D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease
Provided herein are compounds, compositions, and methods for the treatment of viral infections, for example, Flaviviridae infections, including HCV infections. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents. In certain embodiments, the compounds are D-amino acid phosphoramidate halogeno pyrimidine nucleoside analog compounds which display remarkable efficacy and bioavailability for the treatment of, for example, HCV infection in a human. In certain embodiments, the compounds are of Formula I: or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: PD, X, R 1 , R 2 , R A , and R B are as described herein.
1. A compound according to Formula XII:
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof, wherein:
X is phenyl or naphthyl;
R 1 is unsubstituted alkyl or substituted alkyl;
R 2 is hydroxyl or amino;
R A is fluoro, chloro, bromo, or iodo; and
R B is hydroxyl, fluoro, or chloro.
2. The compound of claim 1 according to Formula II:
wherein R 1 is unsubstituted alkyl and R 2 is NH 2 ,
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
3. The compound of claim 1 according to Formula III:
wherein R 1 is unsubstituted alkyl and R 2 is NH 2 ,
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
4. The compound of claim 1 according to Formula IV:
wherein R 1 is unsubstituted alkyl and R 2 is NH 2 ,
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
5. The compound of claim 1 according to Formula V:
wherein R 1 is unsubstituted alkyl and R 2 is NH 2 ,
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
6. The compound of claim 1 according to Formula VI:
wherein R 1 is unsubstituted alkyl and R 2 is NH 2 , or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
7. The compound of claim 1 according to Formula XI:
wherein R 1 is unsubstituted alkyl and R 2 is NH 2 ,
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
8. The compound of claim 1 according to Formula VII:
wherein R 1 is unsubstituted alkyl and R 2 is NH 2 ,
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
9. The compound of claim 1 according to Formula VIII:
wherein R 1 is unsubstituted alkyl and R 2 is NH 2 ,
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
10. The compound of claim 1 according to Formula IX:
wherein R 1 is unsubstituted alkyl and R 2 is NH 2 ,
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
11. The compound of claim 1 according to Formula X:
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
12. The compound of claim 1 wherein R 1 is methyl, CF 3 , CCl 3 , CFCl 2 , CF 2 Cl, ethyl, CH 2 CF 3 , CF 2 CF 3 , propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, or 2,3-dimethylbutyl.
13. The compound of claim 1 wherein —R 1 is isopropyl.
14. The compound of claim 1 according to Formula XIIa or XIIb:
15. The compound of claim 1 , wherein:
R 2 is —NR 1′ R 2′ ; and
R 1′ and R 2′ are each independently hydrogen, methyl, CF 3 , CCl 3 , CFCl 2 , CF 2 Cl, ethyl, CH 2 CF 3 , CF 2 CF 3 , propyl, isopropyl, butyl, isobutyl, secbutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, ethenyl, n-propenyl, isopropenyl, ethynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, adamantyl, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, 3-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, 1,3,5-trithianyl, phenyl, biphenyl, naphthyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, thienopyridyl, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, or xanthenyl.
16. The compound according to claim 1 selected from
or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof.
17. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient, carrier, or diluent; wherein the composition is an oral formulation.
18. A method for the treatment of a host infected with a virus, comprising administering an effective amount of a compound of claim 1 ; wherein the host is a human; and wherein the virus is a hepatitis C virus.
19. The method of claim 18 comprising directing a substantial amount of the compound, or pharmaceutically acceptable salt or stereoisomer thereof, to a liver of the host.
20. The method of claim 18 comprising administering a second anti-viral agent in combination or alternation with the compound or the composition, wherein the second anti-viral agent is an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, or a combination thereof.
21. The method of claim 20 , wherein the second anti-viral agent is samatasvir, simeprevir, sofosbuvir, telaprevir, boceprevir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, or a combination thereof.