and a C 6 to C 12 aromatic hydrocarbon.
- the C 1 to C 8 alcohol refers to a straight/branched and/or cyclic/acyclic alcohol having such number of carbons.
- the C 1 to C 8 alcohol includes, but is not limited to, methanol, ethanol, n ⁇ propanol, isopropanol, isobutanol, hexanol, and cyclohexanol.
- the C 2 to C 8 ether refers to a straight/branched and/or cyclic/acyclic ether having such number of carbons.
- the C 2 to C 8 ether includes, but is not limited to, dimethyl ether, diethyl ether, di ⁇ isopropyl ether, di ⁇ n ⁇ butyl ether, methyl ⁇ t ⁇ butyl ether (MTBE) , tetrahydrofuran, and dioxane.
- the C 3 to C 7 ketone refers to a straight/branched and/or cyclic/acyclic ketone having such number of carbons.
- the C 3 to C 7 ketone includes, but is not limited to, acetone, methyl ethyl ketone, propanone, butanone, methyl isobutyl ketone, methyl butyl ketone, and cyclohexanone.
- the C 3 to C 7 ester refers to a straight/branched and/or cyclic/acyclic ester having such number of carbons.
- the C 3 to C 7 ester includes, but is not limited to, ethyl acetate, propyl acetate, n ⁇ butyl acetate, etc.
- the C 1 to C 2 chlorocarbon refers to a chlorocarbon having such number of carbons.
- the C 1 to C 2 chlorocarbon includes, but is not limited to, chloroform, methylene chloride (DCM) , carbon tetrachloride, 1, 2 ⁇ dichloroethane, and tetrachloroethane.
- a C 2 to C 7 nitrile refers to a nitrile have such number of carbons.
- the C 2 to C 7 nitrile includes, but is not limited to, acetonitrile, propionitrile, etc.
- a miscellaneous solvent refers to a solvent commonly employed in organic chemistry, which includes, but is not limited to, diethylene glycol, diglyme (diethylene glycol dimethyl ether) , 1, 2 ⁇ dimethoxy ⁇ ethane, dimethylformamide, dimethylsulfoxide, ethylene glycol, glycerin, hexamethylphsphoramide, hexamethylphosphoroustriame, N ⁇ methyl ⁇ 2 ⁇ pyrrolidinone, nitromethane, pyridine, triethyl amine, and acetic acid.
- the term C 5 to C 12 saturated hydrocarbon refers to a straight/branched and/or cyclic/acyclic hydrocarbon.
- the C 5 to C 12 saturated hydrocarbon includes, but is not limited to, n ⁇ pentane, petroleum ether (ligroine) , n ⁇ hexane, n ⁇ heptane, cyclohexane, and cycloheptane.
- C 6 to C 12 aromatic refers to substituted and unsubstituted hydrocarbons having a phenyl group as their backbone.
- Preferred hydrocarbons include benzene, xylene, toluene, chlorobenzene, o ⁇ xylene, m ⁇ xylene, p ⁇ xylene, xylenes, with toluene being more preferred.
- halo or “halogen” as used herein, includes chloro, bromo, iodo and fluoro.
- blocking group refers to a chemical group which exhibits the following characteristics.
- the “group” is derived from a “protecting compound. ” Groups that are selective for primary hydroxyls over secondary hydroxyls that can be put on under conditions consistent with the stability of the phosphoramidate (pH 2 ⁇ 8) and impart on the resulting product substantially different physical properties allowing for an easier separation of the 3’ ⁇ phosphoramidate ⁇ 5’ ⁇ new group product from the unreacted desired compound.
- the group must react selectively in good yield to give a protected substrate that is stable to the projected reactions (see Protective Groups in Organic Synthesis, 3nd ed. T.W. Greene and P.G.M.
- Examples of groups include, but are not limited to: benzoyl, acetyl, phenyl ⁇ substituted benzoyl, tetrahydropyranyl, trityl, DMT (4, 4’ ⁇ dimethoxytrityl) , MMT (4 ⁇ monomethoxytrityl) , trimethoxytrityl, pixyl (9 ⁇ phenylxanthen ⁇ 9 ⁇ yl) group, thiopixyl (9 ⁇ phenylthioxanthen ⁇ 9 ⁇ yl) or 9 ⁇ (p ⁇ methoxyphenyl) xanthine ⁇ 9 ⁇ yl (MOX) , etc.; C (O) ⁇ alkyl, C (O) Ph, C (O) aryl, CH2O ⁇ alkyl, CH2O ⁇ aryl, SO2 ⁇ alkyl, SO2 ⁇ aryl, tert ⁇ butyldi
- Acetals such as MOM or THP and the like are considered possible groups. Fluorinated compounds are also contemplated in so far that they can be attached to the compound and can be selectively removed by passing through a fluorous solid phase extraction media ( ) .
- a specific example includes a fluorinated trityl analog, trityl analog 1 ⁇ [4 ⁇ (1H, 1H, 2H, 2H ⁇ perfluorodecyl) phenyl) ⁇ 1, 1 ⁇ diphenylmethanol.
- fluorinated analogs of trityl, BOC, FMOC, CBz, etc. are also contemplated.
- Sulfonyl chlorides like p ⁇ toluenesulfonyl chloride can react selectively on the 5′ position.
- Esters could be formed selectively such as acetates and benzoates.
- Dicarboxylic anhydrides such as succinic anhydride and its derivatives can be used to generate an ester linkage with a free carboxylic acid, such examples include, but are not limited to oxalyl, malonyl, succinyl, glutaryl, adipyl, pimelyl, superyl, azelayl, sebacyl, phthalyl, isophthalyl, terephthalyl, etc.
- the free carboxylic acid increases the polarity dramatically and can also be used as a handle to extract the reaction product into mildy basic aqueous phases such as sodium bicarbonate solutions.
- the phosphoramidate group is relatively stable in acidic media, so groups requiring acidic reaction conditions, such as, tetrahydropyranyl, could also be used.
- protecting group which is derived from a “protecting compound, ” has its plain and ordinary meaning, i.e., at least one protecting or blocking group is bound to at least one functional group (e.g., —OH, —NH 2 , etc. ) that allows chemical modification of at least one other functional group.
- protecting groups include, but are not limited to, benzoyl, acetyl, phenyl ⁇ substituted benzoyl, tetrahydropyranyl, trityl, DMT (4, 4’ ⁇ dimethoxytrityl) , MMT (4 ⁇ monomethoxytrityl) , trimethoxytrityl, pixyl (9 ⁇ phenylxanthen ⁇ 9 ⁇ yl) group, thiopixyl (9 ⁇ phenylthioxanthen ⁇ 9 ⁇ yl) or 9 ⁇ (p ⁇ methoxyphenyl) xanthine ⁇ 9 ⁇ yl (MOX) , etc.; C (O) ⁇ alkyl, C (O) Ph, C (O) aryl, C (O) O (lower alkyl) , C (O) O (lower alkylene) aryl (e.g., —C (O) OCH2Ph) , C (O) Oaryl, CH 2 O
- protecting compound refers to a compound that contains a “protecting group” and that is capable of reacting with a compound that contains functional groups that are capable of being protected.
- the term “leaving group” has the same meaning to the skilled artisan (Advanced Organic Chemistry: reactions, mechanisms and structure —Fourth Edition by Jerry March, John Wiley and Sons Ed.; 1992 pages 351 ⁇ 357) and represents a group which is part of and attached to a substrate molecule; in a reaction where the substrate molecule undergoes a displacement reaction (with for example a nucleophile) , the leaving group is then displaced.
- leaving groups include, but are not limited to: halogen (F, Cl, Br, and I) , preferably Cl, Br, or I; tosylate, mesylate, triflate, acetate, camphorsulfonate, aryloxide, and aryloxide substituted with at least one electron withdrawing group (e.g., p ⁇ nitrophenoxide, 2 ⁇ chlorophenoxide, 4 ⁇ chlorophenoxide, 2, 4 ⁇ dinitrophenoxide, pentafluorophenoxide, etc. ) , etc.
- electron withdrawing group is accorded its plain meaning here.
- electron withdrawing groups include, but are not limited to, a halogen, ⁇ NO2, ⁇ C (O) (lower alkyl) , ⁇ C (O) (aryl) , ⁇ C (O) O (lower alkyl) , ⁇ C (O) O (aryl) , etc.
- basic reagent means a compound that is capable of deprotonating a hydroxyl group.
- Examples of basic reagents include, but are not limited to, a (lower alk) oxide ( (lower alkyl) OM) in combination with an alcoholic solvent, where (lower alk) oxides include, but are not limited to, MeO-, EtO-, nPrO-, iPrO-, tBuO-, iAmO ⁇ (iso ⁇ amyloxide) , etc., and where M is an alkali metal cation, such as Li+, Na+, K+, etc.
- Alcoholic solvents include (lower alkyl) OH, such as, for example, MeOH, EtOH, nPrOH, iPrOH, tBuOH, iAmOH, etc.
- Non ⁇ alkoxy bases can also be used such as sodium hydride, sodium hexamethyldisilazane, lithium hexamethyldisilazane, lithium diisopropylamide, calcium hydride, sodium carbonate, potassium carbonate, cesium carbonate, DBU, DBN, Grignard reagents, such as (lower alkyl) Mg (halogen) , which include but are not limited to MeMgCl, MeMgBr, tBuMgCl, tBuMgBr, etc.
- base embraces the term “basic reagent” and is meant to be a compound that is capable of deprotonating a proton containing compound, i.e., a Bronsted base.
- a base include, but are not limited to pyridine, collidine, 2, 6 ⁇ (loweralkyl) ⁇ pyridine, dimethyl ⁇ aniline, imidazole, N ⁇ methyl ⁇ imidazole, pyrazole, N ⁇ methyl ⁇ pyrazole, triethylamine, di ⁇ isopropylethylamine, etc.
- electron withdrawing group is accorded its plain meaning Examples of electron withdrawing groups include, but are not limited to, a halogen (F, Cl, Br, or I) , ⁇ NO 2 , ⁇ C (O) (lower alkyl) , ⁇ C (O) (aryl) , ⁇ C (O) O (lower alkyl) , ⁇ C (O) O (aryl) , etc.
- co ⁇ crystallates include co ⁇ crystallates of 4, RP ⁇ 4, or SP ⁇ 4 in combination with salts, which embraces pharmaceutically acceptable salts.
- salts refers to a compound comprising a cation and an anion, which can produced by the protonation of a proton ⁇ accepting moiety and/or deprotonation of a proton ⁇ donating moiety. It should be noted that protonation of the proton ⁇ accepting moiety results in the formation of a cationic species in which the charge is balanced by the presence of a physiological anion, whereas deprotonation of the proton ⁇ donating moiety results in the formation of an anionic species in which the charge is balanced by the presence of a physiological cation.
- pharmaceutically acceptable salt means a salt that is pharmaceutically acceptable.
- pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonicacid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3 ⁇ (4 ⁇ hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2 ⁇ ethane ⁇ disulfonic acid, 2 ⁇ hydroxyethanesulfonic acid, benzenesulfonic acid, 4 ⁇ chlorobenzenesulfonic acid, 2 ⁇ naphthalenesulfonic acid, 4 ⁇ toluenesulfonic acid, camphorsulf
- alkyl refers to an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 30 carbon atoms.
- C 1 ⁇ M alkyl refers to an alkyl comprising 1 to M carbon atoms, where M is an integer having the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
- C 1 ⁇ 4 alkyl refers to an alkyl containing 1 to 4 carbon atoms.
- lower alkyl denotes a straight or branched chain hydrocarbon residue comprising 1 to 6 carbon atoms.
- C 1 ⁇ 20 alkyl refers to an alkyl comprising 1 to 20 carbon atoms.
- C 1 ⁇ 10 alkyl refers to an alkyl comprising 1 to 10 carbons.
- alkyl groups include, but are not limited to, lower alkyl groups include methyl, ethyl, propyl, i ⁇ propyl, n ⁇ butyl, i ⁇ butyl, t ⁇ butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.
- (ar) alkyl or (heteroaryl) alkyl indicate the alkyl group is substituted by an aryl or a heteroaryl group respectively.
- the term “lower alkyl” refers to an alkyl of 1 ⁇ 8 carbon atoms.
- alkoxy refers to “alkyl ⁇ O ⁇ “ .
- alkenyl refers to an unsubstituted hydrocarbon chain radical having from 2 to 10 carbon atoms having one or two olefinic double bonds, preferably one olefinic double bond.
- C 2 ⁇ N alkenyl refers to an alkenyl comprising 2 to N carbon atoms, where N is an integer having the following values: 3, 4, 5, 6, 7, 8, 9, or 10.
- C 2 ⁇ 10 alkenyl refers to an alkenyl comprising 2 to 10 carbon atoms.
- C 2 ⁇ 4 alkenyl refers to an alkenyl comprising 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, 1 ⁇ propenyl, 2 ⁇ propenyl (allyl) or 2 ⁇ butenyl (crotyl) .
- heterocyclic refers to a mono ⁇ or multiple ⁇ cyclic compound with at least one hetero atom selecting from O, S, N, or P.
- the heterocyclic compound can be aromatic (i.e., heteroaryl) or non ⁇ aromatic, saturated or non ⁇ saturated; and includes monocylic 3 ⁇ 8 member rings, and bi or tri fused ring systems.
- heterocyclic compounds include aziridine, oxirane, thiirane, azirine, oxirene, thiirene, azetidine, oxetane, thietane, azete, oxete, thiete, pyrrolidine, oxolane, thiolane, pyrrole, furan, thiophene, piperidine, oxane, thiane, pyridine, pyran, thiopyran, azepane, oxepane, thiepane, azepine, oxepine, thiepine, indole, quinolone, azepine, carbazole, acridine, and dibenzoazepine.
- aryl refers to substituted or unsubstituted single ring or multiple ⁇ ring fused system, such as phenyl (Ph) , biphenyl, or naphthyl.
- aryl unless otherwise specified, includes substituted and unsubstituted aryl group (e.g., phenyl or substituted phenyl) .
- the aryl group can be substituted with one or more moieties selected from among hydroxyl, F, Cl, Br, I, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T.W. Greene and P.G.M. Wuts, “Protective Groups in Organic Synthesis, ” 3rd ed., John Wiley &Sons, 1999.
- heteroaryl means a monocyclic ⁇ or polycyclic aromatic ring comprising carbon atoms, hydrogen atoms, and one or more heteroatoms (e.g., 1 to 3 heteroatoms) , independently selected from nitrogen, oxygen, and sulfur. As is well known to those skilled in the art, heteroaryl rings have less aromatic character than their all ⁇ carbon counter parts.
- heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1, 2, 3, ) ⁇ and (1, 2, 4) ⁇ triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, phenyl, isoxazolyl, and oxazolyl.
- a heteroaryl group can be unsubstituted or substituted with one or two suitable substituents.
- a heteroaryl group is a monocyclic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred to herein as " (C 2 ⁇ C 5 ) heteroaryl” .
- aryloxide refers to substituted or unsubstitutedphenoxide (PhO—) , p ⁇ phenyl ⁇ phenoxide (p ⁇ Ph ⁇ PhO ⁇ ) , or naphthoxide, preferably the term aryloxide refers to substituted or unsubstitutedphenoxide.
- the aryloxide group can be substituted with one or more moieties selected from among hydroxyl, F, Cl, Br, I, ⁇ C (O) (lower alkyl) , ⁇ C (O) O (lower alkyl) , amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T.W. Greene and P.G.M. Wuts, “Protective Groups in Organic Synthesis, ” 3rd ed., John Wiley &Sons, 1999.
- preparation or “dosage form” is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the desired dose and pharmacokinetic parameters.
- excipient refers to a compound that is used to prepare a pharmaceutical composition, and is generally safe, non ⁇ toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.
- crystalline refers to a situation where a solid sample of either SP ⁇ 4 or RP ⁇ 4 has crystalline characteristics when determined by X ⁇ ray powder diffraction or a single crystal X ⁇ ray technique.
- crystal ⁇ like refers to a situation where a solid sample of either SP ⁇ 4 or RP ⁇ 4 has crystalline characteristics when determined by one means, e.g., visually or by optical or polarizing microscopy, but does not have crystalline characteristics when determined by another means, e.g., x ⁇ ray powder diffraction.
- Methods of visually determining the crystallinity of a solid sample by visual or by optical or by polarizing microscopy are disclosed in USP ⁇ 695> and ⁇ 776> , both of which are incorporated by reference.
- a solid sample of either SP ⁇ 4 or RP ⁇ 4 that is “crystal ⁇ like” may be crystalline under certain conditions but may become non ⁇ crystalline when subjected to other conditions.
- amorphous refers to a situation where a solid sample of either SP ⁇ 4 or RP ⁇ 4 is neither crystalline nor crystal ⁇ like.
- Compound I ⁇ 3 was prepared according to the synthesis procedure of Compound I ⁇ 1, except that 2 ⁇ morpholinoacetic acid was replaced by 3 ⁇ morpholinopropanoic acid.
- Compound I ⁇ 5 was prepared according to the synthesis procedure of Compound I ⁇ 1, except that 2 ⁇ morpholinoacetic acid was replaced by 4 ⁇ morpholinobutanoic acid.
- Compound I ⁇ 7 was prepared according to the synthesis procedure of Compound I ⁇ 1, except that 2 ⁇ morpholinoacetic acid was replaced by 4 ⁇ (dimethylamino) butanoic acid.
- Compound I ⁇ 8 was prepared according to the synthesis procedures of Compound I ⁇ 1 and compound 2, except that 2 ⁇ morpholinoacetic acid was replaced by 4 ⁇ ( (tert ⁇ butoxycarbonyl) (pyridin ⁇ 2 ⁇ yl) amino) butanoic acid and 4 ⁇ methylbenzenesulfonic acid was substituted by HCl gas.
- Compound I ⁇ 9 was prepared according to the synthesis procedures of Compound I ⁇ 1 and compound 2, except that 2 ⁇ morpholinoacetic acid was replaced by 4 ⁇ ( (tert ⁇ butoxycarbonyl) (isoquinolin ⁇ 1 ⁇ yl) amino) butanoic acid and 4 ⁇ methylbenzenesulfonic acid was substituted by HCl gas.
- Compound I ⁇ 10 was prepared according to the synthesis procedure of Compound I ⁇ 1, except that 2 ⁇ morpholinoacetic acid was replaced by 2 ⁇ (7H ⁇ pyrrolo [2, 3 ⁇ b] pyridin ⁇ 7 ⁇ yl) acetic acid.
- Compound I ⁇ 11 was prepared according to the synthesis procedure of Compound I ⁇ 1, except that 2 ⁇ morpholinoacetic acid was replaced by 4 ⁇ (1H ⁇ pyrrolo [2, 3 ⁇ b] pyridin ⁇ 1 ⁇ yl) butanoic acid.
- Compound I ⁇ 12 was prepared according to the synthesis procedure of Compound I ⁇ 1, except that 2 ⁇ morpholinoacetic acid was replaced by 2 ⁇ (1H ⁇ pyrrolo [2, 3 ⁇ b] pyridin ⁇ 1 ⁇ yl) acetic acid.
- Compound I ⁇ 14 was prepared according to the synthesis procedure of Compound I ⁇ 13, except that compound 13 ⁇ 1 was replaced by ethyl L ⁇ alaninate.
- Example 15 Preparation of isopropyl ( (S) ⁇ ( ( (2R, 3R, 4R, 5R) ⁇ 5 ⁇ (2, 4 ⁇ dioxo ⁇ 3, 4 ⁇ dihydropyrimidin ⁇ 1 (2H) ⁇ yl) ⁇ 4 ⁇ fluoro ⁇ 4 ⁇ methyl ⁇ 3 ⁇ ( ( (3 ⁇ morpholinopropyl) carbamoyl) oxy) tetrahydrofuran ⁇ 2 ⁇ yl) methoxy) (phenoxy) phosphoryl) ⁇ L ⁇ alaninate (I ⁇ 15)
- Compound I ⁇ 16 was prepared according to the synthesis procedure of Compound I ⁇ 15, except that compound 1 was replaced by ethyl ( (S) ⁇ ( ( (2R, 3R, 4R, 5R) ⁇ 5 ⁇ (2, 4 ⁇ dioxo ⁇ 3, 4 ⁇ dihydropyrimidin ⁇ 1 (2H) ⁇ yl) ⁇ 4 ⁇ fluoro ⁇ 3 ⁇ hydroxy ⁇ 4 ⁇ methyltetrahydrofuran ⁇ 2 ⁇ yl) methoxy) (phenoxy) phosphoryl) ⁇ L ⁇ alaninate.
- Compound I ⁇ 17 was prepared according to the synthesis procedure of Compound I ⁇ 15, except that 3 ⁇ morpholinopropan ⁇ 1 ⁇ amine was replaced by 2 ⁇ (1H ⁇ pyrrolo [2, 3 ⁇ b] pyridin ⁇ 1 ⁇ yl) ethan ⁇ 1 ⁇ amine.
- Donor solution buffer HBSS buffer with 0.3% DMSO and 5 ⁇ M LY: add 150 ⁇ L DMSO and 50 ⁇ L LY (5mM) into 50 ml HBSS buffer (pH 7.4) ; HBSS buffer with 0.1% DMSO and 5 ⁇ M LY ; add 50 ⁇ L DMSO and 50 ⁇ L LY (5 mM) into 50 mL HBSS buffer (pH7.4) .
- Receiver solution buffer Prepare HBSS buffer with 0.4% DMSO: add 200 ⁇ L DMSO into 50 ml HBSS buffer (pH7.4 ) .
- Donor samples (1: 10 diluted) : 6 ⁇ L of donor sample + 54 ⁇ L 0.4% DMSO HBSS+ 60 ⁇ L ACN with IS (Osalmid or Imipramine) ;
- Receiver sample 60 ⁇ L of receiver sample+ 60 ⁇ L ACN with IS (Osalmid or Imipramine) .
- Aqueous solubility was determined by suspending a sufficient amount of compound in water to give a maximum final concentration of ⁇ 10 mg ⁇ ml -1 of the parent free ⁇ form of the compound. The suspension was equilibrated at 25 °C for 24 hours before the pH was measured. The suspension was then filtered through a glass fiber C filter into a 96 ⁇ well plate. The filtrate was then diluted by a factor of 101. Quantitation was by HPLC with reference to a standard solution of approximately 0.1 mg ⁇ ml -1 in DMSO. Different volumes of the standard, diluted and undiluted sample solutions were injected. The solubility was calculated using the peak areas determined by integration of the peak found at the same retention time as the principal peak in the standard injection.
- the compounds of this invention unexpectedly exhibited a much higher solubility that would make the compounds of this invention more ideal for manufacturing the pharmaceutical compositions of this invention and for clinical treatment of patients affected with HCV.
- Replicon containing cells were seeded at either 3,000 cells/well (50 ⁇ L) in 96 ⁇ well white/opaque plates, or 1,500 cells/well (25 ⁇ L) in 384 ⁇ well white/opaque plates. 50 ⁇ L of 2 ⁇ compound were added in the 96 ⁇ well plate or 25 ⁇ L of 2 ⁇ compound were added in the 384 well plate. The plates were incubated at 37°C. in a humidified 5% CO2 atmosphere for 4 days. After incubation, Bright ⁇ Glo reagent (50 ⁇ L for 96 ⁇ well plate, or 25 ⁇ L for 384 ⁇ well plate) was added to measure the firefly luciferase reporter for HCV replication. Percent inhibition was calculated against the no ⁇ drug control.
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Abstract
The present invention provides compounds compound of Formula (I) or a pharmaceutically accepted salt, ester, or prodrug thereof, and pharmaceutical compositions containing such compounds. Also within the present inventions are methods for treating HCV infection by using one or more of the compounds provided herein.
Description
Cross‐Reference to Related Application
This application claims priority to international application number PCT/CN2015/072391, filed on February 6, 2015, the contents of which are incorporated herein by reference in their entireties.
Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2‐15% of the world's population. There are an estimated 4.5 million infected people in the United States alone, according to the U.S. Center for Disease Control. According to the World Health Organization, there are more than 200 million infected individuals worldwide, with at least 3 to 4 million people being infected each year. Once infected, about 20% of people clear the virus, but the rest can harbor HCV for the rest of their lives. Ten to twenty percent of chronically infected individuals eventually develop liver‐destroying cirrhosis or cancer. The viral disease is transmitted parenterally by contaminated blood and blood products, contaminated needles, or sexually and vertically from infected mothers or carrier mothers to their offspring. Current treatments for HCV infection, which are restricted to immunotherapy with recombinant interferon‐α alone or in combination with the nucleoside analog ribavirin, are of limited clinical benefit. Moreover, there is no established vaccine for HCV. Consequently, there is an urgent need for improved therapeutic agents that effectively combat chronic HCV infection. The present invention provides compounds that promise to provide the much needed solution.
Summary of the Invention
The present invention provides compounds of Formula (I) shown below.
wherein
R1 is aryl or heteroaryl;
each of R2 and R3, independently, is hydrogen, alkyl, or heteroaryl, provided that when one of R2 and R3 is hydrogen or alkyl, the other one must be heteroaryl; or
R2 and R3, together with the nitrogen atom to which they are attached, form a 5‐to 7‐membered heterocyclic ring optionally having one or two more heteroatoms (in addition to the nitrogen atom to which R2 and R3 are attached) each of which is independently O, S, or NR6, wherein R6 is hydrogen, alkyl, acyl, aryl, or heteroaryl; the heterocyclic ring is optionally substituted at its ring carbon atom (s) with alkyl, halo, or alkoxycarbony; or
R4 is hydrogen or alkyl;
R5 is hydrogen or alkyl;
X is a bond, O, NH, or N‐alkyl; and
n is 1, 2, 3, or 4.
In some embodiments, R1 is aryl or heteroaryl. For instance, R1 can be phenyl and optionally substituted with 1‐3 substituents each of which is independently halo or alkyl.
In some other embodiments, R2 is H, and R3 is heteroaryl. For instance, R3 can be pyridinyl or isoquinolinyl. Specific examples of R3 include
In some embodiments, R2 and R3, together with the nitrogen atom to which they are attached, form a 5‐or 6‐membered heterocyclic ring, optionally with one or two more ring hetero atoms (in addition to the nitrogen atom to which R2 and R3 are attached) each of which is independently O, S, or NR6, wherein R6 is hydrogen, alkyl, or aryl; and the heterocyclic ring is optionally substituted at its ring carbon atom with one or more alkoxycarbonyl. As specific examples, the heterocyclic ring can be
In some embodiments, R2 and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl. As specific examples, the heteroaryl can be
In some other embodiments, R4 is methyl or ethyl.
In some other embodiments, R5 is methyl, ethyl or isopropyl.
In some other embodiments, X is a bond, O, NH, or N‐alkyl.
In still some other embodiments, the phosphorous atom is chiral and at least 90% (e.g., at least 97%) is of the S steoroisomer.
In yet still some other embodiments, n is 1, 2, 3, or 4.
In some other embodiments, the compounds of this invention are pharmaceutically acceptable salt of Formula (I) . Examples of such salts include acetate, 4‐toluenesulfonate, hydrobromide, or hydrochloride salts.
Specific examples of the compounds of this invention include, but are not limited to,
isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyl‐3‐ (2‐morpholinoacetoxy) tetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate;
isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyl‐3‐ (2‐morpholinoacetoxy) tetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate 4‐methylbenzenesulfonate;
(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 3‐morpholinopropanoate;
(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 3‐morpholinopropanoate 4‐methylbenzenesulfonate;
(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐morpholinobutanoate;
(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐morpholinobutanoate 4‐methylbenzenesulfonate;
(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐ (dimethylamino) butanoate;
(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐ (pyridin‐2‐ylamino) butanoate hydrochloride;
(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐ (isoquinolin‐1‐ylamino) butanoate hydrochloride;
isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐3‐ (2‐ (7H‐pyrrolo [2, 3‐b] pyridin‐7‐yl) acetoxy) ‐5‐(2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyltetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate;
(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐ (1H‐pyrrolo [2, 3‐b] pyridin‐1‐yl) butanoate;
isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐3‐ (2‐ (1H‐pyrrolo [2, 3‐b] pyridin‐1‐yl) acetoxy) ‐5‐(2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyltetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate;
methyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyl‐3‐ ( (3‐morpholinopropanoyl) oxy) tetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐valinate;
(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐ethoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐fluoro‐4‐methyltetrahydrofuran‐3‐yl 3‐morpholinopropanoate;
isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyl‐3‐ ( ( (3‐morpholinopropyl) carbamoyl) oxy) tetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate;
ethyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyl‐3‐ ( ( (3‐morpholinopropyl) carbamoyl) oxy) tetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate;
isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐3‐ ( ( (2‐ (1H‐pyrrolo [2, 3‐b] pyridin‐1‐yl) ethyl) carbamoyl) oxy) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyltetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate;
(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 3‐morpholinopropanoate hydrochloride;
(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 3‐morpholinopropanoate hydrobromide;
(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 3‐morpholinopropanoate mesylate;
(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐ (dimethylamino) butanoate hydrochloride;
(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐ (dimethylamino) butanoate hydrobromide;
(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐ (dimethylamino) butanoate mesylate;
isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐3‐ (2‐ (1H‐pyrrolo [2, 3‐b] pyridin‐1‐yl) acetoxy) ‐5‐(2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyltetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate hydrochloride;
isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐3‐ (2‐ (1H‐pyrrolo [2, 3‐b] pyridin‐1‐yl) acetoxy) ‐5‐(2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyltetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate hydrobromide; and
isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐3‐ (2‐ (1H‐pyrrolo [2, 3‐b] pyridin‐1‐yl) acetoxy) ‐5‐(2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyltetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate hydrobromide.
In another aspect, the present invention provides pharmaceutical compositions comprising at least a compound described above and a pharmaceutically acceptable medium. Such pharmaceutical compositions can be useful for the treatment of HCV infection in a human.
In still another aspect, the present invention provides a method for treating HCV infection, comprising administering to an HCV‐infected human patient with a compound or a pharmaceutical composition of this invention. In some embodiments, the method further includes administering another antiviral agent that is different from the compounds of this invention.
Yet still another aspect of the present invention relates to the use of a compound of this invention for the manufacture of a medicament for treating HCV infection.
Compared to other compounds that have been reported to have potentially therapeutic effect against HCV infection, the compounds of this invention have unexpectedly shown advantages that are significant for making the compounds of this invention more ideal for clinical use. Such advantages include but are not limited to the abilities of forming pharmaceutically acceptable salts that improve the compounds’ water solubility and stabilities and exhibiting similar or even better pharmaceutical effect,
therefore making pharmaceutical compositions containing the compounds of this invention more suitable for clinical use or therapeutic treatment.
Unless otherwise defined, all terms used herein shall have their common meanings as understood by a person skilled in the art to which the present invention relates.
The phrase “a” or “an” entity as used herein refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. As such, the terms “a” (or “an” ) , “one or more” , and “at least one” can be used interchangeably herein.
Unless otherwise contradicting to the intended meaning, a word in its plural form shall also include the meaning of a singular word. For instance, the word “compounds” shall also mean “a compound” unless such a singular meaning would contradict with the intended meaning.
The terms “optional” or “optionally” as used herein means that a subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optional bond” means that the bond may or may not be present, and that the description includes single, double, or triple bonds. As another example, a group “optionally substituted” group means that the group may be substituted or may not be substituted with appropriate substituents.
The term “P*” means that the phosphorus atom is chiral and that it has a corresponding Cahn‐Ingold‐Prelog designation of “R” or “S” which have their accepted plain meanings.
The term “purified, ” as described herein, refers to the purity of a given compound. For example, a compound is “purified” when the given compound is a major component of the composition, i.e., at least 50% w/w pure. Thus, “purified” embraces at least 50% w/w purity, at least 60% w/w purity, at least 70% purity, at least 80% purity, at least 85% purity, at least 90% purity, at least 92% purity, at least 94% purity, at least 96% purity, at least 97% purity, at least 98% purity, at least 99% purity, at least 99.5% purity, and at least 99.9% purity, wherein “substantially pure” embraces at least 97% purity, at least 98% purity, at least 99% purity, at least 99.5% purity, and at least 99.9% purity
The term “metabolite, ” as described herein, refers to a compound produced in vivo after administration to a subject in need thereof.
The term “about” (also represented by~) means that the recited numerical value is part of a range that varies within standard experimental error.
The term “substantially anhydrous” means that a substance contains at most 10% by weight of water, preferably at most 1% by weight of water, more preferably at most 0.5% by weight of water, and most preferably at most 0.1% by weight of water.
As used herein, the term “prodrug” refers to a bioreversible derivative of a drug molecule that undergoes an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. Additional description can be found in, e.g., J. Rautio et al., Nat Rev Drug Discov., 2008 Mar; 7 (3) : 255‐70, which is incorporated hereby by reference in its entirety.
A solvent or anti‐solvent (as used in reactions, crystallization, etc. or lattice and/or adsorbed solvents) includes at least one of a C1 to C8 alcohol, a C2 to C8 ether, a C3 to C7 ketone, a C3 to C7 ester, a C1 to C2 chlorocarbon, a C2 to C7 nitrile, a miscellaneous solvent, a C5 to C12 saturated hydrocarbon, and a C6 to C12 aromatic hydrocarbon. The C1 to C8 alcohol refers to a straight/branched and/or cyclic/acyclic alcohol having such number of carbons. The C1 to C8 alcohol includes, but is not limited to, methanol, ethanol, n‐propanol, isopropanol, isobutanol, hexanol, and cyclohexanol. The C2 to C8 ether refers to a straight/branched and/or cyclic/acyclic ether having such number of carbons. The C2 to C8 ether includes, but is not limited to, dimethyl ether, diethyl ether, di‐isopropyl ether, di‐n‐butyl ether, methyl‐t‐butyl ether (MTBE) , tetrahydrofuran, and dioxane. The C3 to C7 ketone refers to a straight/branched and/or cyclic/acyclic ketone having such number of carbons. The C3 to C7 ketone includes, but is not limited to, acetone, methyl ethyl ketone, propanone, butanone, methyl isobutyl ketone, methyl butyl ketone, and cyclohexanone. The C3 to C7 ester refers to a straight/branched and/or cyclic/acyclic ester having such number of carbons. The C3 to C7 ester includes, but is not limited to, ethyl acetate, propyl acetate, n‐butyl acetate, etc. The C1 to C2 chlorocarbon refers to a chlorocarbon having such number of carbons. The C1 to C2 chlorocarbon includes, but is not limited to, chloroform, methylene chloride (DCM) , carbon tetrachloride, 1, 2‐dichloroethane, and tetrachloroethane. A C2 to C7 nitrile refers to a nitrile have such number of carbons. The C2 to C7 nitrile includes, but is not limited to, acetonitrile, propionitrile, etc. A miscellaneous solvent refers to a solvent
commonly employed in organic chemistry, which includes, but is not limited to, diethylene glycol, diglyme (diethylene glycol dimethyl ether) , 1, 2‐dimethoxy‐ethane, dimethylformamide, dimethylsulfoxide, ethylene glycol, glycerin, hexamethylphsphoramide, hexamethylphosphoroustriame, N‐methyl‐2‐pyrrolidinone, nitromethane, pyridine, triethyl amine, and acetic acid. The term C5 to C12 saturated hydrocarbon refers to a straight/branched and/or cyclic/acyclic hydrocarbon. The C5 to C12 saturated hydrocarbon includes, but is not limited to, n‐pentane, petroleum ether (ligroine) , n‐hexane, n‐heptane, cyclohexane, and cycloheptane. The term C6 to C12 aromatic refers to substituted and unsubstituted hydrocarbons having a phenyl group as their backbone. Preferred hydrocarbons include benzene, xylene, toluene, chlorobenzene, o‐xylene, m‐xylene, p‐xylene, xylenes, with toluene being more preferred.
The term “halo” or “halogen” as used herein, includes chloro, bromo, iodo and fluoro.
The term “blocking group” refers to a chemical group which exhibits the following characteristics. The “group” is derived from a “protecting compound. ” Groups that are selective for primary hydroxyls over secondary hydroxyls that can be put on under conditions consistent with the stability of the phosphoramidate (pH 2‐8) and impart on the resulting product substantially different physical properties allowing for an easier separation of the 3’‐phosphoramidate‐5’‐new group product from the unreacted desired compound. The group must react selectively in good yield to give a protected substrate that is stable to the projected reactions (see Protective Groups in Organic Synthesis, 3nd ed. T.W. Greene and P.G.M. Wuts, John Wiley &Sons, New York, N.Y., 1999) . Examples of groups include, but are not limited to: benzoyl, acetyl, phenyl‐substituted benzoyl, tetrahydropyranyl, trityl, DMT (4, 4’‐dimethoxytrityl) , MMT (4‐monomethoxytrityl) , trimethoxytrityl, pixyl (9‐phenylxanthen‐9‐yl) group, thiopixyl (9‐phenylthioxanthen‐9‐yl) or 9‐ (p‐methoxyphenyl) xanthine‐9‐yl (MOX) , etc.; C (O) ‐alkyl, C (O) Ph, C (O) aryl, CH2O‐alkyl, CH2O‐aryl, SO2‐alkyl, SO2‐aryl, tert‐butyldimethylsilyl, tert‐butyldiphenylsilyl. Acetals, such as MOM or THP and the like are considered possible groups. Fluorinated compounds are also contemplated in so far that they can be attached to the compound and can be selectively removed by passing through a fluorous solid phase extraction media () . A specific example includes a fluorinated trityl analog, trityl analog 1‐ [4‐ (1H, 1H, 2H, 2H‐perfluorodecyl) phenyl) ‐1, 1‐diphenylmethanol. Other fluorinated analogs of trityl, BOC,
FMOC, CBz, etc. are also contemplated. Sulfonyl chlorides like p‐toluenesulfonyl chloride can react selectively on the 5′ position. Esters could be formed selectively such as acetates and benzoates. Dicarboxylic anhydrides such as succinic anhydride and its derivatives can be used to generate an ester linkage with a free carboxylic acid, such examples include, but are not limited to oxalyl, malonyl, succinyl, glutaryl, adipyl, pimelyl, superyl, azelayl, sebacyl, phthalyl, isophthalyl, terephthalyl, etc. The free carboxylic acid increases the polarity dramatically and can also be used as a handle to extract the reaction product into mildy basic aqueous phases such as sodium bicarbonate solutions. The phosphoramidate group is relatively stable in acidic media, so groups requiring acidic reaction conditions, such as, tetrahydropyranyl, could also be used.
The term “protecting group” which is derived from a “protecting compound, ” has its plain and ordinary meaning, i.e., at least one protecting or blocking group is bound to at least one functional group (e.g., —OH, —NH2, etc. ) that allows chemical modification of at least one other functional group. Examples of protecting groups, include, but are not limited to, benzoyl, acetyl, phenyl‐substituted benzoyl, tetrahydropyranyl, trityl, DMT (4, 4’‐dimethoxytrityl) , MMT (4‐monomethoxytrityl) , trimethoxytrityl, pixyl (9‐phenylxanthen‐9‐yl) group, thiopixyl (9‐phenylthioxanthen‐9‐yl) or 9‐ (p‐methoxyphenyl) xanthine‐9‐yl (MOX) , etc.; C (O) ‐alkyl, C (O) Ph, C (O) aryl, C (O) O (lower alkyl) , C (O) O (lower alkylene) aryl (e.g., —C (O) OCH2Ph) , C (O) Oaryl, CH2O‐alkyl, CH2O‐aryl, SO2‐alkyl, SO2‐aryl, a protecting group comprising at least one silicon atom, such as, tert‐butyldimethylsilyl, tert‐butyldiphenylsilyl, Si (lower alkyl) 2OSi (lower alkyl) 2OH (such as, —Si (iPr) 2OSi (iPr) 2OH) .
The term “protecting compound, ” as used herein and unless otherwise defined, refers to a compound that contains a “protecting group” and that is capable of reacting with a compound that contains functional groups that are capable of being protected.
The term “leaving group” , as used herein, has the same meaning to the skilled artisan (Advanced Organic Chemistry: reactions, mechanisms and structure —Fourth Edition by Jerry March, John Wiley and Sons Ed.; 1992 pages 351‐357) and represents a group which is part of and attached to a substrate molecule; in a reaction where the substrate molecule undergoes a displacement reaction (with for example a nucleophile) , the leaving group is then displaced. Examples of leaving groups include, but are not limited to: halogen (F, Cl, Br, and I) , preferably Cl, Br, or I; tosylate, mesylate, triflate, acetate, camphorsulfonate, aryloxide, and aryloxide substituted with at least one electron
withdrawing group (e.g., p‐nitrophenoxide, 2‐chlorophenoxide, 4‐chlorophenoxide, 2, 4‐dinitrophenoxide, pentafluorophenoxide, etc. ) , etc. The term “electron withdrawing group” is accorded its plain meaning here. Examples of electron withdrawing groups include, but are not limited to, a halogen, ‐NO2, ‐C (O) (lower alkyl) , ‐C (O) (aryl) , ‐C (O) O (lower alkyl) , ‐C (O) O (aryl) , etc.
The term “basic reagent” , as used herein, means a compound that is capable of deprotonating a hydroxyl group. Examples of basic reagents include, but are not limited to, a (lower alk) oxide ( (lower alkyl) OM) in combination with an alcoholic solvent, where (lower alk) oxides include, but are not limited to, MeO-, EtO-, nPrO-, iPrO-, tBuO-, iAmO‐ (iso‐amyloxide) , etc., and where M is an alkali metal cation, such as Li+, Na+, K+, etc. Alcoholic solvents include (lower alkyl) OH, such as, for example, MeOH, EtOH, nPrOH, iPrOH, tBuOH, iAmOH, etc. Non‐alkoxy bases can also be used such as sodium hydride, sodium hexamethyldisilazane, lithium hexamethyldisilazane, lithium diisopropylamide, calcium hydride, sodium carbonate, potassium carbonate, cesium carbonate, DBU, DBN, Grignard reagents, such as (lower alkyl) Mg (halogen) , which include but are not limited to MeMgCl, MeMgBr, tBuMgCl, tBuMgBr, etc.
The term “base” embraces the term “basic reagent” and is meant to be a compound that is capable of deprotonating a proton containing compound, i.e., a Bronsted base. In addition to the examples recited above, further examples of a base include, but are not limited to pyridine, collidine, 2, 6‐ (loweralkyl) ‐pyridine, dimethyl‐aniline, imidazole, N‐methyl‐imidazole, pyrazole, N‐methyl‐pyrazole, triethylamine, di‐isopropylethylamine, etc.
The term “electron withdrawing group” is accorded its plain meaning Examples of electron withdrawing groups include, but are not limited to, a halogen (F, Cl, Br, or I) , ‐NO2, ‐C (O) (lower alkyl) , ‐C (O) (aryl) , ‐C (O) O (lower alkyl) , ‐C (O) O (aryl) , etc.
The term “co‐crystallates” include co‐crystallates of 4, RP‐4, or SP‐4 in combination with salts, which embraces pharmaceutically acceptable salts.
The term “salts, ” as described herein, refers to a compound comprising a cation and an anion, which can produced by the protonation of a proton‐accepting moiety and/or deprotonation of a proton‐donating moiety. It should be noted that protonation of the proton‐accepting moiety results in the formation of a cationic species in which the charge is balanced by the presence of a physiological anion, whereas deprotonation of the proton‐
donating moiety results in the formation of an anionic species in which the charge is balanced by the presence of a physiological cation.
The phrase “pharmaceutically acceptable salt” means a salt that is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonicacid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3‐ (4‐hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2‐ethane‐disulfonic acid, 2‐hydroxyethanesulfonic acid, benzenesulfonic acid, 4‐chlorobenzenesulfonic acid, 2‐naphthalenesulfonic acid, 4‐toluenesulfonic acid, camphorsulfonic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, salicylic acid, muconic acid, and the like or (2) basic addition salts formed with the conjugate bases of any of the inorganic acids listed above, wherein the conjugate bases comprise a cationic component selected from among Na+, K+, Mg2+, Ca2+, NHgR”’ 4‐g+, in which R”’ is a C1‐3 alkyl and g is a number selected from among 0, 1, 2, 3, or 4. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.
The term “alkyl” refers to an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 30 carbon atoms. The term “C1‐M alkyl” refers to an alkyl comprising 1 to M carbon atoms, where M is an integer having the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. The term “C1‐4 alkyl” refers to an alkyl containing 1 to 4 carbon atoms. The term “lower alkyl” denotes a straight or branched chain hydrocarbon residue comprising 1 to 6 carbon atoms. “C1‐20 alkyl” as used herein refers to an alkyl comprising 1 to 20 carbon atoms. “C1‐10 alkyl” as used herein refers to an alkyl comprising 1 to 10 carbons. Examples of alkyl groups include, but are not limited to, lower alkyl groups include methyl, ethyl, propyl, i‐propyl, n‐butyl, i‐butyl, t‐butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. The term (ar) alkyl or (heteroaryl) alkyl indicate the alkyl group is substituted by an aryl or a heteroaryl group respectively. The term “lower alkyl” refers to an alkyl of 1‐8 carbon atoms. As used herein, the term alkoxy refers to “alkyl‐O‐“ .
The term “alkenyl” refers to an unsubstituted hydrocarbon chain radical having from 2 to 10 carbon atoms having one or two olefinic double bonds, preferably one olefinic double bond. The term “C2‐N alkenyl” refers to an alkenyl comprising 2 to N carbon atoms, where N is an integer having the following values: 3, 4, 5, 6, 7, 8, 9, or 10. The term “C2‐10 alkenyl” refers to an alkenyl comprising 2 to 10 carbon atoms. The term “C2‐4 alkenyl” refers to an alkenyl comprising 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, 1‐propenyl, 2‐propenyl (allyl) or 2‐butenyl (crotyl) .
The term “heterocyclic” as used herein refers to a mono‐or multiple‐cyclic compound with at least one hetero atom selecting from O, S, N, or P. The heterocyclic compound can be aromatic (i.e., heteroaryl) or non‐aromatic, saturated or non‐saturated; and includes monocylic 3‐8 member rings, and bi or tri fused ring systems. As example, heterocyclic compounds include aziridine, oxirane, thiirane, azirine, oxirene, thiirene, azetidine, oxetane, thietane, azete, oxete, thiete, pyrrolidine, oxolane, thiolane, pyrrole, furan, thiophene, piperidine, oxane, thiane, pyridine, pyran, thiopyran, azepane, oxepane, thiepane, azepine, oxepine, thiepine, indole, quinolone, azepine, carbazole, acridine, and dibenzoazepine.
The term “aryl” as used herein, and unless otherwise specified, refers to substituted or unsubstituted single ring or multiple‐ring fused system, such as phenyl (Ph) , biphenyl, or naphthyl. The term aryl, unless otherwise specified, includes substituted and unsubstituted aryl group (e.g., phenyl or substituted phenyl) . The aryl group can be substituted with one or more moieties selected from among hydroxyl, F, Cl, Br, I, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T.W. Greene and P.G.M. Wuts, “Protective Groups in Organic Synthesis, ” 3rd ed., John Wiley &Sons, 1999.
As used herein, the term "heteroaryl" means a monocyclic‐or polycyclic aromatic ring comprising carbon atoms, hydrogen atoms, and one or more heteroatoms (e.g., 1 to 3 heteroatoms) , independently selected from nitrogen, oxygen, and sulfur. As is well known to those skilled in the art, heteroaryl rings have less aromatic character than their all‐carbon counter parts. Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1, 2, 3, ) ‐and (1, 2, 4) ‐triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, phenyl,
isoxazolyl, and oxazolyl. A heteroaryl group can be unsubstituted or substituted with one or two suitable substituents. In examples of this invention, a heteroaryl group is a monocyclic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred to herein as " (C2‐C5) heteroaryl" .
The term “aryloxide, ” as used herein, and unless otherwise specified, refers to substituted or unsubstitutedphenoxide (PhO—) , p‐phenyl‐phenoxide (p‐Ph‐PhO‐) , or naphthoxide, preferably the term aryloxide refers to substituted or unsubstitutedphenoxide. The aryloxide group can be substituted with one or more moieties selected from among hydroxyl, F, Cl, Br, I, ‐C (O) (lower alkyl) , ‐C (O) O (lower alkyl) , amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T.W. Greene and P.G.M. Wuts, “Protective Groups in Organic Synthesis, ” 3rd ed., John Wiley &Sons, 1999.
The term “preparation” or “dosage form” is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the desired dose and pharmacokinetic parameters.
The term “excipient” as used herein refers to a compound that is used to prepare a pharmaceutical composition, and is generally safe, non‐toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.
The term “crystalline” refers to a situation where a solid sample of either SP‐4 or RP‐4 has crystalline characteristics when determined by X‐ray powder diffraction or a single crystal X‐ray technique.
The term “crystal‐like” refers to a situation where a solid sample of either SP‐4 or RP‐4 has crystalline characteristics when determined by one means, e.g., visually or by optical or polarizing microscopy, but does not have crystalline characteristics when determined by another means, e.g., x‐ray powder diffraction. Methods of visually determining the crystallinity of a solid sample by visual or by optical or by polarizing microscopy are disclosed in USP <695> and <776> , both of which are incorporated by reference. A solid sample of either SP‐4 or RP‐4 that is “crystal‐like” may be crystalline under certain conditions but may become non‐crystalline when subjected to other conditions.
The term “amorphous” refers to a situation where a solid sample of either SP‐4 or RP‐4 is neither crystalline nor crystal‐like.
The following examples are provided to illustrate certain embodiments of this invention and shall not be interpreted to limit the scope of the invention in any way.
Example 1. Preparation of isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyl‐3‐ (2‐morpholinoacetoxy) tetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate (I‐1)
Compound 1 (0.30 g, 0.57 mmol) , compound 2 (0.12 g, 0.68 mmol) and DiPEA (0.22 g, 1.70 mmol) were dissolved in DCM (15 mL) . After stirring for 5 min at the room temperature, TBTU (0.22 g, 0.68 mmol) was added and the mixture was stirred for 20 hrs. The solvent was evaporated and the residue was triturated with EA (100 mL) . The combined organic layer was washed with water (2x50 mL) and brine (50 mL) , dried over Na2SO4, filtered, concentrated and purified by flash column chromatography to give the title productI‐1 (0.28 g, 76%) .
1H‐NMR (400 MHz, CDCl3) δ: 8.59 (s, 1H) , 7.50 (d, J = 8.4Hz, 1H) , 7.34 (t, J = 8.0Hz, 2H) , 7.23 (d, J = 8.4Hz, 2H) , 7.18 (t, J = 7.2Hz, 1H) , 6.19 (d, J = 18.8Hz, 1H) , 5.58 (d, J = 8.0Hz, 1H) , 5.24 (dd, J1 = 9.2Hz, J2 = 20.0Hz, 1H) , 5.05‐4.95 (m, 1H) , 4.55‐4.50 (m, 1H) , 4.34 (dd, J1 = 1.2Hz, J2 = 7.2Hz, 1H) , 4.27‐4.22 (m, 1H) , 4.02‐3.92 (m, 1H) , 3.85 (t, J = 10.4Hz, 1H) , 3.75 (t, J = 4.4Hz, 3H) , 3.37 (d, J = 3.6Hz, 2H) , 2.65‐2.58 (m, 4H) , 1.40‐1.38 (m, 6H) , 1.24 (d, J = 6.4Hz, 6H) .
Example 2. Preparation of isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyl‐3‐ (2‐morpholinoacetoxy) tetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate 4‐methylbenzenesulfonate (I‐2)
Compound I‐1 (0.500 g, 0.76 mmol) was dissolved in DCM (12 mL) and 4‐methylbenzenesulfonic acid (0.145 g, 0.76 mmol) was added. Then the mixture was stirred for another 0.5 h, concentrated and recrystallized to give the desired salt (0.450 g) .
1H‐NMR (400 MHz, CDCl3) δ: 7.71 (d, J = 7.2Hz, 2H) , 7.50 (d, J = 7.2Hz, 1H) , 7.30‐7.27 (m, 2H) , 7.21‐7.14 (m, 6H) , 6.05 (brs, 1H) , 5.63 (d, J = 7.8Hz, 1H) , 5.30 (brs, 1H) , 4.95‐4.91 (m, 1H) , 4.52‐4.28 (m, 3H) , 3.95‐3.65 (m, 6H) , 3.25‐3.08 (m, 2H) , 2.82 (s, 4H) , 2.32 (s, 3H) , 1.44‐1.35 (m, 6H) , 1.18 (d, J = 6.0Hz, 6H) .
Example 3. Preparation of (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 3‐morpholinopropanoate (I‐3)
Compound I‐3 was prepared according to the synthesis procedure of Compound I‐1, except that 2‐morpholinoacetic acid was replaced by 3‐morpholinopropanoic acid.
1H‐NMR (400 MHz, CDCl3) δ: 8.43 (s, 1H) , 7.57 (d, J = 8.0Hz, 1H) , 7.36 (t, J = 8.0Hz, 2H) , 7.26‐7.23 (m, 2H) , 7.20 (t, J = 7.6Hz, 1H) , 6.24 (d, J = 18.8Hz, 1H) , 5.54 (d, J = 8.4Hz, 1H) , 5.28 (dd, J1 = 9.2Hz, J2 = 20.8Hz, 1H) , 5.05‐4.99 (m, 1H) , 4.60‐4.55 (m, 1H) , 4.34 (d, J = 9.6Hz, 1H) , 4.30‐4.25 (m, 1H) , 4.03‐3.95 (m, 1H) , 3.87 (t, J = 6.4Hz, 1H) , 3.69‐3.67 (m, 4H) , 2.74‐2.70 (m, 2H) , 2.65‐2.62 (m, 2H) , 2.48 (br, 4H) , 1.40‐1.37 (m, 6H) , 1.26 (d, J = 6.4Hz, 6H) .
Example 4. Preparation of (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 3‐morpholinopropanoate 4‐methylbenzenesulfonate (I‐4)
Compound I‐3 (0.500 g, 0.75mmol) was dissolved in DCM (12 mL) and 4‐methylbenzenesulfonic acid (0.142 g, 0.75 mmol) was added. Then the mixture was stirred for another 0.5 h, concentrated and recrystallized to give the desired salt (0.465 g) .
1H‐NMR (400 MHz, CDCl3) δ: 10.85 (s, 1H) , 7.74 (d, J = 8.0Hz, 2H) , 7.48 (t, J = 8.4Hz, 1H) , 7.34 (t, J = 8.4Hz, 2H) , 7.30‐7.14 (m, 5H) , 6.21‐6.06 (m, 1H) , 5.67 (d, J = 8.4Hz, 1H) , 5.36‐5.22 (m, 1H) , 5.03‐4.93 (m, 1H) , 4.56‐4.32 (m, 3H) , 4.13‐3.85 (m, 6H) , 3.60‐3.43 (m, 6H) , 3.02‐2.99 (m, 2H) , 2.35 (s, 3H) , 1.39‐1.32 (m, 6H) , 1.21 (d, J = 6.4Hz, 6H) .
Example 5. Preparation of (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐morpholinobutanoate (I‐5)
Compound I‐5 was prepared according to the synthesis procedure of Compound I‐1, except that 2‐morpholinoacetic acid was replaced by 4‐morpholinobutanoic acid.
1H‐NMR (400 MHz, CDCl3) δ: 7.53 (d, J = 8.4Hz, 1H) , 7.33 (t, J = 7.6Hz, 2H) , 7.23‐7.19 (m, 3H) , 6.21 (d, J = 18.4Hz, 1H) , 5.57 (d, J = 8.0Hz, 1H) , 5.21 (dd, J1 = 8.8Hz, J2 = 20.0Hz, 1H) , 5.04‐4.97 (m, 1H) , 4.56‐4.51 (m, 1H) , 4.33‐4.30 (m, 1H) , 4.26‐4.21 (m, 1H) , 4.06‐3.96 (m, 1H) , 3.72‐3.70 (m, 4H) , 2.48‐2.46 (m, 4H) , 2.42‐2.36 (m, 2H) , 1.89‐1.81 (m, 2H) , 1.38‐1.32 (m, 6H) , 1.24 (d, J = 6.4Hz, 6H) .
Example 6. Preparation of (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐morpholinobutanoate 4‐methylbenzenesulfonate (I‐6)
Compound I‐5 (0.277 g, 0.40mmol) was dissolved in DCM (10 mL) and 4‐methylbenzenesulfonic acid (0.077 g, 0.40mmol) was added. Then the mixture was stirred for another 0.5 hour, concentrated and recrystallized to give the desired salt I‐6 (0.310 g, 89%) .
1H‐NMR (400 MHz, CDCl3) δ: 10.44 (s, 1H) , 9.05 (s, 1H) , 7.73 (d, J = 8.0Hz, 2H) , 7.50 (t, J = 8.4Hz, 1H) , 7.33 (t, J = 8.4Hz, 2H) , 7.30‐7.11 (m, 5H) , 6.14 (d, J = 16.4Hz, 1H) , 5.68 (d, J = 8.0Hz, 1H) , 5.30‐5.20 (m, 1H) , 4.99‐4.96 (m, 1H) , 4.45‐4.25 (m, 4H) , 3.95‐3.87 (m, 5H) , 3.56‐3.47 (m, 2H) , 3.21‐3.10 (m, 2H) , 2.83‐2.69 (m, 2H) , 2.51‐2.34 (m, 2H) , 2.25 (s, 3H) , 2.12‐2.10 (m, 2H) , 1.37‐1.31 (m, 6H) , 1.21 (d, J = 5.6Hz, 6H) .
Example 7. Preparation of (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐ (dimethylamino) butanoate (I‐7)
Compound I‐7 was prepared according to the synthesis procedure of Compound I‐1, except that 2‐morpholinoacetic acid was replaced by 4‐ (dimethylamino) butanoic acid.
1H‐NMR (400 MHz, CDCl3) δ: 7.52 (d, J = 8.0Hz, 1H) , 7.35 (t, J = 7.2Hz, 2H) , 7.23 (t, J = 8.4Hz, 2H) , 7.19 (d, J = 7.2Hz, 1H) , 6.22 (d, J = 18.8Hz, 1H) , 5.54 (d, J = 8.0Hz, 1H) , 5.22 (dd, J1 = 9.2Hz, J2 = 20.4Hz, 1H) , 5.03‐4.97 (m, 1H) , 4.56‐4.52 (m, 1H) , 4.32‐4.31 (m, 1H) , 4.26‐4.21 (m, 1H) , 4.13‐4.11 (m, 1H) , 4.08‐4.03 (m, 1H) , 4.00‐3.95 (m, 1H) , 2.50 (t, J = 7.2Hz, 2H) , 2.42‐2.36 (m, 3H) , 2.26 (s, 6H) , 1.89‐1.81 (m, 2H) , 1.37‐1.32 (m, 6H) , 1.23 (d, J = 6.4Hz, 6H) .
Example 8. Preparation of (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐ (pyridin‐2‐ylamino) butanoate hydrochloride (I‐8)
Compound I‐8 was prepared according to the synthesis procedures of Compound I‐1 and compound 2, except that 2‐morpholinoacetic acid was replaced by 4‐ ( (tert‐butoxycarbonyl) (pyridin‐2‐yl) amino) butanoic acid and 4‐methylbenzenesulfonic acid was substituted by HCl gas.
1H‐NMR (400 MHz, CDCl3) δ: 8.00 (brs, 1H) , 7.66‐7.64 (m, 1H) , 7.55 (d, J = 8.0Hz, 1H) , 7.33 (t, J = 7.6Hz, 2H) , 7.24 (t, J = 8.4Hz, 2H) , 7.17 (t, J = 7.6Hz, 1H) , 7.02 (dd, J1 = 5.6Hz, J2 = 6.8Hz,
1H) , 6.22 (d, J = 18.4Hz, 1H) , 5.47 (dd, J1 = 1.2Hz, J2 = 20.8Hz, 1H) , 5.20 (dd, J1 = 9.2Hz, J2 = 20.8Hz, 1H) , 5.03‐4.94 (m, 1H) , 4.57‐4.54 (m, 1H) , 4.31‐4.29 (m, 1H) , 4.27‐4.22 (m, 1H) , 4.01‐3.98 (m, 2H) , 3.96‐3.88 (m, 1H) , 2.51 (t, J = 8.4Hz, 2H) , 2.05‐1.96 (m, 2H) , 1.38‐1.32 (m, 6H) , 1.22 (d, J = 6.4Hz, 6H) .
Example 9. Preparation of (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐ (isoquinolin‐1‐ylamino) butanoate hydrochloride (I‐9)
Compound I‐9 was prepared according to the synthesis procedures of Compound I‐1 and compound 2, except that 2‐morpholinoacetic acid was replaced by 4‐ ( (tert‐butoxycarbonyl) (isoquinolin‐1‐yl) amino) butanoic acid and 4‐methylbenzenesulfonic acid was substituted by HCl gas.
1H‐NMR (400 MHz, CDCl3) δ: 8.38 (d, J = 6.0Hz, 1H) , 8.08 (d, J = 1.6Hz, 1H) , 7.92 (d, J = 8.4Hz, 1H) , 7.86 (d, J = 8.0Hz, 1H) , 7.72‐7.68 (m, 1H) , 7.63‐7.59 (m, 2H) , 7.55 (d, J = 8.0Hz, 1H) , 7.33 (t, J = 8.8Hz, 2H) , 7.23 (t, J = 8.8Hz, 2H) , 7.16 (t, J = 7.6Hz, 1H) , 6.21 (d, J = 18.4Hz, 1H) , 5.44‐5.42 (m, 1H) , 5.21‐5.13 (m, 1H) , 5.01‐4.94 (m, 1H) , 4.56‐4.52 (m, 1H) , 4.29‐4.24 (m, 2H) , 4.10‐4.07 (m, 1H) , 4.01‐3.93 (m, 2H) , 2.60‐2.57 (m, 2H) , 2.00‐1.98 (m, 2H) , 1.38‐1.34 (m, 6H) , 1.21 (d, J = 6.4Hz, 6H) .
Example 10. Preparation of isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐3‐ (2‐ (7H‐pyrrolo [2, 3‐b] pyridin‐7‐yl) acetoxy) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyltetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate (I‐10)
Compound I‐10 was prepared according to the synthesis procedure of Compound I‐1, except that 2‐morpholinoacetic acid was replaced by 2‐ (7H‐pyrrolo [2, 3‐b] pyridin‐7‐yl) acetic acid.
1H‐NMR (400 MHz, CDCl3) δ: 9.59 (brs, 1H) , 7.49 (d, J = 8.0Hz, 1H) , 7.31 (t, J = 8.4Hz, 2H) , 7.23‐7.17 (m, 3H) , 6.20 (d, J = 18.4Hz, 1H) , 5.71 (d, J = 7.6Hz, 1H) , 5.03‐4.97 (m, 1H) , 4.56‐4.51 (m, 1H) , 4.47‐4.43 (m, 1H) , 4.36‐4.30 (m, 1H) , 4.15‐4.09 (m, 1H) , 3.98‐3.90 (m, 2H) , 1.40‐1.35 (m, 6H) , 1.24 (d, J = 6.4Hz, 6H) .
Example 11. Preparation of (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐ (1H‐pyrrolo [2, 3‐b] pyridin‐1‐yl) butanoate (I‐11)
Compound I‐11 was prepared according to the synthesis procedure of Compound I‐1, except that 2‐morpholinoacetic acid was replaced by 4‐ (1H‐pyrrolo [2, 3‐b] pyridin‐1‐yl) butanoic acid.
1H‐NMR (400 MHz, CDCl3) δ: 9.73 (brs, 1H) , 8.30 (dd, J1 = 4.8Hz, J2 = 1.6Hz, 1H) , 7.91 (dd, J1 = 1.6Hz, J2 = 8.0Hz, 1H) , 7.54 (d, J = 8.0Hz, 1H) , 7.34 (t, J = 8.0Hz, 2H) , 7.23‐7.21 (m, 3H) , 7.17 (t,
J = 7.6Hz, 1H) , 7.07 (dd, J1 = 4.8Hz, J2 = 8.0Hz, 1H) , 6.46 (d, J = 3.6Hz, 1H) , 6.22 (d, J = 18.4Hz, 1H) , 5.55 (d, J = 8.0Hz, 1H) , 5.23 (dd, J1 = 8.8Hz, J2 = 20.4Hz, 1H) , 5.02‐4.92 (m, 1H) , 4.57‐4.53 (m, 1H) , 4.40‐4.36 (m, 2H) , 4.29‐4.24 (m, 2H) , 4.13‐4.08 (m, 1H) , 4.03‐3.93 (m, 1H) , 2.44 (t, J = 6.8Hz, 2H) , 2.26‐2.20 (m, 2H) , 1.38‐1.35 (m, 6H) , 1.21 (d, J = 6.4Hz, 6H) .
Example 12. Preparation of isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐3‐ (2‐ (1H‐pyrrolo [2, 3‐b] pyridin‐1‐yl) acetoxy) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyltetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate (I‐12)
Compound I‐12 was prepared according to the synthesis procedure of Compound I‐1, except that 2‐morpholinoacetic acid was replaced by 2‐ (1H‐pyrrolo [2, 3‐b] pyridin‐1‐yl) acetic acid.
1H‐NMR (400 MHz, CDCl3) δ: 8.68 (brs, 1H) , 8.29 (dd, J1 = 4.8Hz, J2 = 1.6Hz, 1H) , 7.93 (dd, J1 = 1.6Hz, J2 = 7.6Hz, 1H) , 7.47 (d, J = 8.8Hz, 1H) , 7.31 (t, J = 8.0Hz, 2H) , 7.25‐7.14 (m, 4H) , 7.09 (dd, J1 = 4.8Hz, J2 = 8.0Hz, 1H) , 6.54 (d, J = 3.6Hz, 1H) , 6.18 (d, J = 18.4Hz, 1H) , 5.50 (d, J = 8.4Hz, 1H) , 5.20 (s, 2H) , 4.96‐4.90 (m, 1H) , 4.53‐4.48 (m, 1H) , 4.30‐4.23 (m, 2H) , 3.94‐3.89 (m, 2H) , 1.36‐1.31 (m, 6H) , 1.17 (d, J = 6.0Hz, 6H) .
Example 13. Preparation of methyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyl‐3‐ ( (3‐morpholinopropanoyl) oxy) tetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐valinate (I‐13)
Compound I‐13 was prepared according to the following scheme:
To a stirred solution of phenyl phosphorodichloridate (2.005 g, 9.5 mmol) in DCM (15 mL) was added a solution of triethylamine (5.235 g, 51.8 mmol) and pentafluorophenol (1.595 g, 8.6 mmol) in DCM (20 mL) at ‐50 ℃. The mixture was stirred at this temperature for 20 min and then a solution of 13‐1 (0.980 g, 8.6 mmol) and triethylamine (0.872 g, 8.6 mmol) in DCM (15 mL) was added drop wise. Then the mixture was stirred for another 3 hours at ‐50 ℃. The solvent was evaporated and the residue was triturated with EA (50 mL) . The combined organic layer was washed with water (2x50 mL) and brine (50 mL) , dried over Na2SO4, filtered, concentrated and purified by flash column chromatography to give the title intermediate 13‐2 (3.100 g) as oil.
To a stirred solution of the starting material 13‐3 (0.200 g, 0.77 mmol, J. Med. Chem. 2005, 48, 5504‐5508) in dry THF (10 mL) was added tert‐butylmagnesium chloride (1.62 mL, 1.6 mmol) drop wise at 0 ℃. After 30 minutes, a solution of intermediate 13‐2 (0.350 g, 0.77 mmol) in THF (5 mL) was added drop wise. The mixture was stirred for another 1 hour at this temperature and then was allowed to stir at room temperature for 18 hours. Saturated NH4Cl (50 mL) was added and the mixture was extracted with EA (2x50 mL) . The combined organic layer was washed with water and brine, dried over Na2SO4, filtered,
concentrated and purified by flash column chromatography to give the title compound 13‐4 (0.165g, 40%) .
Compound 13‐4 (0.165 g, 0.31 mmol) , compound 2 (0.051 g, 0.31 mmol) and DiPEA (0.080 g, 0.62 mmol) were dissolved in DCM (8 mL) . After stirring for 5 min at the room temperature, TBTU (0.119 g, 0.37 mmol) was added and the mixture was stirred for 20 hrs. The solvent was evaporated and the residue was triturated with EA (50 mL) . The combined organic layer was washed with water (2x30 mL) and brine (30 mL) , dried over Na2SO4, filtered, concentrated and purified by flash column chromatography to give the title product I‐13 (0.108 g, 54%) .
1H‐NMR (400 MHz, CDCl3) δ: 8.12 (s, 1H) , 7.52 (d, J = 8.0Hz, 1H) , 7.31 (t, J = 8.0Hz, 2H) , 7.23‐7.15 (m, 3H) , 6.21 (d, J = 19.2Hz, 1H) , 5.52 (d, J = 8.4Hz, 1H) , 5.24 (dd, J1 = 9.2Hz, J2 = 20.8Hz, 1H) , 4.58‐4.54 (m, 1H) , 4.32‐4.23 (m, 2H) , 3.81‐3.77 (m, 1H) , 3.67‐3.65 (m, 7H) , 2.72‐2.69 (m, 2H) , 2.63‐2.60 (m, 2H) , 2.46 (br, 4H) , 2.07‐2.02 (m, 1H) , 1.37 (d, J = 22.4Hz, 3H) , 0.93‐0.85 (m, 6H) .
Example 14. Preparation of (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐2‐( ( ( (S) ‐ ( ( (S) ‐1‐ethoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐fluoro‐4‐methyltetrahydrofuran‐3‐yl 3‐morpholinopropanoate (I‐14)
Compound I‐14 was prepared according to the synthesis procedure of Compound I‐13, except that compound 13‐1 was replaced by ethyl L‐alaninate.
1H‐NMR (400 MHz, CDCl3) δ: 8.45 (s, 1H) , 7.53 (d, J = 8.0Hz, 1H) , 7.35‐7.32 (m, 2H) , 7.26‐7.23‐7.16 (m, 3H) , 6.21 (d, J = 18.8Hz, 1H) , 5.53 (d, J = 8.4Hz, 1H) , 5.25 (dd, J1 = 9.2Hz, J2 = 20.4Hz, 1H) , 4.57‐4.52 (m, 1H) , 4.35‐4.24 (m, 2H) , 4.20‐4.11 (m, 2H) , 4.06‐3.96 (m, 1H) , 3.87‐3.81 (m, 1H) , 3.69‐3.65 (m, 4H) , 2.71‐2.69 (m, 2H) , 2.64‐2.61 (m, 2H) , 2.42 (brs, 4H) , 1.42‐1.37 (m, 6H) , 1.26 (t, J = 7.2Hz, 3H) .
Example 15. Preparation of isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyl‐3‐ ( ( (3‐morpholinopropyl) carbamoyl) oxy) tetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate (I‐15)
Compound I‐15 was prepared according to the following scheme:
Compound 15‐1 (0.144 g, 1.0 mmol) and DiPEA (0.300 g, 2.3 mmol) were dissolved in DCM (12 mL) . Triphosgene (0.158 g, 0.53 mmol) was added in portions at 0℃ and the mixture was stirred for 3 hrs. The solvent was evaporated and the residue was redissolved in DCM (10 mL) .
To a stirred solution of the starting material 1 (0.085 g, 0.16 mmol) in dry DCM (10 mL) was added tert‐butylmagnesium chloride (0.20 ml, 0.2 mmol) drop wise at 0 ℃. After 30 min, a solution of the above intermediate 15‐2 in DCM (10 mL) was added drop wise. The mixture was stirred for another 1 h at this temperature and then was allowed to stir at room temperature overnight. Saturated NH4Cl (30 mL) was added and the mixture was extracted with EA (2x30 mL) . The combined organic layer was washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by flash column chromatography to give the title compound I‐15 (0.068g, 61%) .
1H‐NMR (400 MHz, CDCl3) δ: 7.53 (d, J = 8.0Hz, 1H) , 7.34‐7.30 (m, 2H) , 7.22 (d, J = 8.0Hz, 2H) , 7.15 (t, J = 7.2Hz, 1H) , 6.50 (t, J = 5.2Hz, 1H) , 6.22 (d, J = 18.8Hz, 1H) , 5.44 (d, J = 8.0Hz, 1H) , 5.09 (dd, J1 = 9.2Hz, J2 = 21.2Hz, 1H) , 5.02‐4.95 (m, 1H) , 4.57‐4.53 (m, 1H) , 4.33‐4.24 (m, 3H) , 4.05‐3.97 (m, 1H) , 3.75‐3.72 (m, 4H) , 3.38‐3.31 (m, 1H) , 3.29‐3.21 (m, 1H) , 2.58‐2.46 (m, 6H) , 1.75‐1.72 (m, 2H) , 1.38‐1.32 (m, 6H) , 1.22 (d, J = 6.0Hz, 6H) .
Example 16. Preparation of ethyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyl‐3‐ ( ( (3‐morpholinopropyl) carbamoyl) oxy) tetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate (I‐16)
Compound I‐16 was prepared according to the synthesis procedure of Compound I‐15, except that compound 1 was replaced by ethyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐3‐hydroxy‐4‐methyltetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate.
1H‐NMR (400 MHz, CDCl3) δ: 8.29 (brs, 1H) , 7.54 (d, J = 8.4Hz, 1H) , 7.35‐7.31 (m, 2H) , 7.22 (d, J = 8.4Hz, 2H) , 7.16 (t, J = 7.6Hz, 1H) , 6.48 (t, J = 4.8Hz, 1H) , 6.22 (d, J = 18.8Hz, 1H) , 5.40 (d, J = 8.4Hz, 1H) , 5.09 (dd, J1 = 8.8Hz, J2 = 20.8Hz, 1H) , 4.57‐4.53 (m, 1H) , 4.28‐4.24 (m, 2H) , 4.18‐4.11 (m, 3H) , 4.08‐4.01 (m, 1H) , 3.72‐3.70 (m, 4H) , 3.41‐3.33 (m, 1H) , 3.30‐3.23 (m, 1H) , 2.55‐2.40 (m, 6H) , 1.71‐1.65 (m, 2H) , 1.39‐1.33 (m, 6H) , 1.24 (t, J = 7.2Hz, 3H) .
Example 17. Preparation of isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐3‐ ( ( (2‐ (1H‐pyrrolo [2, 3‐b] pyridin‐1‐yl) ethyl) carbamoyl) oxy) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyltetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate (I‐17)
Compound I‐17 was prepared according to the synthesis procedure of Compound I‐15, except that 3‐morpholinopropan‐1‐amine was replaced by 2‐ (1H‐pyrrolo [2, 3‐b] pyridin‐1‐yl) ethan‐1‐amine.
1H‐NMR (400 MHz, CDCl3) δ: 9.06 (brs, 1H) , 8.29 (dd, J1 = 1.2Hz, J2 = 4.8Hz, 1H) , 7.91 (dd, J1 = 1.2Hz, J2 = 8.0Hz, 1H) , 7.49 (d, J = 8.4Hz, 1H) , 7.34‐7.30 (m, 2H) , 7.24‐7.09 (m, 4H) , 7.07‐7.05 (m, 1H) , 6.46 (d, J = 3.6Hz, 1H) , 6.14 (t, J = 5.2Hz, 1H) , 5.40 (d, J = 8.4Hz, 1H) , 5.01‐4.94 (m, 1H) , 4.53‐4.43 (m, 3H) , 4.24‐4.16 (m, 3H) , 4.03‐3.97 (m, 1H) , 3.68‐3.65 (m, 2H) , 1.37‐1.30 (m, 6H) , 1.21 (d, J = 6.4Hz, 6H) .
Example 18. Preparation of compound I‐3 hydrochloride (I‐18)
Compound I‐3 (0.500 g, 0.75mmol) was dissolved in iPrOH (2 mL) and concentrated HCl (0.09ml, 1.12 mmol) was added. Then the mixture was stirred for another 1 h and filtrated to give the desired salt (0.350 g) .
1H‐NMR (400 MHz, CDCl3) δ: 13.16 (brs, 1H) , 8.63 (s, 1H) , 7.41 (d, J = 8.0Hz, 2H) , 7.28 (t, J = 7.6Hz, 2H) , 7.19‐7.09 (m, 3H) , 6.07 (d, J = 18.0Hz, 1H) , 5.61 (d, J = 6.8Hz, 1H) , 5.21 (dd, J1 = 8.0Hz, J2 = 18.4Hz, 1H) , 4.97‐4.88 (m, 1H) , 4.41‐4.28 (m, 3H) , 4.17‐3.85 (m, 6H) , 3.39‐3.09 (m, 6H) , 2.98‐2.69 (m, 2H) , 1.34‐1.30 (m, 6H) , 1.17 (d, J = 6.0Hz, 6H) .
Example 19. Preparation of compound I‐3 hydrobromide (I‐19)
Compound I‐3 (0.500 g, 0.75mmol) was dissolved in iPrOH (2 mL) and concentrated HBr (0.07ml, 1.12 mmol) was added. Then the mixture was stirred for another 1 h and filtrated to give the desired salt (0.400 g) .
1H‐NMR (400 MHz, CDCl3) δ: 11.96 (brs, 1H) , 8.56 (s, 1H) , 7.41 (d, J = 8.0Hz, 2H) , 7.29 (t, J = 7.6Hz, 2H) , 7.19‐7.10 (m, 3H) , 6.07 (d, J = 18.8Hz, 1H) , 5.64 (dd, J1 = 2.0Hz, J2 = 8.4Hz, 1H) , 5.22 (dd, J1 = 8.4Hz, J2 = 17.2Hz, 1H) , 4.97‐4.87 (m, 1H) , 4.43‐4.29 (m, 3H) , 4.25‐4.12 (m, 2H) ,
3.97‐3.82 (m, 4H) , 3.42‐3.11 (m, 6H) , 2.98‐2.77 (m, 2H) , 1.34‐1.29 (m, 6H) , 1.17 (d, J = 6.4Hz, 6H).
Example 20. Preparation of compound I‐3 mesylate (I‐20)
Compound I‐3 (0.500 g, 0.75mmol) was dissolved in iPrOH (2 mL) and Methanesulfonic acid (0.07 mL, 1.12 mmol) was added. Then the mixture was stirred for another 1 h and filtrated to give the desired salt (0.385 g) .
1H‐NMR (400 MHz, DMSO‐d6) δ: 11.56 (brs, 1H) , 9.74 (s, 1H) , 7.72 (d, J = 8.0Hz, 2H) , 7.40 (t, J = 8.0Hz, 2H) , 7.22‐7.17 (m, 3H) , 6.06‐6.00 (m, 1H) , 5.68 (dd, J1 = 2.0Hz, J2 = 8.0Hz, 1H) , 5.33 (br, 1H) , 4.90‐4.81 (m, 1H) , 4.34‐4.24 (m, 3H) , 3.99‐3.84 (m, 2H) , 3.74‐3.63 (m, 4H) , 3.40‐3.30 (m, 4H) , 3.12‐2.99 (m, 4H) , 2.36 (s, 3H) , 1.37‐1.31 (m, 6H) , 1.22 (d, J = 6.4Hz, 3H) , 1.17 (d, J = 6.4Hz, 3H) .
Example 21. Preparation of compound I‐5 hydrochloride (I‐21)
Compound I‐5 (0.500 g, 0.73mmol) was dissolved in iPrOH (2 mL) and concentrated HCl (0.09ml, 1.12 mmol) was added. Then the mixture was stirred for another 1 h and filtrated to give the desired salt (0.370 g) .
1H‐NMR (400 MHz, CDCl3) δ: 13.55 (brs, 1H) , 7.37 (d, J = 8.0Hz, 2H) , 7.26 (t, J = 7.6Hz, 2H) , 7.16‐7.11 (m, 3H) , 6.05 (d, J = 18.4Hz, 1H) , 5.64 (d, J = 7.2Hz, 1H) , 5.15 (dd, J1 = 8.4Hz, J2 = 18.8Hz, 1H) , 4.97‐4.89 (m, 1H) , 4.30‐4.15 (m, 4H) , 3.99‐3.85 (m, 5H) , 3.40‐3.35 (m, 2H) , 3.21‐3.10 (m, 2H) , 2.80‐2.30 (m, 4H) , 2.05‐1.90 (m, 2H) , 1.37‐1.31 (m, 6H) , 1.17 (d, J = 6.0Hz, 6H) .
Example 22. Preparation of compound I‐5 hydrobromide (I‐22)
Compound I‐5 (0.500 g, 0.73mmol) was dissolved in iPrOH (2 mL) and concentrated HBr (0.07ml, 1.12 mmol) was added. Then the mixture was stirred for another 1 h and filtrated to give the desired salt (0.410 g) .
1H‐NMR (400 MHz, CDCl3) δ: 11.56 (brs, 1H) , 7.37 (d, J = 8.0Hz, 2H) , 7.25 (t, J = 8.0Hz, 2H) , 7.17‐7.10 (m, 3H) , 6.07 (d, J = 18.4Hz, 1H) , 5.65 (d, J = 7.6Hz, 1H) , 5.17‐5.14 (m, 1H) , 4.99‐4.87 (m, 1H) , 4.32‐4.13 (m, 4H) , 3.98‐3.83 (m, 5H) , 3.43‐3.30 (m, 2H) , 3.25‐3.08 (m, 2H) , 2.83‐2.35 (m, 4H) , 2.06‐1.93 (m, 2H) , 1.37‐1.30 (m, 6H) , 1.17 (d, J = 6.0Hz, 6H) .
Example 23. Preparation of compound I‐5 mesylate (I‐23)
Compound I‐5 (0.500 g, 0.73 mmol) was dissolved in iPrOH (2 mL) and Methanesulfonic acid (0.07 mL, 1.12 mmol) was added. Then the mixture was stirred for another 1 h and filtrated to give the desired salt (0.370 g) .
1H‐NMR (400 MHz, DMSO‐d6) δ: 11.10 (brs, 1H) , 9.70 (s, 1H) , 7.67 (d, J = 8.0Hz, 2H) , 7.36 (t, J = 8.0Hz, 2H) , 7.20‐7.13 (m, 3H) , 6.06‐6.01 (m, 1H) , 5.69 (d, J = 7.6Hz, 1H) , 5.26‐5.20 (m, 1H) , 4.92‐4.80 (m, 1H) , 4.25‐4.05 (m, 4H) , 3.83‐3.65 (m, 5H) , 3.42‐3.03 (m, 4H) , 2.90‐2.43 (m, 4H) , 2.39 (s, 3H) , 2.10‐1.90 (m, 2H) , 1.37‐1.31 (m, 6H) , 1.17 (d, J = 6.0Hz, 6H)
Example 24. Preparation of compound I‐12 hydrochloride (I‐24)
Compound I‐12 (0.500 g, 0.73mmol) was dissolved in iPrOH (2 mL) and concentrated HCl (0.09mL, 1.12 mmol) was added. Then the mixture was stirred for another 1 h and filtrated to give the desired salt (0.355 g) .
1H‐NMR (400 MHz, CDCl3) δ: 8.39‐8.34 (m, 3H) , 7.45‐7.39 (m, 3H) , 7.24‐7.20 (m, 4H) , 7.10‐7.04 (m, 1H) , 6.80 (d, J = 2.8Hz, 1H) , 6.19 (d, J = 18.8Hz, 1H) , 5.43‐5.39 (m, 2H) , 5.29 (dd, J1 = 8.4Hz, J2 = 18.8Hz, 1H) , 4.98‐4.91 (m, 1H) , 4.63‐4.56 (m, 2H) , 4.45‐4.43 (m, 2H) , 4.03‐3.97 (m, 1H) , 1.36‐1.30 (m, 6H) , 1.18 (d, J = 6.4Hz, 6H) .
Example 25. Preparation of compound I‐12 hydrobromide (I‐25)
Compound I‐12 (0.500 g, 0.73mmol) was dissolved in iPrOH (2 mL) and concentrated HBr (0.07ml, 1.12 mmol) was added. Then the mixture was stirred for another 1 h and filtrated to give the desired salt (0.390 g) .
1H‐NMR (400 MHz, CDCl3) δ: 8.54 (d, J = 7.6Hz, 1H) , 8.39‐8.37 (m, 1H) , 7.56 (t, J = 6.0Hz, 2H) , 7.48 (d, J = 8.0Hz, 1H) , 7.26‐7.20 (m, 4H) , 7.12 (t, J = 7.2Hz, 1H) , 6.89 (s, 1H) , 6.16‐6.05 (m, 2H) , 5.62 (d, J = 18.4Hz, 1H) , 5.51 (d, J = 8.4Hz, 1H) , 5.32‐5.26 (m, 2H) , 5.00‐4.91 (m, 1H) , 4.80‐4.72 (m, 1H) , 4.64‐4.60 (m, 1H) , 4.51‐4.49 (m, 1H) , 4.02‐3.98 (m, 1H) , 1.39‐1.32 (m, 6H) , 1.19 (d, J = 6.4Hz, 6H) .
Example 26. Preparation of compound I‐12 mesylate (I‐26)
Compound I‐12 (0.500 g, 0.73mmol) was dissolved in iPrOH (2 mL) and Methanesulfonic acid (0.07ml, 1.12 mmol) was added. Then the mixture was stirred for another 1 h and filtrated to give the desired salt (0.386 g) .
1H‐NMR (400 MHz, CDCl3) δ: 8.54‐8.48 (m, 2H) , 7.51‐7.44 (m, 3H) , 7.30‐7.21 (m, 4H) , 7.14‐7.11 (m, 1H) , 6.84 (d, J = 2.8Hz, 1H) , 6.13 (d, J = 18.4Hz, 1H) , 5.65‐5.45 (m, 2H) , 5.33‐5.25 (m, 1H) , 5.02‐4.88 (m, 1H) , 4.56‐4.53 (m, 2H) , 4.45‐4.43 (m, 2H) , 3.99‐3.89 (m, 1H) , 2.89 (s, 3H) , 1.41‐1.31 (m, 6H) , 1.19 (d, J = 6.4Hz, 6H) .
Example 27. Caco‐2 permeability
The purpose of this study was to evaluate the intestinal permeability of the test compounds using Caco‐2 cell monolayers. The protocol is described with the present tense as the following although the test was actually conducted:
1) Prewarm HBSS Buffer in 37℃ water bath;
2) Take compounds from ‐20℃, sonicate for a few minutes (no less than 1 minute) ;
3) Solution preparation:
Donor solution buffer: HBSS buffer with 0.3% DMSO and 5 μM LY: add 150 μL DMSO and 50 μL LY (5mM) into 50 ml HBSS buffer (pH 7.4) ; HBSS buffer with 0.1% DMSO and 5 μM LY ; add 50 μL DMSO and 50 μL LY (5 mM) into 50 mL HBSS buffer (pH7.4) .
Receiver solution buffer: Prepare HBSS buffer with 0.4% DMSO: add 200 μL DMSO into 50 ml HBSS buffer (pH7.4 ) .
4) Take cell culture plate out of incubator, wash the cell monolayers with HBSS buffer, and then measure TEER values at Rm temperature;
5) Centrifuge the compound solution (from step 3) at 4000 rpm for 5min before loading to donor chambers;
6) Add solution based on the volumes listed in the folowing table (make sure to take extra 100uL of donor sample for T0 as Backup) ;
7) To determine LY concentration in the apical chamber, take a 100 μL sample from apical chambers into an opaque plate for LYT0;
8) Prewarm apical and basolateral plates at 37℃ for about 5 min, then begin transport by placing the apical plate onto basolateral plate;
9) Keep the plates in incubator at 37℃ for 90 min;
10) Standard Curve preparation;
11) Seperate the apical plate from the basolateral plate after 90‐min incubation;
12) Take 100 μL samples from basolateral plate to an opaque plate as LYT90;
13) Measure LY concentrations for LYT0 and LYT90 by Fluorometer (at excitation of 485 nm/emission of 535 nm) ;
14) Sample preparation for LC‐MS/MS:
Donor samples (1: 10 diluted) : 6 μL of donor sample + 54 μL 0.4% DMSO HBSS+ 60 μL ACN with IS (Osalmid or Imipramine) ;
Receiver sample: 60 μL of receiver sample+ 60 μL ACN with IS (Osalmid or Imipramine) .
Compound | Sofosbuvir | I‐1 | I‐3 | I‐5 | I‐8 | I‐12 |
Papp×106/cm·s‐1 (A‐B) | 0.19 | 0.85 | 1.16 | 1.53 | 0.92 | 0.63 |
As summarized in the above table, many test compounds of this invetion showed unexpectedly better permeability than Sofosbuvir.
Example 28. Thermodynamic Aqueous Solubility
Aqueous solubility was determined by suspending a sufficient amount of compound in water to give a maximum final concentration of ≧10 mg·ml-1 of the parent free‐form of the compound. The suspension was equilibrated at 25 ℃ for 24 hours before the pH was measured. The suspension was then filtered through a glass fiber C filter into a 96‐well plate. The filtrate was then diluted by a factor of 101. Quantitation was by HPLC with reference to a standard solution of approximately 0.1 mg·ml-1 in DMSO. Different volumes of the standard, diluted and undiluted sample solutions were injected. The solubility was calculated using the peak areas determined by integration of the peak found at the same retention time as the principal peak in the standard injection.
Compared to other compounds reported to have efficacy in treating HCV infection, the compounds of this invention unexpectedly exhibited a much higher solubility that would make the compounds of this invention more ideal for manufacturing the pharmaceutical compositions of this invention and for clinical treatment of patients affected with HCV.
Compound | Sofosbuvir | I‐2 | I‐4 | I‐6 | I‐8 | I‐9 | I‐18 |
Solubility (mg/mL) | 2.0 | 6.0 | 5.2 | 4.7 | >2.0 | >2.0 | >7.0 |
Compound | Sofosbuvir | I‐19 | I‐20 | I‐21 | I‐22 | I‐23 | |
Solubility (mg/mL) | 2.0 | >7.0 | 3.9 | 5.1 | 4.2 | 3.8 |
Example 29. Biological Activity
Replicon containing cells were seeded at either 3,000 cells/well (50 μL) in 96‐well white/opaque plates, or 1,500 cells/well (25 μL) in 384‐well white/opaque plates. 50 μL of 2× compound were added in the 96‐well plate or 25 μL of 2× compound were added in the 384 well plate. The plates were incubated at 37℃. in a humidified 5% CO2 atmosphere for 4 days. After incubation, Bright‐Glo reagent (50 μL for 96‐well plate, or 25 μL for 384‐well plate) was added to measure the firefly luciferase reporter for HCV replication. Percent inhibition was calculated against the no‐drug control.
Compared to other compounds reported to have efficacy in treating HCV infection, most of the compounds of this invention unexpectedly exhibited EC50 value lower than 0.2 uM or even 0.15 or 0.10 uM. All the tested compounds exhibited lower cytotoxicity (CC50>100uM) than the control which is a drug currently in the market for inhibiting HCV virus (CC50 = 63uM) .
Compound | EC50 (uM) | Compound | EC50 (uM) | Compound | EC50 (uM) |
I‐1 | 0.312 | I‐2 | 0.235 | I‐3 | 0.156 |
I‐4 | 0.083 | I‐5 | 0.145 | I‐6 | 0.099 |
I‐7 | 0.075 | I‐8 | 0.187 | I‐9 | 0.290 |
I‐10 | 0.133 | I‐11 | 0.539 | I‐12 | 0.082 |
I‐13 | 3.28 | I‐14 | 0.159 | I‐15 | 4.87 |
I‐16 | 0.694 | I‐17 | 9.86 | Sofosbuvir | 0.134 |
Example 30. Rat PK Study
Compounds in the present invention were evaluated in vivo to determine liver levels of the active uridine triphosphate metabolite after oral administration. Each compound was administered as a single 30 mg/kg oral dose for rats, livers were removed, and liver extracts were assayed for levels of the 2’‐deoxy‐2’‐α‐F‐2’‐β‐C‐methyluridine triphosphate (NTP) . The following table shows the results of the PK study.
Compared to other compounds reported to have efficacy in treating HCV infection, most of the compounds of this invention exhibited unexpectedly higher Cmax values than Sofosbuvir. More importantly, all the tested compounds had much more drug exposure of the active NTP metabolite in the liver.
All the above results showed that the present invention provided a new kind of compounds with excellent PK properties, as anti‐HCV inhibitors.
Examples of the present invention is only to illustrate the technical concept and features, its purpose is to allow a person skilled in the art is able to understand the content and according to the present invention to implement, and not to limit the scope of the present invention. All publications referred to herein are incorporated by reference in their entireties. Where the spirit of the present invention made equivalent transformation or modification, should be covered by the present invention within the scope of protection.
Claims (25)
- A compound of Formula (I) or a pharmaceutically accepted salt, ester, or prodrug thereof,whereinR1 is aryl, heteroaryl, arylalkyl, or heteroarylalkyl;each of R2 and R3 independently is hydrogen, alkyl, or heteroaryl, provided that when one of R2 and R3 is hydrogen or alkyl, the other one must be heteroaryl; orR2 and R3, together with the nitrogen atom to which they are attached, form a 5‐to 7‐membered optionally substituted heterocyclic optionally having one or two more heteroatoms (in addition to the nitrogen atom to which R2 and R3 are attached) each of which is independently O, S, or NR6, wherein R6 is hydrogen, alkyl, acyl, aryl, or heteroaryl; the heterocyclic is optionally substituted at its ring carbon atom (s) with alkyl, halo, or alkoxycarbony;R4 is hydrogen or alkyl;R5 is hydrogen or alkyl;X is a bond, O, NH, or N‐alkyl;n is 1, 2, 3, or 4.
- The compound of claim 1, wherein R1 is aryl or heteroaryl.
- The compound of claim 1 or 2, wherein R1 is phenyl or naphthyl.
- The compound of any of claims 1‐3, wherein R2 is H, and R3 is heteroaryl.
- The compound of claim 1, wherein R2 and R3, together with the nitrogen atom to which they are attached, form a 5‐to 7‐membered heterocyclic optionally having one or more heteroatoms each of which is independently O, S, or NR6, wherein R6 is hydrogen, alkyl, acyl, aryl, or heteroaryl; the heterocyclic is optionally substituted at its ring carbon atom (s) with alkyl, halo, or alkoxycarbony.
- The compound of claim 1, wherein the heterocyclic formed by R2 and R3, together with the nitrogen atom to which they are attached, is heteroaryl.
- The compound of claim 1, wherein R4 is methyl or ethyl.
- The compound of claim 1, wherein R5 is methyl, ethyl or isopropyl.
- The compound of claim 1, wherein X is a bond, O or NH.
- The compound of claim 1, wherein n is 1, 2, 3 or 4.
- The compound of claim 1, wherein the phosphorous atom is chiral and at least 90%is of the S steoroisomer.
- The compound of claim 14, wherein at least 97%of the phosphorous atom is of the S steoroisomer.
- The compound of any of claims 1‐15, wherein the compound is a pharmaceutically acceptable salt.
- The compound of any of claims 1‐16, wherein the compound is an acetate, 4‐methylbenzenesulfonate, mesylate, hydrochloride, or hydrobromide salt.
- The compound of claim 1, wherein the compound isisopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyl‐3‐ (2‐morpholinoacetoxy) tetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate;isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyl‐3‐ (2‐morpholinoacetoxy) tetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate 4‐methylbenzenesulfonate;(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 3‐morpholinopropanoate;(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 3‐morpholinopropanoate 4‐methylbenzenesulfonate;(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐morpholinobutanoate;(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐morpholinobutanoate 4‐methylbenzenesulfonate;(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐ (dimethylamino) butanoate;(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐ (pyridin‐2‐ylamino) butanoate hydrochloride;(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐ (isoquinolin‐1‐ylamino) butanoate hydrochloride;isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐3‐ (2‐ (7H‐pyrrolo [2, 3‐b] pyridin‐7‐yl) acetoxy) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyltetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate;(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐ (1H‐pyrrolo [2, 3‐b] pyridin‐1‐yl) butanoate;isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐3‐ (2‐ (1H‐pyrrolo [2, 3‐b] pyridin‐1‐yl) acetoxy) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyltetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate;methyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyl‐3‐ ( (3‐morpholinopropanoyl) oxy) tetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐valinate;(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐ethoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐fluoro‐4‐methyltetrahydrofuran‐3‐yl 3‐morpholinopropanoate;isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyl‐3‐ ( ( (3‐morpholinopropyl) carbamoyl) oxy) tetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate;ethyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyl‐3‐ ( ( (3‐morpholinopropyl) carbamoyl) oxy) tetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate;isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐3‐ ( ( (2‐ (1H‐pyrrolo [2, 3‐b] pyridin‐1‐yl) ethyl) carbamoyl) oxy) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyltetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate;(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 3‐morpholinopropanoate hydrochloride;(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 3‐morpholinopropanoate hydrobromide;(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 3‐morpholinopropanoate mesylate;(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐ (dimethylamino) butanoate hydrochloride;(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐ (dimethylamino) butanoate hydrobromide;(2R, 3R, 4R, 5R) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐2‐ ( ( ( (S) ‐ ( ( (S) ‐1‐isopropoxy‐1‐oxopropan‐2‐yl) amino) (phenoxy) phosphoryl) oxy) methyl) ‐4‐methyltetrahydrofuran‐3‐yl 4‐ (dimethylamino) butanoate mesylate;isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐3‐ (2‐ (1H‐pyrrolo [2, 3‐b] pyridin‐1‐yl) acetoxy) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyltetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate hydrochloride;isopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐3‐ (2‐ (1H‐pyrrolo [2, 3‐b] pyridin‐1‐yl) acetoxy) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyltetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate hydrobromide; orisopropyl ( (S) ‐ ( ( (2R, 3R, 4R, 5R) ‐3‐ (2‐ (1H‐pyrrolo [2, 3‐b] pyridin‐1‐yl) acetoxy) ‐5‐ (2, 4‐dioxo‐3, 4‐dihydropyrimidin‐1 (2H) ‐yl) ‐4‐fluoro‐4‐methyltetrahydrofuran‐2‐yl) methoxy) (phenoxy) phosphoryl) ‐L‐alaninate hydrobromide.
- A pharmaceutical composition comprising a compound of any of claims 1‐18 and a pharmaceutically acceptable medium.
- A method for treating a hepatitis C virus infection in a human, comprising administering to the human in need thereof an effective amount of a compound of any of claims 1‐18 or a pharmaceutical composition of claim 19.
- The pharmaceutical composition according to claim 19, characterized in that said pharmaceutical composition further comprises a second therapeutic agent, and said second therapeutic agent is an HCV antiviral agent, an immunomodulator, or an anti‐infective agent.
- The pharmaceutical composition according to claim 21, characterized in that the HCV antiviral agent is an HCV protease inhibitor, an HCV NS5A inhibitor or an HCV NS5B polymerase inhibitor.
- Use of a compound of any of claims 1‐17 in the manufacturing of a medicament for the treatment of a hepatitis C virus infection in a human.
- The use according to claim 23, characterized in that the medicament further comprises at least a second therapeutic agent selected from the group consisting of an HCV antiviral agent, an immunomodulator, and an anti‐infective agent.
- The use according to claim 24, characterized in that the HCV antiviral agent is an HCV protease inhibitor, an HCV NS5A inhibitor or an HCV NS5B polymerase inhibitor.
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CN103608020A (en) * | 2011-06-10 | 2014-02-26 | 弗·哈夫曼-拉罗切有限公司 | Method of treating dengue fever |
WO2014062596A1 (en) * | 2012-10-17 | 2014-04-24 | Merck Sharp & Dohme Corp. | 2'-methyl substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases |
CN104031104A (en) * | 2013-03-08 | 2014-09-10 | 南京圣和药业有限公司 | Novel nucleoside phosphoramidite chemical compounds and applications thereof |
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JP2013527145A (en) * | 2010-03-31 | 2013-06-27 | ギリード・ファーマセット・エルエルシー | Stereoselective synthesis of phosphorus-containing activators |
RU2534613C2 (en) * | 2013-03-22 | 2014-11-27 | Александр Васильевич Иващенко | Alkyl2-{[(2r,3s,5r)-5-(4-amino-2-oxo-2h-pyrimidine-1-yl)- -hydroxy- tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-proptonates, nucleoside inhibitors of rna-polymerase hcv ns5b, methods for producing and using them |
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CN103608020A (en) * | 2011-06-10 | 2014-02-26 | 弗·哈夫曼-拉罗切有限公司 | Method of treating dengue fever |
WO2014062596A1 (en) * | 2012-10-17 | 2014-04-24 | Merck Sharp & Dohme Corp. | 2'-methyl substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases |
CN104031104A (en) * | 2013-03-08 | 2014-09-10 | 南京圣和药业有限公司 | Novel nucleoside phosphoramidite chemical compounds and applications thereof |
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