# Patent

## Title
Solid forms of a thiophosphoramidate nucleotide prodrug

## Abstract

The present application relates to solid state forms, for example, crystalline forms of 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate, pharmaceutical compositions that can include one or more solid forms of 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate, and methods of treating or ameliorating diseases and/or conditions with one or more solid forms of 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate. Also disclosed herein are methods of treating diseases and/or conditions with one or more solid forms of 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate in combination with one or more other agents.

## Background
CROSS-REFERENCE TO RELATED APPLICATION
This application is a continuation of U.S. Ser. No. 13/794,380, filed Mar. 11, 2013, which claims priority under 35 U.S.C. 119(e) to U.S. provisional application No. 61/613,972, filed on Mar. 21, 2012. The entire contents of which is incorporated herein by reference.


TECHNICAL FIELD
The present application relates to solid state forms, for example, crystalline forms of 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate, pharmaceutical compositions that can include one or more solid forms of 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate, and methods of treating or ameliorating diseases and/or conditions with one or more solid forms of 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate. Also disclosed herein are methods of treating diseases and/or conditions with one or more solid forms of 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate in combination with one or more other agents.
BACKGROUND
Nucleoside analogs are a class of compounds that have been shown to exert antiviral and anticancer activity both in vitro and in vivo, and thus, have been the subject of widespread research for the treatment of viral infections and cancer. Nucleoside analogs are usually therapeutically inactive compounds that are converted by host or viral enzymes to their respective active anti-metabolites, which, in turn, may inhibit polymerases involved in viral or cell proliferation. The activation occurs by a variety of mechanisms, such as the addition of one or more phosphate groups and, or in combination with, other metabolic processes.
SUMMARY
Some embodiments disclosed herein generally relate to solid forms of 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate (hereinafter “Compound 1”) which has the structure below:




In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form A.
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form B.
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form C.
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form D.
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form E.
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form F.
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form G.
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form H.
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form I.
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form J.
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form K.
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form L.
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form M.
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form N.
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Amorphous Form O.
Some embodiments disclosed herein generally relate to a process for producing Form A that can include:
a) contacting Compound 1 with a first amount of ethyl acetate to form a mixture;
b) heating the mixture until the solids are dissolved;
c) cooling the mixture to allow precipitation of a solid;
d) optionally adding a second amount of ethyl acetate and repeating steps a, b and c; and
e) isolating Form A from said mixture.
Some embodiments disclosed herein generally relate to a process for producing Form J that can include:
a) contacting Amorphous Form O with ethanol to form a mixture; and
b) isolating Form J from said mixture.
Some embodiments disclosed herein generally relate to a process for producing a solvated solid form of Compound 1 that can include:
a) contacting Compound 1 with a solvent to form a mixture; and
b) isolating the solvated solid form of Compound 1 from said mixture.
Some embodiments disclosed herein generally relate to a method of ameliorating or treating a viral infection (for example, a HCV infection) in a subject, said method can include administering to said subject an effective amount of one or more solid forms of Compound 1 as described herein.
Some embodiments disclosed herein relate to a pharmaceutical composition that can include one or more solid forms of Compound 1 as described herein.
Some embodiments disclosed herein generally relate to a pharmaceutical composition that can include one or more solid forms of Compound 1, and one or more additional agent(s).
Some embodiments disclosed herein relate to a method of ameliorating and/or treating a HCV infection that can include administering to a subject identified as suffering from the HCV infection an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, one or more solid forms of Compound 1, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, in combination with an agent selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an other antiviral compound, a compound of Formula (BB) and a compound of Formula (DD), or a pharmaceutically acceptable salt of any of the foregoing.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an XRPD spectrum of Form A.
FIG. 2 is a DSC spectrum of Form A.
FIG. 3 is a 13C ssNMR spectrum of Form A.
FIG. 4 is an XRPD spectrum of Form B.
FIG. 5 is a 13C ssNMR spectrum of Form B.
FIG. 6 is an XRPD spectrum of Form C.
FIG. 7 is a 13C ssNMR spectrum of Form C.
FIG. 8 is an XRPD spectrum of Form D.
FIG. 9 is a 13C ssNMR spectrum of Form D.
FIG. 10 is an XRPD spectrum of a mixture of Form A and Form E.
FIG. 11 is a 13C ssNMR spectrum of a mixture of Form A and Form E.
FIG. 12 is an XRPD spectrum of a mixture of Form A and Form F.
FIG. 13 is a 13C ssNMR spectrum of a mixture of Form A and Form F.
FIG. 14 is an XRPD spectrum of Form G.
FIG. 15 is a 13C ssNMR spectrum of Form G.
FIG. 16 is an XRPD spectrum of Form H.
FIG. 17 is a 13C ssNMR spectrum of Form H.
FIG. 18 is an XRPD spectrum of Form I.
FIG. 19 is a 13C ssNMR spectrum of Form I.
FIG. 20 is an XRPD spectrum of Form J.
FIG. 21 is a DSC spectrum of Form J.
FIG. 22 is a 13C ssNMR spectrum of Form J.
FIG. 23 is an XRPD spectrum of Form K.
FIG. 24 is a 13C ssNMR spectrum of Form K.
FIG. 25 is an XRPD spectrum of Form L.
FIG. 26 is a 13C ssNMR spectrum of Form L.
FIG. 27 is an XRPD spectrum of Form M.
FIG. 28 is a 13C ssNMR spectrum of Form M.
FIG. 29 is an XRPD spectrum of Form N.
FIG. 30 is a 13C ssNMR spectrum of Form N.
FIG. 31 is an XRPD spectrum of Amorphous Form O.
FIG. 32 shows examples of additional agents that can be used to treat HCV.
FIG. 33 shows examples of Compounds of Formula (BB).
FIG. 34 shows the generic Formula (DD).



DETAILED DESCRIPTION
Definitions
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. As used herein, the following definitions shall apply unless otherwise indicated.
The term “crystalline” refers to a substance that has its atoms, molecules or ions packed in a regularly ordered three-dimensional pattern. The term “substantially crystalline” refers to a substance where a substantial portion of the substance is crystalline. For example, substantially crystalline materials can have more than about 85% crystallinity (e.g., more than about 90% crystallinity, more than about 95% crystallinity, or more than about 99% crystallinity).
The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 11:942-944 (1972)).
The term “nucleoside” refers to a compound composed of an optionally substituted pentose moiety or modified pentose moiety attached to a heterocyclic base or tautomer thereof via a N-glycosidic bond, such as attached via the 9-position of a purine-base or the 1-position of a pyrimidine-base. Examples include, but are not limited to, a ribonucleoside comprising a ribose moiety and a deoxyribonucleoside comprising a deoxyribose moiety. A modified pentose moiety is a pentose moiety in which an oxygen atom has been replaced with a carbon and/or a carbon has been replaced with a sulfur or an oxygen atom. A “nucleoside” is a monomer that can have a substituted base and/or sugar moiety. Additionally, a nucleoside can be incorporated into larger DNA and/or RNA polymers and oligomers. In some instances, the nucleoside can be a nucleoside analog drug.
The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.
As used herein, the term “room temperature” refers to a temperature in the range of about 20° C. to about 25° C., such as a temperature in the range of about 21° C. to about 23° C.
Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. In addition, the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition or device, the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components. Likewise, a group of items linked with the conjunction ‘and’ should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as ‘and/or’ unless expressly stated otherwise. Similarly, a group of items linked with the conjunction ‘or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as ‘and/or’ unless expressly stated otherwise.
With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.
It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Unless otherwise stated, all tautomeric forms of Compound 1 are intended to be included.
Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included. For example all tautomers of phosphate groups are intended to be included. Furthermore, all tautomers of heterocyclic bases known in the art are intended to be included, including tautomers of natural and non-natural purine-bases and pyrimidine-bases.
It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2 (deuterium).
It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.
Example Embodiments of Compound 1
All XRPD spectra provided herein are measured on a degrees 2-Theta scale, and all 13C solid state NMR's are referenced to adamantane at 29.5 ppm.
Form A
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form A.
In some embodiments, Form A can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak in the range of from about 6.8 to about 7.2 degrees, a peak in the range of from about 8.3 to about 8.7 degrees, a peak in the range of from about 15.6 to about 16.0 degrees, a peak in the range of from about 21.2 to about 21.6 degrees, a peak in the range of from about 21.8 to about 22.2 degrees, a peak in the range of from about 22.4 to about 22.8 degrees, and a peak in the range of from about 23.1 to about 23.5 degrees.
In some embodiments, Form A can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak in the range of from about 6.8 to about 7.2 degrees, a peak in the range of from about 8.3 to about 8.7 degrees, a peak in the range of from about 15.6 to about 16.0 degrees and a peak in the range of from about 21.2 to about 21.6 degrees.
In some embodiments, Form A can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 7.0 degrees, a peak at about 8.5 degrees, a peak at about 15.8 degrees, a peak at about 21.4 degrees, a peak at about 22.0 degrees, a peak at about 22.6 degrees, and a peak at about 23.3 degrees.
In some embodiments, Form A can be characterized by a peak at about 8.5 degrees, a peak at about 15.8 degrees, and a peak at about 21.4 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form A can be characterized by a peak at about 8.5 degrees, a peak at about 15.8 degrees, a peak at about 21.4 degrees, a peak at about 22.0 degrees, a peak at about 22.6 degrees, and a peak at about 23.3 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form A can be characterized by a peak at about 7.0 degrees, a peak at about 8.5 degrees, a peak at about 15.8 degrees, and a peak at about 21.4 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form A can be characterized by a peak at about 7.0 degrees, a peak at about 8.5 degrees, a peak at about 15.8 degrees, a peak at about 21.4 degrees, a peak at about 22.0 degrees, a peak at about 22.6 degrees, and a peak at about 23.3 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form A can exhibit an X-ray powder diffraction pattern as shown in FIG. 1.
In some embodiments, Form A can be characterized by one or more peaks in an X-ray powder diffraction pattern selected from the table below.












No.
2-Theta °
Intensity %

















1
7.0*
91.8


2
8.5*
100.0


3
10.0
70.0


4
11.0
73.4


5
14.7
90.3


6
15.5
76.7


7
15.8*
79.6


8
16.6
90.9


9
17.8
81.1


10
18.0
99.2


11
18.8
72.2


12
19.9
76.1


13
20.8
73.5


14
21.4*
77.0


15
22.0**
68.9


16
22.6**
73.0


17
23.3**
68.8


18
25.8
71.7


19
28.7
67.4





Peaks with an asterisk (*) are major peaks


Peaks with a double asterisk (**) are secondary peaks






In some embodiments, Form A can be characterized by a DSC thermogram as shown in FIG. 2. In some embodiments, Form A can be characterized by a melting point in the range of from about 137° C. to about 139° C. In other embodiments, Form A can be characterized by a melting point of about 138° C. In some embodiments, Form A can be characterized by a melting point of about 138.4° C. In some embodiments, Form A can be characterized by an endotherm in the range of from about 137° C. to about 139° C. In other embodiments, Form A can be characterized by an endotherm of about 138° C. In some embodiments, Form A can be characterized by an endotherm of about 138.4° C.
In some embodiments, Form A can be characterized by a peak at about 130.4 ppm, a peak at about 69.5 ppm, a peak at about 66.9 ppm, and a peak at about 20.6 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form A can be characterized by a peak at about 172.0 ppm, a peak at about 146.6 ppm, a peak at about 130.4 ppm, a peak at about 104.1 ppm, a peak at about 69.5 ppm, a peak at about 66.9 ppm, and a peak at about 20.6 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form A can exhibit a 13C NMR solid state spectrum as shown in FIG. 3.
In some embodiments, Form A can be characterized by one or more peaks in a 13C NMR solid state spectrum selected from the table below.













ν(F1)
Intensity


Peak #
[ppm]
[rel]

















1
173.0
24.12


2
172.0*
23.11


3
170.2
24.80


4
151.3
28.62


5
150.5
38.71


6
146.6*
14.23


7
143.9
12.74


8
130.4*
36.15


9
126.2
27.80


10
122.9
3.91


11
120.4
33.00


12
104.1*
23.68


13
102.2
23.18


14
92.8
20.65


15
92.2
17.13


16
84.1
27.03


17
79.7
68.89


18
75.0
28.02


19
73.5
33.05


20
69.5*
34.76


21
69.2
27.63


22
66.9*
40.98


23
50.4
22.59


24
21.9
100.00


25
20.6*
39.44





Peaks with an asterisk (*) are major peaks






Form B
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form B.
In some embodiments, Form B can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak in the range of from about 5.5 to about 5.9 degrees, a peak in the range of from about 9.2 to about 9.6 degrees, a peak in the range of from about 16.8 to about 17.2 degrees, and a peak in the range of from about 26.0 to about 26.4 degrees.
In some embodiments, Form B can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 5.7 degrees, a peak at about 9.4 degrees, a peak at about 17.0 degrees, and a peak at about 26.2 degrees.
In some embodiments, Form B can be characterized by a peak at about 5.7 degrees, a peak at about 9.4 degrees, a peak at about 17.0 degrees, and a peak at about 26.2 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form B can be characterized by an X-ray diffraction pattern of FIG. 4.
In some embodiments, Form B can be characterized by one or more peaks in an X-ray powder diffraction pattern selected from the table below.












No.
2-Theta °
Intensity %

















1
5.720*
71.8


2
9.395*
31.2


3
17.042*
100.0


4
26.219*
28.5





Peaks with an asterisk (*) are major peaks






In some embodiments, Form B can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 173.2 ppm, a peak at about 129.9 ppm, a peak at about 118.3 ppm, a peak at about 68.5 ppm, a peak at about 27.1 ppm, or a peak at about 19.5 ppm.
In some embodiments, Form B can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 173.2 ppm, a peak at about 129.9 ppm, a peak at about 118.3 ppm, a peak at about 72.3 ppm, a peak at about 68.5 ppm, a peak at about 49.2 ppm, a peak at about 27.1 ppm and a peak at about 19.5 ppm. In some embodiments, Form B can be a methyl tert-butyl solvate.
In some embodiments, Form B can be characterized by a peak at about 118.3 ppm, a peak at about 68.5 ppm, and a peak at about 27.1 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form B can be characterized by a peak at about 173.2 ppm, a peak at about 129.9 ppm, a peak at about 118.3 ppm, a peak at about 68.5 ppm, a peak at about 27.1 ppm, and a peak at about 19.5 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form B can be characterized by a 13C NMR solid state spectrum of FIG. 5.
In some embodiments, Form B (methyl tert-butyl ether solvate) can be characterized by one or more peaks in a 13C NMR solid state spectrum selected from the table below.













ν(F1)
Intensity


Peak
[ppm]
[rel]

















1
173.2*
55.0


2
169.9
24.91


3
151.1
50.46


4
144.7
20.81


5
129.9*
100.00


6
123.3
47.74


7
118.3*
77.98


8
103.5
41.84


9
92.8
29.78


10
82.4
43.94


11
79.8
88.11


12
74.1
57.28


13
72.3*
20.83


14
68.5*
76.94


15
68.1
67.80


16
50.9
12.62


17
50.3
27.03


18
49.2*
57.83


19
27.1*
61.90


20
22.6
76.64


21
22.2
75.51


22
22.0
16.01


23
21.7
65.44


24
19.5*
52.58





Peaks with an asterisk (*) are major peaks






In some embodiments, Form B can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 170.3 ppm, a peak at about 150.5 ppm, a peak at about 129.8 ppm, a peak at about 118.2 ppm, a peak at about 79.8 ppm, a peak at about 27.2 ppm, and a peak at about 21.8 ppm.
In other embodiments, Form B can be a cyclohexane solvate.
In some embodiments, Form B can be characterized by a peak at about 150.5 ppm, a peak at about 129.8 ppm, a peak at about 118.2 ppm, and a peak at about 21.8 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form B can be characterized by a peak at about 170.3 ppm, a peak at about 150.5 ppm, a peak at about 129.8 ppm, a peak at about 118.2 ppm, a peak at about 79.8 ppm, a peak at about 27.2 ppm, and a peak at about 21.8 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form B (cyclohexane solvate) can be characterized by one or more peaks in a 13C NMR solid state spectrum selected from the table below.













ν(F1)
Intensity


Peak #
[ppm]
[rel]

















1
172.6
20.01


2
170.3*
26.09


3
150.5*
39.10


4
146.6
15.32


5
144.4
12.23


6
129.8*
31.00


7
126.3
25.02


8
122.6
15.89


9
120.4
26.04


10
118.2*
30.57


11
104.1
18.00


12
102.2
17.34


13
92.8
19.56


14
84.2
16.62


15
79.8*
53.48


16
75.0
22.56


17
73.6
20.49


18
69.5
21.11


19
68.1
19.74


20
66.9
21.59


21
64.0
13.37


22
50.5
20.41


23
40.8
12.34


24
27.2*
21.00


25
21.8*
100.00


26
18.6
15.87





Peaks with an asterisk (*) are major peaks






Form C
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form C.
In some embodiments, Form C can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak in the range of from about 4.8 to about 5.2 degrees, a peak in the range of from about 6.4 to about 6.8 degrees, a peak in the range of from about 8.0 to about 8.4 degrees, a peak in the range of from about 9.0 to about 9.4 degrees, a peak in the range of from about 9.4 to about 9.8 degrees, a peak in the range of from about 16.1 to about 16.5 degrees, and a peak in the range of from about 22.1 to about 22.5 degrees.
In some embodiments, Form C can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 5.0 degrees, a peak at about 6.6 degrees, a peak at about 8.2 degrees, a peak at about 9.2 degrees, a peak at about 9.6 degrees, a peak at about 16.3 degrees, and a peak at about 22.3 degrees.
In some embodiments, Form C can be characterized by a peak at about 5.0 degrees, a peak at about 6.6 degrees, a peak at about 8.2 degrees, and a peak at about 22.3 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form C can be characterized by a peak at about 5.0 degrees, a peak at about 6.6 degrees, a peak at about 8.2 degrees, a peak at about 9.2 degrees, a peak at about 9.6 degrees, a peak at about 16.3 degrees, and a peak at about 22.3 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form C can be characterized by an X-ray powder diffraction pattern of FIG. 6.
In some embodiments, Form C can be characterized by one or more peaks in an X-ray powder diffraction pattern selected from the table below.












No.
2-Theta °
Intensity %

















1
4.980*
27.4


2
6.573*
31.0


3
8.174*
39.0


4
9.151**
47.4


5
9.585**
56.2


6
16.337**
62.7


7
22.340*
28.1





Peaks with an asterisk (*) are major peaks


Peaks with a double asterisk (**) are secondary peaks






In some embodiments, Form C can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 173.7 ppm, a peak at about 151.9 ppm, a peak at about 103.2 ppm, a peak at about 83.3 ppm, a peak at about 80.8 ppm, a peak at about 73.3 ppm, a peak at about 25.1 ppm, and a peak at about 20.1 ppm.
In some embodiments, Form C can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 173.7 ppm, a peak at about 151.9 ppm, a peak at about 103.2 ppm, a peak at about 83.3 ppm, a peak at about 80.8 ppm, a peak at about 73.3 ppm, a peak at about 63.8 ppm, a peak at about 25.1 ppm, and a peak at about 20.1 ppm.
In some embodiments, Form C can be characterized by a peak at about 173.7 ppm, a peak at about 83.3 ppm, a peak at about 80.8 ppm, and a peak at about 25.1 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form C can be characterized by a peak at about 173.7 ppm, a peak at about 151.9 ppm, a peak at about 103.2 ppm, a peak at about 83.3 ppm, a peak at about 80.8 ppm, a peak at about 73.3 ppm, a peak at about 25.1 ppm, and a peak at about 20.1 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form C can be characterized by a 13C NMR solid state spectrum of FIG. 7.
In some embodiments, Form C can be characterized by one or more peaks in a 13C NMR solid state spectrum selected from the table below.













ν(F1)
Intensity


Peak
[ppm]
[rel]

















1
173.7*
72.2


2
163.6
27.15


3
162.7
27.66


4
152.6
33.02


5
151.9*
39.39


6
151.3
17.72


7
150.4
19.06


8
144.1
20.92


9
140.7
19.90


10
129.6
32.86


11
126.7
18.14


12
126.1
20.87


13
125.5
22.15


14
123.3
27.16


15
122.8
35.54


16
103.2*
40.00


17
102.5
24.12


18
101.9
21.60


19
93.3
34.02


20
92.4
35.66


21
83.3*
51.71


22
81.5
57.50


23
80.8*
54.60


24
80.3
75.92


25
73.3*
88.51


26
69.4
39.18


27
68.3
39.61


28
65.5
23.22


29
64.9
26.70


30
63.8*
54.98


31
51.8
21.78


32
50.6
28.73


33
25.1*
71.94


34
20.8
88.14


35
20.1*
100.00


36
18.8
24.24





Peaks with an asterisk (*) are major peaks






Form D
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form D.
In some embodiments, Form D can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak in the range of from about 7.9 to about 8.3 degrees, a peak in the range of from about 13.2 to about 13.6 degrees, a peak in the range of from about 14.2 to about 14.6 degrees, a peak in the range of from about 17.0 to about 17.4 degrees, a peak in the range of from about 29.4 to about 29.8 degrees, and a peak in the range of from about 34.8 to about 35.2 degrees.
In some embodiments, Form D can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 8.1 degrees, a peak at about 13.4 degrees, a peak at about 14.4 degrees, a peak at about 17.2 degrees, a peak at about 29.6 degrees, and a peak at about 35.0 degrees.
In some embodiments, Form D can be characterized by a peak at about 8.1 degrees, a peak at about 13.4 degrees, a peak at about 29.6 degrees, and a peak at about 35.0 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form D can be characterized by a peak at about 8.1 degrees, a peak at about 13.4 degrees, a peak at about 14.4 degrees, a peak at about 17.2 degrees, a peak at about 29.6 degrees, and a peak at about 35.0 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form D can be characterized by an X-ray powder diffraction pattern of FIG. 8.
In some embodiments, Form D can be characterized by one or more peaks in an X-ray powder diffraction pattern selected from the table below.












No.
2-Theta °
Intensity %

















1
8.105*
55.6


2
13.357*
44.1


3
14.424**
100.0


4
17.215**
66.0


5
29.590*
29.1


6
35.019*
25.3





Peaks with an asterisk (*) are major peaks


Peaks with a double asterisk (**) are secondary peaks






In some embodiments, Form D can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 139.1 ppm, a peak at about 125.3 ppm, a peak at about 120.8 ppm, a peak at about 105.2 ppm, a peak at about 72.8 ppm, a peak at about 67.5 ppm, and a peak at about 63.0 ppm.
In some embodiments, Form D can be characterized by a peak at about 125.3 ppm, a peak at about 105.2 ppm, a peak at about 72.8 ppm, and a peak at about 67.5 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form D can be characterized by a peak at about 139.1 ppm, a peak at about 125.3 ppm, a peak at about 120.8 ppm, a peak at about 105.2 ppm, a peak at about 72.8 ppm, a peak at about 67.5 ppm, and a peak at about 63.0 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form D can be characterized by a 13C NMR solid state spectrum of FIG. 9.
In some embodiments, Form D can be characterized by one or more peaks in a 13C NMR solid state spectrum selected from the table below.













ν(F1)
Intensity


Peak #
[ppm]
[rel]

















1
172.5
31.47


2
170.3
39.91


3
163.0
36.97


4
152.7
57.96


5
150.4
41.72


6
143.3
19.06


7
139.1*
20.55


8
130.9
74.16


9
130.2
33.92


10
125.3*
71.51


11
124.4
39.60


12
120.8*
61.60


13
105.2*
73.13


14
92.3
31.47


15
91.0
29.46


16
81.8
47.28


17
79.9
100.00


18
78.5
65.96


19
73.6
52.41


20
72.8*
51.48


21
69.4
48.17


22
67.5*
45.52


23
63.0*
84.89


24
53.6
23.06


25
50.8
25.81


26
23.7
50.37


27
22.8
89.54


28
22.0
51.17


29
21.3
98.72


30
20.8
54.41


31
18.3
54.61





Peaks with an asterisk (*) are major peaks






Form E
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form E.
In some embodiments, Form E can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak in the range of from about 7.6 to about 8.0 degrees, a peak in the range of from about 10.4 to about 10.8 degrees, a peak in the range of from about 12.7 to about 13.1 degrees, a peak in the range of from about 21.4 to about 21.8 degrees, a peak in the range of from about 24.3 to about 24.7 degrees, and a peak in the range of from about 24.8 to about 25.2 degrees.
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form E.
In some embodiments, Form E can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak in the range of from about 7.6 to about 8.0 degrees, a peak in the range of from about 12.7 to about 13.1 degrees, a peak in the range of from about 21.4 to about 21.8 degrees, and a peak in the range of from about 24.8 to about 25.2 degrees.
In some embodiments, Form E can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 7.8 degrees, a peak at about 10.6 degrees, a peak at about 12.9 degrees, a peak at about 21.6 degrees, a peak at about 24.5 degrees, and a peak at about 25.0 degrees.
In some embodiments, Form E can be characterized by a peak at about 7.8 degrees, a peak at about 10.6 degrees, a peak at about 12.9 degrees, a peak at about 21.6 degrees, a peak at about 24.5 degrees, and a peak at about 25.0 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form E can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak from about 7.6 to about 8.0 degrees, a peak from about 10.4 to about 10.8 degrees, a peak from about 12.7 to about 13.1 degrees, a peak from about 24.3 to about 24.7 degrees, and a peak from about 24.8 to about 25.2 degrees.
In some embodiments, Form E can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 7.8 degrees, a peak at about 10.6 degrees, a peak at about 12.9 degrees, a peak at about 24.5 degrees, and a peak at about 25.0 degrees.
In some embodiments, Form E can be characterized by a peak at about 7.8 degrees, a peak at about 12.9 degrees, and a peak at about 25.0 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form E can be characterized by a peak at about 7.8 degrees, a peak at about 12.9 degrees, a peak at about 21.6 degrees and a peak at about 25.0 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form E can be characterized by a peak at about 7.8 degrees, a peak at about 10.6 degrees, a peak at about 12.9 degrees, a peak at about 24.5 degrees, and a peak at about 25.0 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form E can be characterized by one or more peaks in an X-ray powder diffraction pattern selected from the table below.












No.
2-Theta °
Intensity %

















1
7.765*
58.9


2
10.563**
22.3


3
12.901*
40.7


4
21.571*
26.4


5
24.466**
51.4


6
25.016*
31.6





Peaks with an asterisk (*) are major peaks


Peaks with a double asterisk (**) are secondary peaks






In some embodiments, Form E can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 173.0 ppm, a peak at about 150.7 ppm, a peak at about 130.2 ppm, a peak at about 118.3 ppm, a peak at about 73.9 ppm, a peak at about 67.0 ppm, and a peak at about 22.0 ppm.
In some embodiments, Form E can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 173.0 ppm, a peak at about 150.7 ppm, a peak at about 130.2 ppm, a peak at about 118.3 ppm, a peak at about 73.9 ppm, a peak at about 68.0 ppm, a peak at about 67.0 ppm, and a peak at about 22.0 ppm.
In some embodiments, Form E can be characterized by a peak at about 130.2 ppm, a peak at about 118.3 ppm, a peak at about 73.9 ppm, and a peak at about 67.0 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form E can be characterized by a peak at about 173.0 ppm, a peak at about 150.7 ppm, a peak at about 130.2 ppm, a peak at about 118.3 ppm, a peak at about 73.9 ppm, a peak at about 67.0 ppm, and a peak at about 22.0 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form E can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 173.0 ppm, a peak at about 150.7 ppm, a peak at about 118.3 ppm, or a peak at about 73.9 ppm. In some embodiments, Form E can be characterized by a peak at about 118.3 ppm, and a peak at about 73.9 ppm in a 13C NMR solid state spectrum. In some embodiments, Form E can be characterized by a peak at about 173.0 ppm, a peak at about 150.7 ppm, a peak at about 118.3 ppm, and a peak at about 73.9 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form E can be characterized by one or more peaks in a 13C NMR solid state spectrum selected from the table below.













ν(F1)
Intensity


Peak #
[ppm]
[rel]

















1
173.0*
56.27


2
172.1
10.64


3
170.1
29.76


4
151.3
14.75


5
150.7*
55.30


6
146.7
6.43


7
145.2
17.07


8
144.0
6.43


9
130.2*
78.40


10
126.2
14.42


11
123.7
34.51


12
120.5
15.84


13
118.3*
65.27


14
104.1
11.22


15
103.2
33.55


16
102.2
11.20


17
92.7
28.19


18
84.1
12.31


19
82.4
35.17


20
80.1
73.44


21
79.8
36.49


22
75.0
14.45


23
73.9*
48.37


24
69.2
53.62


25
68.0*
59.07


26
67.0*
32.83


27
50.4
28.84


28
22.0*
100.00


29
21.7
93.59


30
21.4
58.58


31
20.6
18.91


32
19.4
40.73





Peaks with an asterisk (*) are major peaks






Form F
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form F.
In some embodiments, Form F can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak in the range of from about 5.8 to about 6.2 degrees, a peak in the range of from about 6.8 to about 7.2 degrees, a peak in the range of from about 17.3 to about 17.7 degrees, and a peak in the range of from about 17.8 to about 18.2 degrees.
In some embodiments, Form F can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 6.0 degrees, a peak at about 7.0 degrees, a peak at about 17.5 degrees, and a peak at about 18.0 degrees.
In some embodiments, Form F can be characterized by a peak at about 7.8 degrees, a peak at about 12.9 degrees, a peak at about 21.6 degrees, and a peak at about 25.0 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form F can be characterized by a peak at about 6.0 degrees, a peak at about 7.0 degrees, a peak at about 17.5 degrees, and a peak at about 18.0 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form F can be characterized by one or more peaks in an X-ray powder diffraction pattern selected from the table below.












No.
2-Theta °
Intensity %

















1
6.090*
100.0


2
6.970*
32.4


3
17.538*
30.7


4
18.048*
56.0





Peaks with an asterisk (*) are major peaks






In some embodiments, Form F can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 170.2 ppm, a peak at about 150.5 ppm, a peak at about 130.4 ppm, a peak at about 79.7 ppm, a peak at about 73.5 ppm, a peak at about 66.9 ppm, a peak at about 21.8 ppm, and a peak at about 20.6 ppm.
In some embodiments, Form F can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 170.2 ppm, a peak at about 150.5 ppm, a peak at about 130.4 ppm, a peak at about 79.7 ppm, a peak at about 73.5 ppm, a peak at about 68.2 ppm, a peak at about 66.9 ppm, a peak at about 25.7 ppm, a peak at about 21.8 ppm, and a peak at about 20.6 ppm.
In some embodiments, Form F can be characterized by a peak at about 130.4 ppm, a peak at about 73.5 ppm, a peak at about 66.9 ppm, and a peak at about 20.6 ppm in a 13C NMR solid state spectrum. In still a further embodiment, Form F can be characterized by a peak at about 6.1 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form F can be characterized by a peak at about 170.2 ppm, a peak at about 150.5 ppm, a peak at about 130.4 ppm, a peak at about 79.7 ppm, a peak at about 73.5 ppm, a peak at about 66.9 ppm, a peak at about 21.8 ppm, and a peak at about 20.6 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form F can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 170.2 ppm, a peak at about 150.5 ppm, a peak at about 79.7 ppm, a peak at about 73.5 ppm, or a peak at about 21.8 ppm. In some embodiments, Form F can be characterized by a peak at about 73.5 ppm in a 13C NMR solid state spectrum. In some embodiments, Form F can be characterized by a peak at about 170.2 ppm, a peak at about 150.5 ppm, a peak at about 79.7 ppm, a peak at about 73.5 ppm, and a peak at about 21.8 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form F can be characterized by one or more peaks in a 13C NMR solid state spectrum selected from the table below.













ν(F1)
Intensity


Peak #
[ppm]
[rel]

















1
173.0
21.53


2
172.0
24.07


3
170.2*
27.88


4
151.3
28.85


5
150.5*
40.71


6
146.6
11.13


7
145.2
6.82


8
143.9
11.03


9
130.4*
33.74


10
126.2
25.38


11
123.1
8.05


12
120.4
29.96


13
104.0
20.89


14
103.2
9.89


15
102.2
20.47


16
92.8
22.77


17
92.2
18.97


18
84.0
21.12


19
81.9
7.45


20
79.7*
71.06


21
75.0
24.15


22
73.5*
30.33


23
69.5
29.78


24
69.2
27.71


25
68.2*
20.78


26
66.9*
34.82


27
50.4
28.03


28
25.7*
7.70


29
21.8*
100.00


30
20.6*
39.64





Peaks with an asterisk (*) are major peaks






Form G
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form G.
In some embodiments, Form G can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak in the range of from about 5.7 to about 6.1 degrees, a peak in the range of from about 7.3 to about 7.7 degrees, a peak in the range of from about 7.6 to about 8.0 degrees, a peak in the range of from about 12.3 to about 12.7 degrees, a peak in the range of from about 17.5 to about 17.9 degrees, and a peak in the range of from about 18.0 to about 18.4 degrees.
In some embodiments, Form G can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak in the range of from about 5.7 to about 6.1 degrees, a peak in the range of from about 7.3 to about 7.7 degrees, a peak in the range of from about 7.6 to about 8.0 degrees and a peak in the range of from about 17.5 to about 17.9 degrees.
In some embodiments, Form G can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 5.9 degrees, a peak at about 7.5 degrees, a peak at about 7.8 degrees, a peak at about 12.5 degrees, a peak at about 17.7 degrees, and a peak at about 18.2 degrees.
In some embodiments, Form G can be characterized by a peak at about 5.9 degrees, a peak at about 7.5 degrees, a peak at about 7.8 degrees, and a peak at about 17.7 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form G can be characterized by a peak at about 5.9 degrees, a peak at about 7.5 degrees, a peak at about 7.8 degrees, a peak at about 12.5 degrees, a peak at about 17.7 degrees, and a peak at about 18.2 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form G can be characterized by an X-ray powder diffraction pattern of FIG. 14.
In some embodiments, Form G can be characterized by one or more peaks in an X-ray powder diffraction pattern selected from the table below.












No.
2-Theta °
Intensity %

















1
5.857*
100.0


2
7.498*
41.6


3
7.835*
32.1


4
12.522**
23.5


5
17.733*
53.0


6
18.193**
23.5





Peaks with an asterisk (*) are major peaks


Peaks with a double asterisk (**) are secondary peaks






In some embodiments, Form G can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 172.9 ppm, a peak at about 150.8 ppm, a peak at about 130.4 ppm, a peak at about 119.6 ppm, a peak at about 118.7 ppm, a peak at about 83.1 ppm, a peak at about 69.0 ppm, and a peak at about 20.4 ppm.
In some embodiments, Form G can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 172.9 ppm, a peak at about 150.8 ppm, a peak at about 130.4 ppm, a peak at about 119.6 ppm, a peak at about 118.7 ppm, a peak at about 83.1 ppm, a peak at about 69.0 ppm, a peak at about 54.2 ppm, and a peak at about 20.4 ppm.
In some embodiments, Form G can be characterized by a peak at about 119.6 ppm, a peak at about 118.7 ppm, a peak at about 83.1 ppm, and a peak at about 69.0 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form G can be characterized by a peak at about 172.9 ppm, a peak at about 150.8 ppm, a peak at about 130.4 ppm, a peak at about 119.6 ppm, a peak at about 118.7 ppm, a peak at about 83.1 ppm, a peak at about 69.0 ppm, and a peak at about 20.4 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form G can be characterized by a 13C NMR solid state spectrum of FIG. 15.
In some embodiments, Form G can be characterized by one or more peaks in a 13C NMR solid state spectrum selected from the table below.













ν(F1)
Intensity


Peak
[ppm]
[rel]

















1
172.9*
47.8


2
172.5
60.77


3
170.1
31.87


4
150.8*
97.73


5
145.6
17.22


6
143.7
10.94


7
130.4*
78.80


8
123.6
13.92


9
122.8
39.28


10
122.2
22.62


11
119.6*
30.97


12
118.7*
83.25


13
103.6
49.34


14
103.2
27.56


15
93.1
34.63


16
92.6
30.12


17
83.1*
44.78


18
82.6
41.59


19
80.2
49.48


20
79.9
89.47


21
79.5
48.95


22
74.4
42.00


23
73.5
36.87


24
73.3
36.16


25
69.0*
46.99


26
68.8
93.22


27
68.5
53.49


28
68.3
50.90


29
68.0
70.75


30
54.2*
17.40


31
50.5
44.46


32
23.4
36.90


33
22.9
82.85


34
22.6
100.00


35
21.8
87.94


36
21.4
85.89


37
20.4*
70.1


38
20.1
39.2





Peaks with an asterisk (*) are major peaks






Form H
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form H.
In some embodiments, Form H can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak in the range of from about 7.9 to about 8.3 degrees, a peak in the range of from about 13.8 to about 14.2 degrees, a peak in the range of from about 17.0 to about 17.4 degrees, and a peak in the range of from about 19.9 to about 20.3 degrees.
In some embodiments, Form H can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 8.1 degrees, a peak at about 14.0 degrees, a peak at about 17.2 degrees, and a peak at about 20.1 degrees.
In some embodiments, Form H can be characterized by a peak at about 8.1 degrees, a peak at about 14.0 degrees, a peak at about 17.2 degrees, and a peak at about 20.1 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form H can be characterized by an X-ray powder diffraction pattern of FIG. 16.
In some embodiments, Form H can be characterized by one or more peaks in an X-ray powder diffraction pattern selected from the table below.












No.
2-Theta °
Intensity %

















1
8.132*
81.7


2
14.020*
34.6


3
17.226*
61.7


4
20.902*
27.3





Peaks with an asterisk (*) are major peaks






In some embodiments, Form H can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 173.4 ppm, a peak at about 153.4 ppm, a peak at about 152.2 ppm, a peak at about 129.8 ppm, a peak at about 119.8 ppm, a peak at about 104.6 ppm, a peak at about 79.4 ppm, and a peak at about 20.6 ppm.
In some embodiments, Form H can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 173.4 ppm, a peak at about 153.4 ppm, a peak at about 152.2 ppm, a peak at about 129.8 ppm, a peak at about 119.8 ppm, a peak at about 104.6 ppm, a peak at about 79.4 ppm, a peak at about 20.6 ppm, and a peak at about 2.2 ppm.
In some embodiments, Form H can be characterized by a peak at about 173.4 ppm, a peak at about 153.4 ppm, a peak at about 119.8 ppm, and a peak at about 104.6 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form H can be characterized by a peak at about 173.4 ppm, a peak at about 153.4 ppm, a peak at about 152.2 ppm, a peak at about 129.8 ppm, a peak at about 119.8 ppm, a peak at about 104.6 ppm, a peak at about 79.4 ppm, and a peak at about 20.6 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form H can be characterized by a 13C NMR solid state spectrum of FIG. 17.
In some embodiments, Form H can be characterized by one or more peaks in a 13C NMR solid state spectrum selected from the table below.













ν(F1)
Intensity


Peak
[ppm]
[rel]

















1
173.4*
70.7


2
164.4
44.87


3
153.4*
31.83


4
152.2*
61.17


5
141.4
42.94


6
129.8*
70.37


7
123.6
53.72


8
119.8*
55.92


9
104.6*
76.16


10
92.3
56.76


11
82.6
35.67


12
81.9
32.74


13
79.4*
100.00


14
73.4
96.98


15
68.9
54.71


16
61.7
73.15


17
53.6
47.24


18
23.4
79.96


19
22.9
86.96


20
21.6
41.15


21
20.6*
90.05


22
2.2*
14.59





Peaks with an asterisk (*) are major peaks






Form I
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form I.
In some embodiments, Form I can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak in the range of from about 6.2 to about 6.6 degrees, a peak in the range of from about 9.1 to about 9.5 degrees, a peak in the range of from about 10.6 to about 11.0 degrees, and a peak in the range of from about 11.6 to about 12.0 degrees.
In some embodiments, Form I can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 6.4 degrees, a peak at about 9.3 degrees, a peak at about 10.8 degrees, and a peak at about 11.8 degrees.
In some embodiments, Form I can be characterized by a peak at about 6.4 degrees, a peak at about 9.3 degrees, a peak at about 10.8 degrees, and a peak at about 11.8 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form I can be characterized by an X-ray powder diffraction pattern of FIG. 18.
In some embodiments, Form I can be characterized by one or more peaks in an X-ray powder diffraction pattern selected from the table below.












No.
2-Theta °
Intensity %

















1
6.434*
59.2


2
9.283*
30.8


3
10.831*
55.3


4
11.794*
28.3





Peaks with an asterisk (*) are major peaks






In some embodiments, Form I can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 173.0 ppm, a peak at about 152.1 ppm, a peak at about 126.1 ppm, a peak at about 102.7 ppm, a peak at about 74.5 ppm, a peak at about 71.2 ppm, a peak at about 63.3 ppm, and a peak at about 23.3 ppm.
In some embodiments, Form I can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 173.1 ppm, a peak at about 168.6 ppm, a peak at about 152.1 ppm, a peak at about 123.6 ppm, a peak at about 102.6 ppm, a peak at about 71.4 ppm, a peak at about 63.5 ppm, a peak at about 61.9 ppm, a peak at about 22.4 ppm, and a peak at about 15.5 ppm. In some embodiments, Form I can be an ethyl acetate solvate.
In some embodiments, Form I (ethyl acetate solvate) can be characterized by one or more peaks in a 13C NMR solid state spectrum selected from the table below.













ν(F1)
Intensity


Peak
[ppm]
[rel]

















1
174.2
27.6


2
173.1*
34.33


3
170.3
20.24


4
168.6*
20.76


5
152.1*
41.55


6
151.1
35.37


7
144.9
20.96


8
143.6
18.23


9
129.4
12.59


10
126.1
23.63


11
123.6*
24.98


12
119.3
10.42


13
102.6*
56.41


14
93.2
22.66


15
91.1
23.83


16
81.7
36.81


17
80.6
41.38


18
79.6
68.17


19
74.3
34.18


20
73.2
33.47


21
71.4*
32.36


22
69.3
33.35


23
68.7
34.79


24
63.5*
32.91


25
61.9*
21.88


26
51.3
22.60


27
50.5
21.35


28
22.4*
100.00


29
20.1
52.23


30
15.5*
16.24





Peaks with an asterisk (*) are major peaks






In some embodiments, Form I can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 173.0 ppm, a peak at about 168.4 ppm, a peak at about 152.1 ppm, a peak at about 126.1 ppm, a peak at about 102.7 ppm, a peak at about 74.5 ppm, a peak at about 71.2 ppm, a peak at about 63.3 ppm, and a peak at about 23.3 ppm. In some embodiments, Form I can be an isopropyl acetate solvate.
In some embodiments, Form I can be characterized by a peak at about 102.7 ppm, a peak at about 74.5 ppm, a peak at about 71.2 ppm, and a peak at about 63.3 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form I can be characterized by a peak at about 173.0 ppm, a peak at about 152.1 ppm, a peak at about 126.1 ppm, a peak at about 102.7 ppm, a peak at about 74.5 ppm, a peak at about 71.2 ppm, a peak at about 63.3 ppm, and a peak at about 23.3 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form I can be characterized by a 13C NMR solid state spectrum of FIG. 19.
In some embodiments, Form I (isopropyl acetate solvate) can be characterized by one or more peaks in a 13C NMR solid state spectrum selected from the table below.













ν(F1)
Intensity


Peak
[ppm]
[rel]

















1
174.2
28.4


2
173.0*
35.35


3
170.1
18.49


4
168.4*
18.99


5
152.1*
44.16


6
151.0
35.26


7
144.8
19.59


8
143.5
18.22


9
129.9
26.35


10
126.1*
27.72


11
123.4
33.24


12
122.8
27.21


13
119.6
9.23


14
102.7*
56.58


15
93.2
23.93


16
91.1
24.94


17
81.6
37.12


18
80.5
42.31


19
79.6
73.82


20
74.5*
37.87


21
73.2
37.91


22
71.2*
34.86


23
69.3
62.97


24
68.8
39.70


25
63.3*
34.57


26
51.1
22.87


27
50.3
19.47


28
23.3*
100.00


29
22.8
76.24


30
21.9
75.98


31
21.4
42.76


32
20.4
36.17


33
20.0
38.34





Peaks with an asterisk (*) are major peaks






Form J
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form J.
In some embodiments, Form J can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak in the range of from about 5.9 to about 6.3 degrees, a peak in the range of from about 7.3 to about 7.7 degrees, a peak in the range of from about 11.9 to about 12.3 degrees, a peak in the range of from about 13.1 to about 13.5 degrees, a peak in the range of from about 13.8 to about 14.2 degrees, a peak in the range of from about 18.3 to about 18.7 degrees, a peak in the range of from about 22.4 to about 22.8 degrees, a peak in the range of from about 33.0 to about 33.4 degrees, a peak in the range of from about 33.8 to about 34.2 degrees, and a peak in the range of from about 35.1 to about 35.5 degrees.
In some embodiments, Form J can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak in the range of from about 5.9 to about 6.3 degrees, a peak in the range of from about 7.3 to about 7.7 degrees, a peak in the range of from about 11.9 to about 12.3 degrees, a peak in the range of from about 13.1 to about 13.5 degrees, a peak in the range of from about 13.8 to about 14.2 degrees and a peak in the range of from about 18.3 to about 18.7 degrees.
In some embodiments, Form J can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 6.1 degrees, a peak at about 7.5 degrees, a peak at about 12.1 degrees, a peak at about 13.3 degrees, a peak at about 14.0 degrees, a peak at about 18.5 degrees, a peak at about 22.6 degrees, a peak at about 33.2 degrees, a peak at about 34.0 degrees, and a peak at about 35.3 degrees.
In some embodiments, Form J can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 6.1 degrees, a peak at about 7.5 degrees, a peak at about 12.1 degrees, a peak at about 13.3 degrees, a peak at about 14.0 degrees, and a peak at about 18.5 degrees.
In some embodiments, Form J can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 6.1 degrees, a peak at about 7.5 degrees, a peak at about 12.1 degrees, a peak at about 13.3 degrees, a peak at about 14.0 degrees, a peak at about 18.5 degrees, a peak at about 22.6 degrees, a peak at about 33.2 degrees, a peak at about 34.0 degrees, and a peak at about 35.3 degrees.
In some embodiments, Form J can be characterized by an X-ray powder diffraction pattern of FIG. 20.
In some embodiments, Form J can be characterized by one or more XRPD peaks selected from the table below.












No.
2-Theta °
Intensity %

















1
6.1*
69.2


2
7.5*
54.4


3
9.0
21.2


4
9.9
21.2


5
10.8
34.0


6
11.1
44.2


7
11.4
26.5


8
12.1*
100.0


9
12.9
24.6


10
13.3*
31.2


11
14.0*
27.2


12
14.8
28.3


13
15.1
30.2


14
15.4
29.5


15
16.1
33.0


16
16.7
41.0


17
17.6
29.8


18
18.0
54.6


19
18.5*
47.3


20
18.9
25.6


21
19.4
41.6


22
19.6
35.8


23
20.3
43.5


24
20.7
59.8


25
21.1
43.8


26
21.7
35.5


27
22.6**
30.1


28
22.3
24.3


29
23.8
23.1


30
24.7
32.7


31
25.2
23.7


32
25.7
20.8


33
26.6
26.7


34
27.5
24.3


35
27.8
23.6


36
28.3
20.7


37
29.6
22.9


38
32.2
20.3


39
33.2**
21.5


40
34.0**
19.2


41
35.3**
19.3


42
35.4
19.4


43
36.5
19.0





Peaks with an asterisk (*) are major peaks


Peaks with a double asterisk (**) are secondary peaks






In some embodiments, Form J can be characterized by a DSC thermogram as shown in FIG. 21. In some embodiments, Form J can be characterized by a DSC thermogram showing a first endotherm in the range of about 121° C. to about 127° C. (for example, at about 126° C.). In some embodiments, Form J can be characterized by a DSC thermogram showing an exotherm in the range of about 127° C. to about 132° C. (for example, at about 129° C.). In some embodiments, Form J can be characterized by a DSC thermogram showing a second endotherm in the range of about 135° C. to about 142° C. (for example, at about 138° C.). In some embodiments, Form J can be characterized by a DSC thermogram showing a first melting temperature in the range of about 121° C. to about 127° C. (for example, at about 126° C.). In some embodiments, Form J can be characterized by a DSC thermogram showing a recrystallization at a temperature in the range of about 127° C. to about 132° C. (for example, at about 129° C.). In some embodiments, Form J can be characterized by a DSC thermogram showing a second melting temperature in the range of about 135° C. to about 142° C. (for example, at about 138° C.). In some embodiments, Form J can be characterized by a melting temperature in the range of about 121° C. to about 127° C. (for example, at about 126° C.).
In some embodiments, Form J can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 175.6 ppm, a peak at about 141.4 ppm, a peak at about 127.8 ppm, a peak at about 123.4 ppm, a peak at about 103.1 ppm, a peak at about 83.5 ppm, a peak at about 81.1 ppm, a peak at about 62.2 ppm, a peak at about 25.6 ppm, and a peak at about 19.6 ppm.
In some embodiments, Form J can be characterized by a peak at about 83.5 ppm, a peak at about 81.1 ppm, a peak at about 62.2 ppm, and a peak at about 25.6 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form J can be characterized by a peak at about 175.6 ppm, a peak at about 141.4 ppm, a peak at about 127.8 ppm, a peak at about 123.4 ppm, a peak at about 103.1 ppm, a peak at about 83.5 ppm, a peak at about 81.1 ppm, a peak at about 62.2 ppm, a peak at about 25.6 ppm, and a peak at about 19.6 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form J can be characterized by a 13C NMR solid state spectrum of FIG. 22.
In some embodiments, Form J can be characterized by one or more peaks in a 13C NMR solid state spectrum selected from the table below.













ν(F1)
Intensity


Peak
[ppm]
[rel]

















1
175.6*
26.8


2
172.6
39.76


3
165.8
13.72


4
162.9
22.43


5
162.5
16.16


6
153.0
15.82


7
152.8
15.88


8
151.5
29.40


9
151.1
11.45


10
150.7
36.85


11
150.1
21.71


12
141.4*
19.34


13
140.1
11.81


14
131.1
29.77


15
129.7
35.60


16
129.5
26.33


17
127.8*
25.20


18
127.1
17.58


19
126.3
27.54


20
123.8
29.09


21
123.4*
32.43


22
122.8
26.21


23
103.1*
37.64


24
101.3
27.86


25
93.8
22.55


26
93.3
16.53


27
91.7
18.80


28
83.5*
35.20


29
81.1*
35.52


30
80.7
100.00


31
79.8
28.76


32
78.6
42.08


33
74.4
37.67


34
73.4
41.04


35
73.1
28.84


36
72.3
39.74


37
70.1
57.8


38
63.7
44.0


39
62.2*
33.4


40
53.1
21.6


41
52.5
16.9


42
50.8
15.9


43
25.6*
36.7


44
23.7
60.6


45
23.0
34.4


46
22.5
64.4


47
22.1
46.4


48
21.7
36.1


49
19.6*
34.5


50
18.8
34.8


51
18.4
29.1





Peaks with an asterisk (*) are major peaks






Form K
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form K.
In some embodiments, Form K can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak in the range of from about 22.4 to about 22.8 degrees, a peak in the range of from about 27.1 to about 27.5 degrees, a peak in the range of from about 28.1 to about 28.5 degrees, and a peak in the range of from about 31.0 to about 31.4 degrees.
In some embodiments, Form K can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 22.6 degrees, a peak at about 27.3 degrees, a peak at about 28.3 degrees, and a peak at about 31.2 degrees.
In some embodiments, Form K can be characterized by a peak at about 22.6 degrees, a peak at about 27.3 degrees, a peak at about 28.3 degrees, and a peak at about 31.2 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form K can be characterized by an X-ray powder diffraction pattern of FIG. 23.
In some embodiments, Form K can be characterized by one or more XRPD peaks selected from the table below.












No.
2-Theta °
Intensity %







1
22.620*
27.5


2
27.257*
26.7


3
28.272*
25.0


4
31.216*
27.0





Peaks with an asterisk (*) are major peaks






In some embodiments, Form K can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 173.9 ppm, a peak at about 173.4 ppm, a peak at about 151.8 ppm, a peak at about 150.5 ppm, a peak at about 101.9 ppm, a peak at about 92.0 ppm, a peak at about 73.5 ppm, a peak at about 22.1 ppm, and a peak at about 20.4 ppm.
In some embodiments, Form K can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 173.9 ppm, a peak at about 173.4 ppm, a peak at about 151.8 ppm, a peak at about 150.5 ppm, a peak at about 101.9 ppm, a peak at about 92.0 ppm, a peak at about 80.4 ppm, a peak at about 73.5 ppm, a peak at about 22.1 ppm, and a peak at about 20.4 ppm.
In some embodiments, Form K can be characterized by a peak at about 173.9 ppm, a peak at about 173.4 ppm, a peak at about 101.9 ppm, and a peak at about 92.0 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form K can be characterized by a peak at about 173.9 ppm, a peak at about 173.4 ppm, a peak at about 151.8 ppm, a peak at about 150.5 ppm, a peak at about 101.9 ppm, a peak at about 92.0 ppm, a peak at about 73.5 ppm, a peak at about 22.1 ppm, and a peak at about 20.4 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form K can be characterized by a 13C NMR solid state spectrum of FIG. 24.
In some embodiments, Form K can be characterized by one or more peaks in a 13C NMR solid state spectrum selected from the table below.













ν(F1)
Intensity


Peak
[ppm]
[rel]

















1
173.9*
40.0


2
173.4*
39.97


3
169.9
23.72


4
168.7
24.10


5
151.8*
45.42


6
150.5*
44.95


7
144.6
27.19


8
144.1
24.43


9
129.8
17.44


10
126.2
30.54


11
125.8
20.97


12
122.5
16.21


13
101.9*
81.01


14
93.4
34.58


15
92.0*
35.25


16
81.6
54.04


17
80.4*
88.61


18
79.7
51.32


19
78.6
62.92


20
73.5*
72.84


21
70.6
49.15


22
69.5
50.72


23
68.1
46.78


24
63.6
47.15


25
50.8
55.38


26
23.2
76.97


27
22.8
67.52


28
22.1*
100.00


29
20.7
68.21


30
20.4*
97.77





Peaks with an asterisk (*) are major peaks






Form L
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form L.
In some embodiments, Form L can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak in the range of from about 5.5 to about 5.9 degrees, a peak in the range of from about 5.8 to about 6.2 degrees, a peak in the range of from about 15.0 to about 15.4 degrees, and a peak in the range of from about 15.9 to about 16.3 degrees.
In some embodiments, Form L can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 5.7 degrees, a peak at about 6.0 degrees, a peak at about 15.2 degrees, and a peak at about 16.1 degrees.
In some embodiments, Form L can be characterized by a peak at about 5.7 degrees, a peak at about 6.0 degrees, a peak at about 15.2 degrees, and a peak at about 16.1 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form L can be characterized by an X-ray powder diffraction pattern of FIG. 25.
In some embodiments, Form L can be characterized by one or more XRPD peaks selected from the table below.












No.
2-Theta °
Intensity %

















1
5.662*
27.0


2
6.036*
27.2


3
15.174*
100.0


4
16.102*
56.5





Peaks with an asterisk (*) are major peaks






In some embodiments, Form L can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 173.2 ppm, a peak at about 151.4 ppm, a peak at about 140.9 ppm, a peak at about 118.5 ppm, a peak at about 81.5 ppm, a peak at about 80.1 ppm, a peak at about 73.4 ppm, a peak at about 61.6 ppm, and a peak at about 20.9 ppm.
In some embodiments, Form L can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 173.2 ppm, a peak at about 151.4 ppm, a peak at about 140.9 ppm, a peak at about 118.5 ppm, a peak at about 81.5 ppm, a peak at about 80.1 ppm, a peak at about 73.4 ppm, a peak at about 61.6 ppm, a peak at about 20.9 ppm, and a peak at about 1.6 ppm.
In some embodiments, Form L can be characterized by a peak at about 81.5 ppm, a peak at about 80.1 ppm, a peak at about 61.6 ppm, and a peak at about 20.9 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form L can be characterized by a peak at about 173.2 ppm, a peak at about 151.4 ppm, a peak at about 140.9 ppm, a peak at about 118.5 ppm, a peak at about 81.5 ppm, a peak at about 80.1 ppm, a peak at about 73.4 ppm, a peak at about 61.6 ppm, and a peak at about 20.9 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form L can be characterized by a 13C NMR solid state spectrum of FIG. 26.
In some embodiments, Form L can be characterized by one or more peaks in a 13C NMR solid state spectrum selected from the table below.













ν(F1)
Intensity


Peak
[ppm]
[rel]

















1
173.2*
32.2


2
172.6
13.04


3
164.3
20.50


4
152.9
15.62


5
152.3
18.02


6
151.4*
22.38


7
150.8
10.20


8
150.6
15.53


9
142.9
7.14


10
140.9*
17.32


11
130.3
17.85


12
129.9
17.36


13
125.7
15.60


14
124.7
11.99


15
123.4
12.87


16
118.5*
18.82


17
103.8
8.86


18
103.3
18.66


19
102.9
15.60


20
101.5
12.23


21
92.7
29.36


22
92.3
25.58


23
81.5*
51.96


24
80.1*
100.00


25
73.4*
51.97


26
69.9
17.16


27
69.3
27.18


28
68.0
11.49


29
63.0
15.93


30
61.9
24.74


31
61.6*
32.16


32
54.0
18.79


33
53.0
14.69


34
52.2
16.30


35
23.7
12.59


36
23.3
12.87


37
23.0
28.2


38
22.5
42.2


39
22.0
47.5


40
21.4
43.2


41
20.9*
50.2


42
20.2
17.4


43
19.8
22.2


44
19.2
15.2


45
18.9
14.8


46
1.6*
12.9





Peaks with an asterisk (*) are major peaks






Form M
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form M.
In some embodiments, Form M can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak in the range of from about 6.1 to about 6.5 degrees, a peak in the range of from about 13.0 to about 13.4 degrees, a peak in the range of from about 22.0 to about 22.4 degrees, and a peak in the range of from about 23.3 to about 23.7 degrees.
In some embodiments, Form M can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 6.3 degrees, a peak at about 13.2 degrees, a peak at about 22.2 degrees, and a peak at about 23.5 degrees.
In some embodiments, Form M can be characterized by a peak at about 6.3 degrees, a peak at about 13.2 degrees, a peak at about 22.2 degrees, and a peak at about 23.5 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form M can be characterized by an X-ray powder diffraction pattern of FIG. 27.
In some embodiments, Form M can be characterized by one or more XRPD peaks selected from the table below.












No.
2-Theta °
Intensity %

















1
6.274*
66.2


2
13.200*
40.5


3
22.225*
50.0


4
23.520*
38.7





Peaks with an asterisk (*) are major peaks






In some embodiments, Form M can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 174.0 ppm, a peak at about 170.5 ppm, a peak at about 129.5 ppm, a peak at about 79.6 ppm, a peak at about 69.7 ppm, a peak at about 63.2 ppm, a peak at about 51.8 ppm, a peak at about 24.0 ppm, and a peak at about 19.5 ppm.
In some embodiments, Form M can be characterized by a peak at about 69.7 ppm, a peak at about 63.2 ppm, a peak at about 51.8 ppm, and a peak at about 24.0 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form M can be characterized by a peak at about 174.0 ppm, a peak at about 170.5 ppm, a peak at about 129.5 ppm, a peak at about 79.6 ppm, a peak at about 69.7 ppm, a peak at about 63.2 ppm, a peak at about 51.8 ppm, a peak at about 24.0 ppm, and a peak at about 19.5 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form M can be characterized by a 13C NMR solid state spectrum of FIG. 28.
In some embodiments, Form M can be characterized by one or more peaks in a 13C NMR solid state spectrum selected from the table below.













ν(F1)
Intensity


Peak
[ppm]
[rel]

















1
174.0*
31.8


2
173.2
13.03


3
172.3
7.89


4
170.5*
25.18


5
163.6
11.98


6
163.0
24.93


7
162.4
16.01


8
152.8
24.75


9
151.8
15.28


10
151.3
19.55


11
150.7
13.04


12
150.3
26.82


13
149.8
8.82


14
149.3
28.40


15
141.0
21.01


16
138.9
14.25


17
131.3
17.74


18
130.3
11.77


19
129.5*
32.91


20
127.0
27.77


21
126.6
24.70


22
124.7
17.32


23
124.0
14.60


24
122.4
15.29


25
121.3
12.07


26
118.5
11.42


27
103.5
34.79


28
102.7
10.83


29
102.2
27.86


30
101.7
8.62


31
92.5
36.95


32
83.2
31.87


33
81.5
45.71


34
80.6
14.75


35
80.1
18.58


36
79.6*
100.00


37
74.3
44.8


38
73.3
44.3


39
70.5
10.0


40
69.7*
44.6


41
67.5
8.1


42
64.5
8.8


43
64.0
9.6


44
63.2*
39.5


45
61.4
8.0


46
53.3
20.6


47
51.8*
33.6


48
24.0*
37.0


49
23.7
47.1


50
23.3
62.9


51
22.4
67.7


52
21.9
44.5


53
21.6
52.4


54
20.5
8.9


55
19.5*
49.4





Peaks with an asterisk (*) are major peaks






Form N
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form N.
In some embodiments, Form N can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak in the range of from about 12.2 to about 12.6 degrees, a peak in the range of from about 15.1 to about 15.5 degrees, a peak in the range of from about 16.9 to about 17.3 degrees, and a peak in the range of from about 17.7 to about 18.1 degrees.
In some embodiments, Form N can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 12.4 degrees, a peak at about 15.3 degrees, a peak at about 17.1 degrees, and a peak at about 17.9 degrees.
In some embodiments, Form N can be characterized by a peak at about 12.4 degrees, a peak at about 15.3 degrees, a peak at about 17.1 degrees, and a peak at about 17.9 degrees in an X-ray powder diffraction pattern.
In some embodiments, Form N can be characterized by an X-ray powder diffraction pattern of FIG. 29.
In some embodiments, Form N can be characterized by one or more XRPD peaks selected from the table below.












No.
2-Theta °
Intensity %







1
12.419*
25.7


2
15.310*
41.7


3
17.149*
76.6


4
17.873*
57.0





Peaks with an asterisk (*) are major peaks






In some embodiments, Form N can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 172.6 ppm, a peak at about 130.4 ppm, a peak at about 129.2 ppm, a peak at about 128.4 ppm, a peak at about 82.2 ppm, a peak at about 74.0 ppm, a peak at about 67.7 ppm, and a peak at about 21.3 ppm.
In some embodiments, Form N can be characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 172.6 ppm, a peak at about 130.4 ppm, a peak at about 129.5 ppm, a peak at about 129.2 ppm, a peak at about 128.4 ppm, a peak at about 82.2 ppm, a peak at about 74.0 ppm, a peak at about 67.7 ppm, and a peak at about 21.3 ppm.
In some embodiments, Form N can be characterized by a peak at about 129.2 ppm, a peak at about 128.4 ppm, a peak at about 82.2 ppm, and a peak at about 67.7 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form N can be characterized by a peak at about 172.6 ppm, a peak at about 130.4 ppm, a peak at about 129.2 ppm, a peak at about 128.4 ppm, a peak at about 82.2 ppm, a peak at about 74.0 ppm, a peak at about 67.7 ppm, and a peak at about 21.3 ppm in a 13C NMR solid state spectrum.
In some embodiments, Form N can be characterized by a 13C solid state NMR solid state spectrum of FIG. 30.
In some embodiments, Form N can be characterized by one or more peaks in a 13C NMR solid state spectrum selected from the table below.













ν(F1)
Intensity


Peak
[ppm]
[rel]

















1
172.6*
60.5


2
170.3
21.21


3
169.9
20.31


4
151.5
28.70


5
151.1
40.12


6
150.6
26.12


7
145.2
33.34


8
130.4*
78.13


9
129.5*
87.88


10
129.2*
70.02


11
128.4*
64.31


12
125.5
40.20


13
124.4
31.97


14
124.2
31.70


15
120.8
66.36


16
120.0
74.60


17
103.5
40.76


18
103.2
33.90


19
92.8
37.18


20
82.6
41.88


21
82.2*
37.02


22
79.6
64.84


23
79.3
68.37


24
74.0*
88.74


25
68.6
28.92


26
68.4
57.45


27
68.1
92.39


28
67.7*
51.91


29
50.2
29.20


30
23.0
54.35


31
22.3
18.31


32
21.8
60.50


33
21.3*
100.00


34
21.1
61.99


35
20.6
18.12


36
20.2
58.39


37
19.3
34.4





Peaks with an asterisk (*) are major peaks






Amorphous Form O
In some embodiments, Compound 1 can be 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Amorphous Form O.
In some embodiments, the Amorphous Form O contains less than about 30% crystallinity. In other embodiments, the Amorphous Form O contains less than about 15% crystallinity. In still other embodiments, the Amorphous Form O contains less than about 1.0% crystallinity. In yet still other embodiments, the Amorphous Form O contains substantially no crystallinity. In some embodiments, the Amorphous Form O is substantially amorphous. In other embodiments, the Amorphous Form O is completely amorphous (i.e., 100% amorphous).
Some embodiments described herein relate to a process for producing Form A that can include:

    
    
        a) contacting Compound 1 with a first amount of ethyl acetate to form a mixture;
        b) heating the mixture until the solids are dissolved;
        c) cooling the mixture to allow precipitation of a solid;
        d) optionally adding a second amount of ethyl acetate and repeating steps a, b and c; and
        e) isolating the solid Form A from said mixture.
    
    


In some embodiments, the temperature in step b) can be in the range of from about 55° C. to about 65° C. (for example, about 60° C.).
In some embodiments, the temperature in step c) can be in the range of from about 18° C. to about 24° C. (for example, about 21° C.). In some embodiments, the temperature in step c) can be room temperature (RT).
In some embodiments, the second amount of ethyl acetate in step d) can be approximately equal to the first amount of ethyl acetate used in step a). In other embodiments, the second amount of ethyl acetate in step d) can be up to five times the first amount of ethyl acetate used in step a). In other still other embodiments, the second amount of ethyl acetate in step d) can be less than the first amount of ethyl acetate used in step a). In some embodiments, the first amount of ethyl acetate in step a) can be in the range of from about 1 mL to about 3 mL per gram of Compound 1. In some embodiments, the first amount of ethyl acetate in step a) can be about 2 mL per gram of Compound 1.
In some embodiments, steps a, b and c can be repeated at least one time. In other embodiments, steps a, b and c can be repeated at least 2 times. In some embodiments, steps a, b and c can be repeated one time.
In some embodiments, Form A can be isolated from the mixture by filtration.
Other embodiments described herein relate to a process for producing Form J, that can include
a) contacting Amorphous Form O with ethanol to form a mixture; and
b) isolating Form J from said mixture.
In some embodiments, the mixture can be stirred at room temperature for about 12 hours before isolating Form J. In some embodiments, the mixture can be stirred at a temperature in the range of about 20° C. to about 30° C. for about 12 hours before isolating Form J.
In some embodiments, about 100 mg of Amorphous Form O can be contacted with an amount of ethanol in the range of from about 100 μL to about 200 μL of ethanol. In other embodiments, about 100 mg of Amorphous Form O can be contacted with about 150 μL of ethanol. In some embodiments, the ethanol can be HPLC grade ethanol.
In some embodiments, Form J can be isolated from the mixture by filtration.
Still other embodiments described herein relate to a process for producing a solvated solid form of Compound 1, that can include
a) contacting Compound 1 with a solvent to form a mixture; and
b) isolating the solvated solid form of Compound 1 from said mixture.
In some embodiments, the solvated solid form of Compound 1 can be isolated from the mixture by a method selected from filtration and evaporation.
In some embodiments, the solvent can be MTBE, cyclohexane, nitromethane, acetonitrile, dioxane, THF, dichloromethane, ethyl acetate, isopropyl acetate, chloroform, chlorobenzene, 1,2-dichloroethane, 1,2,3-trichloroethane, or toluene.
In some embodiments, the solvent can be MTBE or cyclohexane and the solvated solid form can be Form B. In other embodiments, the solvent can be nitromethane and the solvated solid form can be Form C. In still other embodiments, the solvent can be dioxane and the solvated solid form can be Form E. In yet still other embodiments, the solvent can be THF and the solvated solid form can be Form F. In some embodiments, the solvent can be dichloromethane and the solvated solid form can be Form G. In other embodiments, the solvent can be acetonitrile and the solvated solid form can be Form H or Form L. In still other embodiments, the solvent can be ethyl acetate or isopropyl acetate and the solvated solid form can be Form I. In yet still other embodiments, the solvent can be chloroform, chlorobenzene, 1,2-dichloroethane or 1,2,3-trichloroethane and the solvated solid form can be Form K. In some embodiments, the solvent can be toluene and the solvated solid form can be Form N.
In some embodiments, the mixture can be sonicated before isolating the solvated solid form.
In some embodiments, the amount of solvent added in step a) above is in the range of from about 0.5 mL to about 10 mL per gram of Compound 1. In some embodiments, the amount of solvent added in step a) above is about 0.83 mL per gram of Compound 1. In other embodiments, the amount of solvent added in step a) above is about 1.0 mL per gram of Compound 1. In still other embodiments, the amount of solvent added in step a) above is about 1.5 mL per gram of Compound 1. In yet still other embodiments, the amount of solvent added in step a) above is about 1.9 mL per gram of Compound 1. In some embodiments, the amount of solvent added in step a) above is about 2.0 mL per gram of Compound 1. In other embodiments, the amount of solvent added in step a) above is about 2.5 mL per gram of Compound 1. In still other embodiments, the amount of solvent added in step a) above is about 3.3 mL per gram of Compound 1. In yet still other embodiments, the amount of solvent added in step a) above is about 4.0 mL per gram of Compound 1. In some embodiments, the amount of solvent added in step a) above is about 5.0 mL per gram of Compound 1. In other embodiments, the amount of solvent added in step a) above is about 6.1 mL per gram of Compound 1. In still other embodiments, the amount of solvent added in step a) above is about 10.0 mL per gram of Compound 1.
In some embodiments, the process further can include removing the solvent from the solvated solid form of Compound 1, including one or more of those described herein, to provide a desolvated solid form of Compound 1. In some embodiments, the desolvated solid form of Compound 1 can be Form D. In other embodiments, the desolvated solid form of Compound 1 can be Form M.
Uses, Formulation and Administration
Pharmaceutically Acceptable Compositions
Some embodiments described herein generally relate to a pharmaceutical composition that can include one or more solid forms of Compound 1 as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle.
Other embodiments described herein relate to a pharmaceutical composition that can include one or more solid forms of Compound 1, and one or more additional agent(s). In some embodiments, the one or more additional agent(s) can be selected from Pegylated interferon-alpha-2a (brand name PEGASYS®) and ribavirin, Pegylated interferon-alpha-2b (brand name PEG-INTRON®) and ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, and a NS5A inhibitor.
In some embodiments, the one or more agents can be selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (BB) and a compound of Formula (DD), or a pharmaceutically acceptable salt any of the aforementioned compounds.
In some embodiments, the one or more agents can be selected from Compounds 1000-1066 and 8001-8012, or a pharmaceutically acceptable salt of any of the aforementioned compounds.
In some embodiments, including those embodiments described previously, the pharmaceutical composition can include a single diastereomer of Compound 1, or a pharmaceutically acceptable salt thereof, (for example, a single diastereomer is present in the pharmaceutical composition at a concentration of greater than 99% compared to the total concentration of the diastereomers of Compound 1). In other embodiments, the pharmaceutical composition can include a mixture of diastereomers of Compound 1, or a pharmaceutically acceptable salt thereof. For example, the pharmaceutical composition can include a concentration of one diastereomer of >50%, ≧60%, ≧70%, ≧80%, ≧90%, ≧95%, or ≧98%, as compared to the total concentration of diastereomers of Compound 1. In some embodiments, the pharmaceutical composition includes a 1:1 mixture of two diastereomers of Compound 1, or a pharmaceutically acceptable salt thereof.
The term “pharmaceutical composition” refers to a mixture of one or more compounds or forms disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
The term “physiologically acceptable” defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound.
As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.
As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
As used herein, an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A “diluent” is a type of excipient.
The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.
The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.
Multiple techniques of administering a compound exist in the art including, but not limited to, oral, rectal, topical, aerosol, injection and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.
One may also administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into the infected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
Uses of the Solid Forms and Pharmaceutically Acceptable Compositions
Some embodiments disclosed herein relate to a method of treating and/or ameliorating a disease or condition that can include administering to a subject an effective amount of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein.
Some embodiments disclosed herein relates to a method of ameliorating or treating a viral infection that can include administering to a subject suffering from the viral infection an effective amount of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein. Other embodiments described herein relate to the use of an effective amount of one or more solid forms of Compound 1 as described herein in the preparation of a medicament for ameliorating or treating a viral infection. Still other embodiments described herein relate to one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, that can be used for ameliorating and/or treating a viral infection by administering an effective amount of said compound(s). In some embodiments, the viral infection can be a hepatitis C viral (HCV) infection.
Some embodiments disclosed herein relate to methods of ameliorating and/or treating a viral infection that can include contacting a cell infected with the virus with an effective amount of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein. Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, in the manufacture of a medicament for ameliorating and/or treating a viral infection that can include contacting a cell infected with the virus with an effective amount of said compound(s). Still other embodiments described herein relate to one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, that can be used for ameliorating and/or treating a viral infection by contacting a cell infected with the virus with an effective amount of said compound(s). In some embodiments, the compound can be one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein. In other embodiments, the compound can be a mono-, di- and/or tri-phosphate of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein. In some embodiments, the virus can be a HCV virus.
Some embodiments disclosed herein relate to methods of inhibiting replication of a virus that can include contacting a cell infected with the virus with an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, or a pharmaceutical composition that includes one or more compounds described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to using one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, in the manufacture of a medicament for inhibiting replication of a virus that can include contacting a cell infected with the virus with an effective amount of said compound(s). Still other embodiments described herein relate to a compound described herein, or a pharmaceutically acceptable salt of a compound described herein, that can be used for inhibiting replication of a virus by contacting a cell infected with the virus with an effective amount of said compound(s). In some embodiments, the compound can be one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein. In other embodiments, the compound can be a mono-, di- and/or tri-phosphate of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein. In some embodiments, the virus can be a HCV virus.
In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can inhibit an RNA dependent RNA polymerase. In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can inhibit a HCV polymerase (for example, NS5B polymerase). Some embodiments described herein relate to a method for inhibiting NS5B polymerase activity of a virus that can include contacting a cell (such as a cell infected with HCV) with an effective amount of a compound described herein, whereby inhibiting the NS5B polymerase activity of the virus (for example, HCV). Other embodiments described herein relate to the use of an effective amount of a compound as described as described herein for preparing a medicament for inhibiting NS5B polymerase activity of a virus, such as the NS5B polymerase activity of a hepatitis C virus. Still other embodiments described herein relate to a compound described herein, or a pharmaceutically acceptable salt of a compound described herein, that can be used for inhibiting NS5B polymerase activity that can include contacting a cell (such as a cell infected with HCV) an effective amount of said compound(s). In some embodiments, the compound can be one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein. In other embodiments, the compound can be a mono-, di- and/or tri-phosphate of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein. In some embodiments, the virus can be a HCV virus.
HCV is an enveloped positive strand RNA virus in the Flaviviridae family. There are various nonstructural proteins of HCV, such as NS2, NS3, NS4A, NS4B, NS5A, and NS5B. NS5B is believed to be an RNA-dependent RNA polymerase involved in the replication of HCV RNA.
Some embodiments described herein relate to a method of treating HCV infection in a subject suffering from a HCV infection that can include administering to the subject an effective amount of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein. Other embodiments described herein relate to the use of an effective amount of a compound as described as described herein for preparing a medicament for treating HCV infection in a subject suffering from a HCV infection. Still other embodiments described herein relate to a compound described herein, or a pharmaceutically acceptable salt of a compound described herein, that can be used for treating HCV infection in a subject suffering from a HCV infection that can include administering an effective amount of said compound(s).
There are a variety of genotypes of HCV, and a variety of subtypes within each genotype. For example, at present it is known that there are eleven (numbered 1 through 11) main genotypes of HCV, although others have classified the genotypes as 6 main genotypes. Each of these genotypes is further subdivided into subtypes (1a-1c; 2a-2c; 3a-3b; 4a-4e; 5a; 6a; 7a-7b; 8a-8b; 9a; 10a; and 11a). In some embodiments, an effective amount of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be effective to treat at least one genotype of HCV. In some embodiments, a compound described herein (for example, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein) can be effective to treat all 11 genotypes of HCV. In some embodiments, a compound described herein (for example, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein) can be effective to treat 3 or more, 5 or more, 7 or more of 9 more genotypes of HCV. In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein is more effective against a larger number of HCV genotypes than the standard of care. In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, is more effective against a particular HCV genotype than the standard of care (such as genotype 1, 2, 3, 4, 5 and/or 6).
Various indicators for determining the effectiveness of a method for treating a HCV infection are known to those skilled in the art. Example of suitable indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in time to seroreversion (virus undetectable in patient serum), an increase in the rate of sustained viral response to therapy, a reduction of morbidity or mortality in clinical outcomes, a reduction in the rate of liver function decrease; stasis in liver function; improvement in liver function; reduction in one or more markers of liver dysfunction, including alanine transaminase, aspartate transaminase, total bilirubin, conjugated bilirubin, gamma glutamyl transpeptidase, and/or other indicator of disease response. Similarly, successful therapy with an effective amount of a compound or a pharmaceutical composition described herein (for example, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein) can reduce the incidence of liver cancer in HCV patients.
Some embodiments described herein relate to a method of treating a condition selected from liver fibrosis, liver cirrhosis, and liver cancer in a subject suffering from one or more of the aforementioned liver conditions that can include administering to the subject an effective amount of a compound or a pharmaceutical composition described herein (for example, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein). One cause of the liver fibrosis, liver cirrhosis, and/or liver cancer can be a HCV infection. Some embodiments described herein relate to a method of increasing liver function in a subject having a HCV infection that can include administering to the subject an effective amount of a compound or a pharmaceutical composition described herein (for example, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein). Also contemplated is a method for reducing or eliminating further virus-caused liver damage in a subject having an HCV infection by administering to the subject an effective amount of a compound or a pharmaceutical composition described herein (for example, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein). In some embodiments, this method comprises slowing or halting the progression of liver disease. In other embodiments, the course of the disease is reversed, and stasis or improvement in liver function is contemplated.
In some embodiments, an effective amount of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, is an amount that is effective to reduce viral titers undetectable levels, for example, to about 100 to about 500, to about 50 to about 100, to about 10 to about 50, or to about 15 to about 25 international units/mL serum. In some embodiments, an effective amount of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, is an amount that is effective to reduce viral load compared to the viral load before administration of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein. For example, wherein the viral load is measured before administration of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, and again after completion of the treatment regime with one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein (for example, 1 month after completion). In some embodiments, an effective amount of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be an amount that is effective to reduce viral load to lower than about 100 genome copies/mL serum. In some embodiments, an effective amount of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, is an amount that is effective to achieve a reduction in viral titer in the serum of the subject in the range of about 1.5-log to about a 2.5-log reduction, about a 3-log to about a 4-log reduction, or a greater than about 5-log reduction compared to the viral load before administration of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein. For example, the viral load can be measured before administration of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, and again after completion of the treatment regime with one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein (for example, 1 month after completion).
In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can result in at least a 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100-fold or more reduction in the replication of HCV relative to pre-treatment levels in a subject, as determined after completion of the treatment regime (for example 1 month after completion). In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can result in a reduction of the replication of HCV relative to pre-treatment levels in the range of about 2 to about 5 fold, about 10 to about 20 fold, about 15 to about 40 fold, or about 50 to about 100 fold. In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can result in a reduction of HCV replication in the range of 1 to 1.5 log, 1.5 log to 2 log, 2 log to 2.5 log, 2.5 to 3 log, 3 log to 3.5 log or 3.5 to 4 log more reduction of HCV replication compared to the reduction of HCV reduction achieved by pegylated interferon in combination with ribavirin, administered according to the standard of care, or may achieve the same reduction as that standard of care therapy in a shorter period of time, for example, in one month, two months, or three months, as compared to the reduction achieved after six months of standard of care therapy with ribavirin and pegylated interferon.
In some embodiments, an effective amount of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, is an amount that is effective to achieve a sustained viral response, for example, non-detectable or substantially non-detectable HCV RNA (e.g., less than about 500, less than about 400, less than about 200, or less than about 100 genome copies per milliliter serum) is found in the subject's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of therapy.
In some embodiments, an effective amount one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can reduce a level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated subject, or to a placebo-treated subject. Methods of measuring serum markers are known to those skilled in the art and include immunological-based methods, e.g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker. A non-limiting list of examples of markers include measuring the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) and total bilirubin (TBIL) using known methods. In general, an ALT level of less than about 45 IU/L (international units/liter), an AST in the range of 10-34 IU/L, ALP in the range of 44-147 IU/L, GGT in the range of 0-51 IU/L, TBIL in the range of 0.3-1.9 mg/dL is considered normal. In some embodiments, an effective amount of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein is an amount effective to reduce ALT, AST, ALP, GGT and/or TBIL levels to with what is considered a normal level.
Subjects who are clinically diagnosed with HCV infection include “naïve” subjects (e.g., subjects not previously treated for HCV, particularly those who have not previously received IFN-alpha-based and/or ribavirin-based therapy) and individuals who have failed prior treatment for HCV (“treatment failure” subjects). Treatment failure subjects include “non-responders” (i.e., subjects in whom the HCV titer was not significantly or sufficiently reduced by a previous treatment for HCV (≦0.5 log IU/mL), for example, a previous IFN-alpha monotherapy, a previous IFN-alpha and ribavirin combination therapy, or a previous pegylated IFN-alpha and ribavirin combination therapy); and “relapsers” (i.e., subjects who were previously treated for HCV, for example, who received a previous IFN-alpha monotherapy, a previous IFN-alpha and ribavirin combination therapy, or a previous pegylated IFN-alpha and ribavirin combination therapy, whose HCV titer decreased, and subsequently increased).
In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be administered to a treatment failure subject suffering from HCV. In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be administered to a non-responder subject suffering from HCV. In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be administered to a relapsed subject suffering from HCV.
After a period of time, infectious agents can develop resistance to one or more therapeutic agents. The term “resistance” as used herein refers to a viral strain displaying a delayed, lessened and/or null response to a therapeutic agent(s). For example, after treatment with an antiviral agent, the viral load of a subject infected with a resistant virus may be reduced to a lesser degree compared to the amount in viral load reduction exhibited by a subject infected with a non-resistant strain. In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be administered to a subject infected with an HCV strain that is resistant to one or more different anti-HCV agents. In some embodiments, development of resistant HCV strains is delayed when patients are treated with one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, compared to the development of HCV strains resistant to other HCV drugs.
In some embodiments, an effective amount of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be administered to a subject for whom other anti-HCV medications are contraindicated. For example, administration of pegylated interferon alpha in combination with ribavirin is contraindicated in subjects with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia) and other subjects at risk from the hematologic side effects of current therapy. In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be provided to a subject that is hypersensitive to interferon or ribavirin.
Some subjects being treated for HCV experience a viral load rebound. The term “viral load rebound” as used herein refers to a sustained ≧0.5 log IU/mL increase of viral load above nadir before the end of treatment, where nadir is a ≧0.5 log IU/mL decrease from baseline. In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be administered to a subject experiencing viral load rebound, or can prevent such viral load rebound when used to treat the subject.
The standard of care for treating HCV has been associated with several side effects (adverse events). In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can decrease the number and/or severity of side effects that can be observed in HCV patients being treated with ribavirin and pegylated interferon according to the standard of care. Examples of side effects include, but are not limited to fever, malaise, tachycardia, chills, headache, arthralgias, myalgias, fatigue, apathy, loss of appetite, nausea, vomiting, cognitive changes, asthenia, drowsiness, lack of initiative, irritability, confusion, depression, severe depression, suicidal ideation, anemia, low white blood cell counts, and thinning of hair. In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be provided to a subject that discontinued a HCV therapy because of one or more adverse effects or side effects associated with one or more other HCV agents.
Table 1 provides some embodiments of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, compared to the standard of care. Examples include the following: in some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, results in a percentage of non-responders that is 10% less than the percentage of non-responders receiving the standard of care; in some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, results number of side effects that is in the range of about 10% to about 30% less than compared to the number of side effects experienced by a subject receiving the standard of care; and in some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, results a severity of a side effect (such as one of those described herein) that is 25% less than compared to the severity of the same side effect experienced by a subject receiving the standard of care. Methods of quantifying the severity of a side effect are known to those skilled in the art.












TABLE 1





Percentage
Percentage
Percentage
Percentage
Number of
Severity


of non-
of
of
of viral load
side
of side


responders
relapsers
resistance
rebound
effects
effects







10% less
10% less
10% less
10% less
10% less
10% less


25% less
25% less
25% less
25% less
25% less
25% less


40% less
40% less
40% less
40% less
40% less
40% less


50% less
50% less
50% less
50% less
50% less
50% less


60% less
60% less
60% less
60% less
60% less
60% less


70% less
70% less
70% less
70% less
70% less
70% less


80% less
80% less
80% less
80% less
80% less
80% less


90% less
90% less
90% less
90% less
90% less
90% less


about 10%
about 10%
about 10%
about 10% to
about 10%
about 10%


to about
to about
to about
about 30%
to about
to about


30% less
30% less
30% less
less
30% less
30% less


about 20%
about 20%
about 20%
about 20% to
about 20%
about 20%


to about
to about
to about
about 50%
to about
to about


50% less
50% less
50% less
less
50% less
50% less


about 30%
about 30%
about 30%
about 30% to
about 30%
about 30%


to about
to about
to about
about 70%
to about
to about


70% less
70% less
70% less
less
70% less
70% less


about 20%
about 20%
about 20%
about 20% to
about 20%
about 20%


to about
to about
to about
about 80%
to about
to about


80% less
80% less
80% less
less
80% less
80% less









As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject is human.
As used herein, the terms “treating,” “treatment,” “therapeutic,” or “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the patient's overall feeling of well-being or appearance.
The term “effective amount” is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, an effective amount of compound can be the amount needed to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials and in vitro studies.
The dosage may range broadly, depending upon the desired effects and the therapeutic indication. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art. Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.01 mg and 3000 mg of each active ingredient, preferably between 1 mg and 700 mg, e.g. 5 to 200 mg. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the subject. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years. In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be administered less frequently compared to the frequency of administration of an agent within the standard of care. In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be administered one time per day. For example, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be administered one time per day to a subject suffering from a HCV infection. In some embodiments, the total time of the treatment regime with one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can less compared to the total time of the treatment regime with the standard of care.
In instances where human dosages for compounds have been established for at least some condition, those same dosages may be used, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage. Where no human dosage is established, as will be the case for newly-discovered pharmaceutical compositions, a suitable human dosage can be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections.
Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.
Combination Therapies
In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be used in combination with one or more additional agent(s).
Examples of additional agents that can be used in combination with one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, include, but are not limited to, agents currently used in a conventional standard of care for treating HCV, HCV protease inhibitors, HCV polymerase inhibitors, NS5A inhibitors, other antiviral compounds, compounds of Formula (BB) (including pharmaceutically acceptable salts and pharmaceutical compositions that can include a compound of Formula (BB), or a pharmaceutically acceptable salt thereof), compounds of Formula (DD) (including pharmaceutically acceptable salts and pharmaceutical compositions that can include a compound of Formula (DD), or a pharmaceutically acceptable salt thereof), and/or combinations thereof. In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be used with one, two, three or more additional agents described herein. In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be used in combination with an agent(s) currently used in a conventional standard of care therapy. For example, for the treatment of HCV, a compound disclosed herein can be used in combination with Pegylated interferon-alpha-2a (brand name PEGASYS®) and ribavirin, or Pegylated interferon-alpha-2b (brand name PEG-INTRON®) and ribavirin.
In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be substituted for an agent currently used in a conventional standard of care therapy. For example, for the treatment of HCV, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be used in place of ribavirin.
In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be used in combination with an interferon, such as a pegylated interferon. Examples of suitable interferons include, but are not limited to, Pegylated interferon-alpha-2a (brand name PEGASYS®), Pegylated interferon-alpha-2b (brand name PEG-INTRON®), interferon alfacon-1 (brand name INFERGEN®), pegylated interferon lambda and/or a combination thereof.
In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be used in combination with a HCV protease inhibitor. A non-limiting list of example HCV protease inhibitors include the following: VX-950 (TELAPREVIR®), MK-5172, ABT-450, BILN-2061, BI-201335, BMS-650032, SCH 503034 (BOCEPREVIR®), GS-9256, GS-9451, IDX-320, ACH-1625, ACH-2684, TMC-435, ITMN-191 (DANOPREVIR®) and/or a combination thereof.
In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be used in combination with a HCV polymerase inhibitor. In some embodiments, the HCV polymerase inhibitor can be a nucleoside inhibitor. In other embodiments, the HCV polymerase inhibitor can be a non-nucleoside inhibitor. Examples of suitable nucleoside inhibitors include, but are not limited to, RG7128, PSI-7851, PSI-7977, PSI-352938, PSI-661, 4′-azidouridine (including known prodrugs of 4′-azidouridine), GS-6620, and TMC649128 and/or combinations thereof. A non-limiting list of example nucleoside inhibitors as provided in FIG. 32. Examples of suitable non-nucleoside inhibitors include, but are not limited to, ABT-333, ANA-598, VX-222, HCV-796, BI-207127, GS-9190, PF-00868554 (FILIBUVIR®), VX-497 and/or combinations thereof. A non-limiting list of example non-nucleoside as provided in FIG. 32.
In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be used in combination with a NS5A inhibitor. A non-limiting list of example NS5A inhibitors include BMS-790052, GSK-2336805, ACH-3102, PPI-461, ACH-2928, GS-5885, BMS-824393 and/or combinations thereof. A non-limiting list of example NS5A inhibitors as provided in FIG. 32.
In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be used in combination with other antiviral compounds. Examples of other antiviral compounds include, but are not limited to, Debio-025, MIR-122 and/or combinations thereof. A non-limiting list of example other antiviral compounds are provided in FIG. 32.
A non-limiting list of additional agents that can be used in combination with more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, include the following compounds provided in FIG. 32: 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065, and 1066.
In some embodiments, one or more solid forms of Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with a compound of Formula (BB), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (BB), or a pharmaceutically acceptable salt thereof (see, U.S. Publication No. 2012/0165286, filed Dec. 20, 2011 the contents of which are incorporated by reference in its entirety):




wherein BBB1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; XBB can be O (oxygen) or S (sulfur); RBB1 can be selected from —ZBB—RBB9, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; ZBB can be selected from O (oxygen), S (sulfur) and N(RBB10); RBB2 and RBB3 can be independently selected from hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C1-6 haloalkyl and an optionally substituted aryl(C1-6 alkyl); or RBB2 and RBB3 can be taken together to form a group selected from an optionally substituted C3-6 cycloalkyl, an optionally substituted C3-6 cycloalkenyl, an optionally substituted C3-6 aryl and an optionally substituted C3-6 heteroaryl; RBB4 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl and an optionally substituted allenyl; RBB5 can be hydrogen or an optionally substituted C1-6 alkyl; RBB6 can be selected from hydrogen, halogen, azido, amino, cyano, an optionally substituted C1-6 alkyl, —ORBB11 and —OC(═O)RBB12; RBB7 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, —ORBB13 and —OC(═O)RBB14; RBB8 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, —ORBB15 and —OC(═O)RBB16; RBB9 can be selected from an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C1-6alkyl), an optionally substituted heteroaryl(C1-6alkyl) and an optionally substituted heterocyclyl(C1-6alkyl); RBB10 can be selected from hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C1-6alkyl), an optionally substituted heteroaryl(C1-6alkyl) and an optionally substituted heterocyclyl(C1-6alkyl); RBB11, RBB13 and RBB15 can be independently hydrogen or an optionally substituted C1-6 alkyl; and RBB12, RBB14 and RBB16 can be independently an optionally substituted C1-6 alkyl or an optionally substituted C3-6 cycloalkyl. In some embodiments, at least one of RBB2 and RBB3 is not hydrogen. A non-limiting list of example compounds of Formula (BB) includes the compound numbered 8001-8012 in FIG. 33.
In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be used in combination with a compound of Formula (DD), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound of Formula (DD), or a pharmaceutically acceptable salt thereof (see, U.S. Publication No. 2010/0249068, filed Mar. 19, 2010, the contents of which are incorporated by reference in its entirety):




wherein each  can be independently a double or single bond; ADD1 can be selected from C (carbon), O (oxygen) and S (sulfur); BDD1 can be an optionally substituted heterocyclic base or a derivative thereof; DDD1 can be selected from C═CH2, CH2, O (oxygen), S (sulfur), CHF, and CF2; RDD1 can be hydrogen, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aralkyl, dialkylaminoalkylene, alkyl-C(═O)—, aryl-C(═O)—, alkoxyalkyl-C(═O)—, aryloxyalkyl-C(═O)—, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl,




an —O-linked amino acid, diphosphate, triphosphate or derivatives thereof; RDD2 and RDD3 can be each independently selected from hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl and an optionally substituted C1-6 haloalkyl, provided that at least one of RDD2 and RDD3 cannot be hydrogen; or RDD2 and RDD3 are taken together to form a group selected from among C3-6 cycloalkyl, C3-6 cycloalkenyl, C3-6 aryl, and a C3-6 heteroaryl; RDD4 and RDD9 can be independently selected from hydrogen, halogen, —NH2, —NHRDDa1, NRDDa1RDDb1, —ORDDa1, —SRDDa1, —CN, —NC, —N3, —NO2, —N(RDDc1)—NRDDa1RDDb1, —N(RDDc1)—ORDDa1, —S—SRDDa1, —C(═O)RDDa1, —C(═O)ORDDa1, —C(═O)NRDDa1RDDb1, —O—(C═O)RDDa1, —O—C(═O)ORDDa1, —O—C(═O)NRDDa1RDDb1, —N(RDDc1)—C(═O)NRDDa1RDDb1, —S(═O)RDDa1, S(═O)2RDDa1, —O—S(═O)2NRDDa1RDDb1, —N(RDDc1)—S(═O)2NRDDa1RDDb1, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted aralkyl and an —O-linked amino acid; RDD5, RDD6 and RDD7 can be independently absent or selected from hydrogen, halogen, —NH2, —NHRDDa1, NRDDa1RDDb1, —ORDDa1, —SRDDa1, —CN, —NC, —N3, —NO2, —N(RDDc1)—NRDDa1RDDb1, —N(RDDc1)—ORDDa1, —S—SRDDa1, —C(═O)RDDa1, —C(═O)ORDDa1, —C(═O)NRDDa1RDDb1, —O—(C═O)RDDa1, —O—C(═O)ORDDa1, —O—C(═O)NRDDa1RDDb1, —N(RDDc1)—C(═O)NRDDa1RDDb1, —S(═O)RDDa1, S(═O)2RDDa1, —O—S(═O)2NRDDa1RDDb1, —N(RDDc1)—S(═O)2NRDDa1RDDb1, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted aralkyl and an —O-linked amino acid; or RDD6 and RDD7 taken together form —O—C(═O)—O—; RDD8 can be absent or selected from the group consisting of hydrogen, halogen, —NH2, —NHRDDa1, NRDDa1RDDb1, —ORDDa1, —SRDDa1, —CN, —NC, —N3, —NO2, —N(RDDc1)—NRDDa1RDDb1, —N(RDDc1)—ORDDa1, —S—SRDDa1, —C(═O)RDDa1, —C(═O)ORDDa1, —C(═O)NRDDa1RDDb1, —O—C(═O)ORDDa1, —O—C(═O)NRDDa1RDDb1, —N(RDDc1)—C(═O)NRDDa1RDDb1, —S(═O)RDDa1, S(═O)2RDDa1, —O—S(═O)2NRDDa1RDDb1, —N(RDDc1)—S(═O)2NRDDa1RDDb1, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted haloalkyl, an optionally substituted hydroxyalkyl and an —O-linked amino acid, or when the bond to RDD7 indicated by  is a double bond, then RDD7 is a C2-6 alkylidene and RDD8 is absent; RDDa1, RDDb1 and RDDc1 can be each independently selected from hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl and an optionally substituted heteroaryl(C1-6 alkyl); RDD10 can be selected from O−, —OH, an optionally substituted aryloxy or aryl-O—,





alkyl-C(═O)—O—CH2—O—, alkyl-C(═O)—S—CH2CH2—O— and an —N-linked amino acid; RDD11 can be selected from O−, —OH, an optionally substituted aryloxy or aryl-O—,





alkyl-C(═O)—O—CH2—O—, alkyl-C(═O)—S—CH2CH2—O— and an —N-linked amino acid; each RDD12 and each RDD13 can be independently —C≡N or an optionally substituted substituent selected from C1-8 organylcarbonyl, C1-8 alkoxycarbonyl and C1-8 organylaminocarbonyl; each RDD14 can be hydrogen or an optionally substituted C1-6-alkyl; each mDD can be independently 1 or 2, and if both RDD10 and RDD11 are





each RDD12, each RDD13, each RDD14 and each mDD can be the same or different. In some embodiments, RDD8 can be halogen, —ORDDa1, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl and an optionally substituted C1-6 haloalkyl.

Additional examples of compounds that can be used in combination with one or more solid forms of Compound 1 described herein, or a pharmaceutically acceptable salt thereof, include those described in the following: WO 99/07733 (Boehringer Ingelheim), WO 99/07734 (Boehringer Ingelheim), WO 00/09558 (Boehringer Ingelheim), WO 00/09543 (Boehringer Ingelheim), WO 00/59929 (Boehringer Ingelheim), WO 02/060926 (BMS), WO 2006/039488 (Vertex), WO 2005/077969 (Vertex), WO 2005/035525 (Vertex), WO 2005/028502 (Vertex), WO 2005/007681 (Vertex), WO 2004/092162 (Vertex), WO 2004/092161 (Vertex), WO 2003/035060 (Vertex), WO 03/087092 (Vertex), WO 02/18369 (Vertex), WO 98/17679 (Vertex), WO 03/010140 (Boehringer Ingelheim), WO 03/026587 (Bristol Myers Squibb), WO 02/100846 A1, WO 02/100851 A2, WO 01/85172 AI (GSK), WO 02/098424 A1 (GSK), WO 00/06529 (Merck), WO 02/06246 A1 (Merck), WO 01/47883 (Japan Tobacco), WO 03/000254 (Japan Tobacco), EP 1 256 628 A2 (Agouron), WO 01/90121 A2 (Idenix), WO 02/069903 A2 (Biocryst Pharmaceuticals Inc.), WO 02/057287 A2 (Merck/Isis), WO 02/057425 A2 (Merck/Isis), WO 2010/117635, WO 2010/117977, WO 2010/117704, WO 2010/1200621, WO 2010/096302, WO 2010/017401, WO 2009/102633, WO 2009/102568, WO 2009/102325, WO 2009/102318, WO 2009/020828, WO 2009/020825, WO 2008/144380, WO 2008/021936, WO 2008/021928, WO 2008/021927, WO 2006/133326, WO 2004/014852, WO 2004/014313, WO 2010/096777, WO 2010/065681, WO 2010/065668, WO 2010/065674, WO 2010/062821, WO 2010/099527, WO 2010/096462, WO 2010/091413, WO 2010/094077, WO 2010/111483, WO 2010/120935, WO 2010/126967, WO 2010/132538, WO 2010/122162 and WO 2006/019831 (PTC therapeutics), wherein all the aforementioned are hereby incorporated by reference for the limited purpose of the chemical structures and chemical compounds disclosed therein.
Further examples of compounds that can be used in combination with one or more solid forms of Compound 1 described herein, or a pharmaceutically acceptable salt thereof, include the following: R1626, R1479 (Roche), MK-0608 (Merck), R1656, (Roche-Pharmasset), Valopicitabine (Idenix), JTK-002/003, JTK-109 (Japan Tobacco), GS-7977 (Gilead), EDP-239 (Enanta), PPI-1301 (Presido Pharmaceuticals), (Gao M. et al. Nature, 465, 96-100 (2010)), JTK-853 (Japan Tobacco), RO-5303253 Hoffmann-La Roche), IDX-184 (Idenix Pharmaceuticals), class I interferons (such as alpha-interferons, beta-interferons, delta-interferons, omega-interferons, tau-inteferons, x-interferons, consensus interferons and asialo-interferons), class II interferons (such as gamma-interferons), pegylated interferons, interferon alpha 1A, interferon alpha 1 B, interferon alpha 2A, and interferon alpha 2B, thalidomide, IL-2; hematopoietins, IMPDH inhibitors (for example, Merimepodib (Vertex Pharmaceuticals Inc.)), natural interferon (such as OMNIFERON, Viragen and SUMIFERON, Sumitomo, and a blend of natural interferons), natural interferon alpha (ALFERON, Hemispherx Biopharma, Inc.), interferon alpha n1 from lymphblastoid cells (WELLFERON, Glaxo Wellcome), oral alpha interferon, Peg-interferon, Peg-interferon alpha 2a (PEGASYS, Roche), recombinant interferon alpha 2a (ROFERON, Roche), inhaled interferon alpha 2b (AERX, Aradigm), Peg-interferon alpha 2b (ALBUFERON, Human Genome Sciences/Novartis, PEGINTRON, Schering), recombinant interferon alpha 2b (INTRON A, Schering), pegylated interferon alpha 2b (PEG-INTRON, Schering, VIRAFERONPEG, Schering), interferon beta-1a (REBIF, Serono, Inc. and Pfizer), consensus interferon alpha (INFERGEN, Valeant Pharmaceutical), interferon gamma-1b (ACTIMMUNE, Intermune, Inc.), synthetic thymosin alpha 1 (ZADAXIN, SciClone Pharmaceuticals Inc.), an antisense agent (for example, ISIS-14803), SCH-6, ITMN-B (InterMune), GS9132 (Gilead), ISIS-14803 (ISIS Pharmaceuticals), ribavirin, amantadine, merimepodib, Levovirin, Viramidine, maxamine, silybum marianum, interleukine-12, amantadine, ribozyme, thymosin, N-acetyl cysteine and cyclosporin.
Some embodiments described herein relate to a method of ameliorating or treating a viral infection that can include contacting a cell infected with the viral infection with an effective amount of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a mono-, di, and/or tri-phosphate thereof, a compound of Formula (BB), and a compound of Formula (DD), or a pharmaceutically acceptable salt of any of the aforementioned compounds.
Some embodiments described herein relate to a method of ameliorating or treating a viral infection that can include administering to a subject suffering from the viral infection an effective amount of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (BB), and a compound of Formula (DD), or a pharmaceutically acceptable salt of any of the aforementioned compounds.
Some embodiments described herein relate to a method of inhibiting viral replication of a virus that can include contacting a cell infected with the virus with an effective amount of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more agents selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (BB), and a compound of Formula (DD), or a pharmaceutically acceptable salt of any of the aforementioned compounds.
Some embodiments described herein relate to the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for ameliorating or treating a HCV infection, wherein the medicament can be manufactured for use in combination with one or more agents selected from an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (BB) and a compound of Formula (DD), or a pharmaceutically acceptable salt any of the aforementioned compounds.
Other embodiments described herein relate to the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for contacting a cell infected with a hepatitis C virus, wherein the medicament can be manufactured for use in combination with one or more agents selected from the group consisting of an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (BB), and a compound of Formula (DD), or a pharmaceutically acceptable salt any of the aforementioned compounds.
Other embodiments described herein relate to the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for inhibiting viral replication of a virus (for example, HCV), wherein the medicament can be manufactured for use in combination with one or more agents selected from the group consisting of an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (BB), and a compound of Formula (DD), or a pharmaceutically acceptable salt any of the aforementioned compounds.
In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be administered with one or more additional agent(s) together in a single pharmaceutical composition. In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be administered with one or more additional agent(s) as two or more separate pharmaceutical compositions. For example, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be administered in one pharmaceutical composition, and at least one of the additional agents can be administered in a second pharmaceutical composition. If there are at least two additional agents, one or more of the additional agents can be in a first pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, and at least one of the other additional agent(s) can be in a second pharmaceutical composition.
In some embodiments, one or more solid forms of Compound 1 described herein can be used in combination with VX-950 (TELAPREVIR®) for treating and/or ameliorating HCV, inhibiting NS5B activity of HCV and/or inhibiting replication of HCV. In some embodiments, Form J can be used in combination with VX-950 (TELAPREVIR®) for treating and/or ameliorating HCV, inhibiting NS5B activity of HCV and/or inhibiting replication of HCV. In some embodiments, one or more solid forms of Compound 1 described herein can be used in combination with VX-222 for treating and/or ameliorating HCV, inhibiting NS5B activity of HCV and/or inhibiting replication of HCV. In some embodiments, Form J can be used in combination with VX-222 for treating and/or ameliorating HCV, inhibiting NS5B activity of HCV and/or inhibiting replication of HCV.
The dosing amount(s) and dosing schedule(s) when using one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, and one or more additional agents are within the knowledge of those skilled in the art. For example, when performing a conventional standard of care therapy using art-recognized dosing amounts and dosing schedules, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be administered in addition to that therapy, or in place of one of the agents of a combination therapy, using effective amounts and dosing protocols as described herein.
The order of administration of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, with one or more additional agent(s) can vary. In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be administered prior to all additional agents. In other embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be administered prior to at least one additional agent. In still other embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be administered concomitantly with one or more additional agent(s). In yet still other embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be administered subsequent to the administration of at least one additional agent. In some embodiments, one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, can be administered subsequent to the administration of all additional agents.
In some embodiments, the combination of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, in combination with one or more additional agent(s) in FIGS. 32-34 (including pharmaceutically acceptable salts and prodrugs thereof) can result in an additive effect. In some embodiments, the combination one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, in combination with one or more additional agent(s) in FIGS. 32-34 (including pharmaceutically acceptable salts and prodrugs thereof) can result in a synergistic effect. In some embodiments, the combination of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, in combination with one or more additional agent(s) in FIGS. 32-34 (including pharmaceutically acceptable salts and prodrugs thereof) can result in a strongly synergistic effect. In some embodiments, the combination of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, in combination with one or more additional agent(s) in FIGS. 32-34 (including pharmaceutically acceptable salts and prodrugs thereof) is not antagonistic.
As used herein, the term “antagonistic” means that the activity of the combination of compounds is less compared to the sum of the activities of the compounds in combination when the activity of each compound is determined individually (i.e. as a single compound). As used herein, the term “synergistic effect” means that the activity of the combination of compounds is greater than the sum of the individual activities of the compounds in the combination when the activity of each compound is determined individually. As used herein, the term “additive effect” means that the activity of the combination of compounds is about equal to the sum of the individual activities of the compound in the combination when the activity of each compound is determined individually.
A potential advantage of utilizing one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, in combination with one or more additional agent(s) in FIGS. 32-34 (including pharmaceutically acceptable salts and prodrugs thereof) may be a reduction in the required amount(s) of one or more compounds of FIGS. 32-34 (including pharmaceutically acceptable salts and prodrugs thereof) that is effective in treating a disease condition disclosed herein (for example, HCV), as compared to the amount required to achieve same therapeutic result when one or more compounds of FIGS. 32-34 (including pharmaceutically acceptable salts and prodrugs thereof) are administered without one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein. For example, the amount of a compound in FIGS. 32-34 (including a pharmaceutically acceptable salt and prodrug thereof), can be less compared to the amount of the compound in FIGS. 32-34 (including a pharmaceutically acceptable salt and prodrug thereof), needed to achieve the same viral load reduction when administered as a monotherapy. Another potential advantage of utilizing one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, in combination with one or more additional agent(s) in FIGS. 32-34 (including pharmaceutically acceptable salts and prodrugs thereof) is that the use of two or more compounds having different mechanism of actions can create a higher barrier to the development of resistant viral strains compared to the barrier when a compound is administered as monotherapy.
Additional advantages of utilizing one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, in combination with one or more additional agent(s) in FIGS. 32-34 (including pharmaceutically acceptable salts and prodrugs thereof) may include little to no cross resistance between one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, and one or more additional agent(s) in FIGS. 32-34 (including pharmaceutically acceptable salts and prodrugs thereof) thereof; different routes for elimination of one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, and one or more additional agent(s) in FIGS. 32-34 (including pharmaceutically acceptable salts and prodrugs thereof); little to no overlapping toxicities between one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, and one or more additional agent(s) in FIGS. 32-34 (including pharmaceutically acceptable salts and prodrugs thereof); little to no significant effects on cytochrome P450; and/or little to no pharmacokinetic interactions between one or more solid forms of Compound 1 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more solid forms of Compound 1 as described herein, and one or more additional agent(s) in FIGS. 32-34 (including pharmaceutically acceptable salts and prodrugs thereof).
In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.
EXAMPLES
Methods & Materials
XRPD (X-ray Powder Diffraction)
Unless otherwise specified, samples were scanned on the Bruker D8 Discover operated at 40 kV, 35 mA. Two frames were registered with an exposure of 120 seconds. Data were integrated over the range of 4.5°-39.0° 2 theta with a step size of 0.02° and merged into one continuous pattern. All XRPD spectra provided herein are measured on a degrees 2-Theta scale.
Differential Scanning Calorimetry (DSC)
The following DSC method was used:
1: Data storage: Off
2: Equilibrate at −20.00° C. or 25.00° C.
3: Modulate+/−1.00° C. every 60 seconds
4: Isothermal for 5.00 min
5: Data storage: On
6: Ramp 2.00-3.00° C./min to 250.00° C.
Solid State Nuclear Magnetic Spectroscopy
Samples were packed into Bruker-Biospin 4 mm ZrO2 rotors (approximately 65 mg or less each depending on sample availability). The rotors were spun inside a Bruker-Biospin 4 mm HFX probe, which was placed in 400 MHz Bruker-Biospin wide bore magnet. Magic angle spinning (MAS) speed of typically 12.5 kHz was used (10.0 kHz if a suspension was characterized instead of a dry powder). The samples were referenced to adamantane at 29.5 ppm. The proton relaxation time was measured using 1H MAS T1 saturation recovery relaxation experiment in order to set up proper recycle delay of the 13C cross-polarization (CP) MAS experiment. The CP contact time was set to 2 ms. A CP proton pulse with linear ramp (from 50% to 100%) was employed. The Hartmann-Hahn match was optimized on external reference sample of glycine. SPINAL 64 decoupling was used with the field strength of approximately 90 kHz.
Synthesis of Compound 1 and the Solid Forms of Compound 1
Example 1
Synthesis of 2′-C-methyluridine 5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate (Compound 1)







Step 1: Compound 3b-1—
To a suspension of 2′-methyluridine (20 g, 77.52 mmol) in dry CH3CN (200 mL) were added cyclopentanone (20 mL) and trimethylorthoformate (20 mL) followed by p-toluenesulfonic acid monohydrate (7.4 g, 38.76 mmol). The reaction mixture was stirred at 40° C. overnight. The solvent was evaporated. The residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried and evaporated to give pure 3b-1 as a white solid (14.5 g, 57.7%). 1H NMR (CDCl3, 400 MHz) 68.86 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 6.06 (s, 1H), 5.73 (d, J=8.0 Hz, 1H), 4.50 (d, J=4.8 Hz, 1H), 4.21 (m, 1H), 4.02-3.86 (m, 2H), 2.17 (m, 1H), 1.98, 1.83, 1.68 (m, 8H), 1.30 (s, 3H).
Step 2: Compound 3b-2—
To a suspension of 3b-1 (20 g, 61.7 mmol) in dry CH3CN (100 mL) was added N-methylimidazole (50 mL) and 2b (80 g, 249.2 mmol). The reaction mixture was stirred at 70° C. for 2 h. Solvent was removed and the residue was dissolved in ethyl acetate (500 mL). The solution was washed with brine, dried and evaporated. The residue was purified on a silica gel column (20-50% ethylacetate (EA) in petroleum ether (PE)) to give 3b-2 as a white foam (two isomers, 12.5 g, 33%). 1H NMR (CDCl3, 400 MHz) 68.79-8.92 (m, 1H), 7.55 (m, 1H), 7.34 (m, 2H), 7.20 (m, 3H), 6.09 (d, J=13.6 Hz, 1H), 5.70-5.61 (m, 1H), 5.06-5.01 (m, 1H), 4.38-4.09 (m, 6H), 2.08 (m, 1H), 1.96 (m, 1H), 1.73 (m, 2H), 1.66 (m, 5H), 1.39 (m, 3H), 1.23 (m, 9H); 31P NMR (CDCl3, 162 MHz) δ67.62, 67.31.
Step 3: Compound 1(rac)—
Compound 3b-2 (10 g, 16.4 mmol) was suspended in 100 mL of 80% formic acid and the reaction mixture was stirred at 50° C. for 1.5 hours. Solvent was evaporated and the residue was co-evaporated with toluene to remove traces of acid and water. The residue was purified by RP HPLC (0.5% HCOOH in MeCN and water as mobile phase) to give Compound 1(rac) (a mixture of two P-diastereomers, 5.6 g, 63%). 1H NMR (CD3OD, 400 MHz) δ 7.79, 7.87 (2d, J=8.0 Hz, 1H), 7.18-7.38 (m, 5H), 5.98, 6.01 (2s, 1H), 5.59, 5.63 (2d, J=8.0 Hz, 1H), 4.95-5.05 (m, 1H), 4.51-4.56 (m, 1H), 4.30-4.44 (m, 1H), 4.05-4.17 (m, 2H), 3.82-3.87 (m, 1H), 1.34, 1.38 (2d, J=7.2 Hz, 3H), 1.17, 1.25 (2d, J=6.0 Hz, 6H), 1.24, 125 (2s, 3H); 31P NMR (CD3OD, 162 MHz) δ68.17, 68.40; ESI-LCMS: m/z 544.0 [M+H]+.
Step 4: Separation of Compound 1 and Compound 1a—
Compound 1(rac) was separated into its diastereomers by two methods: (a) supercritical fluid chromatography (SFC) and (b) crystallization.
(a) Via SFC:
Compound 1(rac) (440 mg, consisting of both Compound 1 and Compound 1a in  ̃1:1 ratio) was subjected to separation by SFC (chiral PAK AD, 5 um. 250*30 mm using 25% MeOH and 75% CO2 as mobile phase) to give Compound 1a (123.8 mg) and Compound 1 (162.5 mg) as a white solid; Compound 1a: 1H NMR (CD3OD, 400 MHz) δ7.87 (d, J=8.4 Hz, 1H), 7.36 (t, J=8.0 Hz, 2H), 7.28 (d, J=8.8 Hz, 2H), 7.19 (t, J=7.6 Hz, 1H), 6.01 (s, 1H), 5.62 (d, J=8.0 Hz, 1H), 5.03-4.97 (m, 1H), 4.56-4.92 (m, 1H), 4.44-4.39 (m, 1H), 4.16-4.13 (m, 1H), 4.10-4.05 (m, 1H), 3.86 (d, J=9.2 Hz, 1H), 1.34 (d, J=7.2 Hz, 3H), 1.25 (d, J=6.4 Hz, 6H), 1.16 (s, 3H); 31P NMR (CD3OD, 162 MHz) δ68.18; ESI-LCMS: m/z=544 [M+H]+. Compound 1: 1H NMR (CD3OD, 400 MHz) δ7.89 (d, J=8.0 Hz, 1H), 7.36 (t, J=8.0 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.20 (t, J=8.0 Hz, 1H), 5.99 (s, 1H), 5.60 (d, J=8.4 Hz, 1H), 5.03-4.97 (m, 1H), 4.56-4.51 (m, 1H), 4.35-4.30 (m, 1H), 4.14-4.10 (m, 2H), 3.83 (d, J=9.2 Hz, 1H), 1.39 (d, J=7.2 Hz, 3H), 1.25 (d, J=6.4 Hz, 6H), 1.17 (s, 3H); 31P NMR (CD3OD, 162 MHz) δ68.42; ESI-LCMS: m/z=566 [M+Na]+.
(b) Via Crystallization:
Method 1:
Compound 1(rac) as a mixture of diastereomers (1:1, 10 g) was dissolved in 100 mL of dichloromethane (DCM)/ether (1:3). Hexane was added dropwise until the solution became cloudy. The solution was left at (room temperature) RT for 5 h and overnight at −20° C. Precipitated crystals were recrystallized from DCM/ether 1:3 v/v, and one more time from DCM/ether 1:2. Compound 1a (3 g) was obtained as a pure single diastereomer. The mother liquor after first crystallization was concentrated, and then dissolved in isopropanol. Hexane was added (30% by volume). The clear solution was left overnight at RT to produce a small amount of crystals, which were used as seeds. The mother liquor was evaporated and crystallized 2 times from hexane/isopropanol (4:1) to give 2.3 g of Compound 1.
Method 2:
50 g of Compound 1(rac) was added to 100 mL of DCM and allowed to stir. After brief stirring almost all of the material was dissolved (<100 mg remained suspended). This was filtered and 300 mL of MTBE added while stirring. About 25 mg of Compound 1 was added as seeds and the solution cooled to 3° C. overnight. Significant precipitation was observed. The cold mixture was filtered and the solid washed with 25 mL of MTBE but not filtered dry. The product was dried on a rotvac at 8 torr and 30° C. This material was recrystallized one additional time using the procedure outline above with precipitation being observed upon the addition of 100 mg of the product from the first crystallization as seeds. XRPD indicated that the material recovered was amorphous. Additional solids had precipitated from the supernatant and were collected by filtration. These were then rinsed with 25 mL of MTBE and dried. 31P NMR showed that this material was Compound 1 with about 4% of Compound 1a.
Example 2
Synthesis of Amorphous Form O
350 mg of Compound 1 was weighed and added to 8 mL of a 1:1 DCM/Methanol (HPLC grade) solution in a vial. The contents were allowed to stir until a clear solution was obtained. This solution was spray dried on a Buchi B-290 Mini with a condenser attached. The resulting spray dried solid was further dried in a vacuum oven at RT overnight to remove any residual solvent. The parameters of the Buchi B-290 Mini are listed below:
Nitrogen flow: 10 L/min;
Nitrogen max pressure: 10 psi;
CO2 max pressure: 15 psi;
Inlet temperature: 95-100° C.;
Outlet temperature: 50° C.;
Aspirator: 100%;
Pump: 30%; and
Nozzle: 1.5
Example 3
Synthesis of Form A
To 1 g of Compound 1 was added 2 mL of ethyl acetate and the mixture was heated to 35° C. and stirred until all solids had dissolved. The mixture was then allowed to cool to room temperature to allow the solids to precipitate out of solution. An additional 2 mL of ethyl acetate was then added to the mixture, and the mixture was again heated to 35° C. until all solids dissolved. The mixture was allowed to cool to allow the solids to precipitate out of solution as above. The solid Form A was then collected by filtration.
Representative XRPD peaks for Form A are shown in the table below. Form A can be identified and/or characterized by one or more of the peaks in the table below.












No.
2-Theta °
Intensity %

















1
7.0*
91.8


2
8.5*
100.0


3
10.0
70.0


4
11.0
73.4


5
14.7
90.3


6
15.5
76.7


7
15.8*
79.6


8
16.6
90.9


9
17.8
81.1


10
18.0
99.2


11
18.8
72.2


12
19.9
76.1


13
20.8
73.5


14
21.4*
77.0


15
22.0**
68.9


16
22.6**
73.0


17
23.3**
68.8


18
25.8
71.7


19
28.7
67.4





Peaks with an asterisk (*) are major peaks


Peaks with a double asterisk (**) are secondary peaks






Representative peaks from the 13C NMR solid state spectrum of Form A are shown in the table below. Form A can be identified and/or characterized by one or more of the peaks selected from the table below.













ν(F1)
Intensity


Peak #
[ppm]
[rel]

















1
173.0
24.12


2
172.0*
23.11


3
170.2
24.80


4
151.3
28.62


5
150.5
38.71


6
146.6*
14.23


7
143.9
12.74


8
130.4*
36.15


9
126.2
27.80


10
122.9
3.91


11
120.4
33.00


12
104.1*
23.68


13
102.2
23.18


14
92.8
20.65


15
92.2
17.13


16
84.1
27.03


17
79.7
68.89


18
75.0
28.02


19
73.5
33.05


20
69.5*
34.76


21
69.2
27.63


22
66.9*
40.98


23
50.4
22.59


24
21.9
100.00


25
20.6*
39.44





Peaks with an asterisk (*) are major peaks






Example 4
Synthesis of the Form B (Methyl Tert-Butyl Ether Solvate) and Form B (Cyclohexane Solvate)
Form B (methyl tert-butyl ether solvate) and Form B (cyclohexane solvate) were determined to be isostructural by XRPD analysis.
Example 4a
Synthesis of Form B (Methyl Tert-Butyl Ether Solvate)
To a vial containing 20 mg of Form A was added 200 μL of HPLC grade methyl tert-butyl ether (MTBE). The vial was stirred at an intermediate speed (250 rpm) on a stir plate at RT for 3 weeks. The mixture was filtered through a 0.22 μm PVDF filter to provide Form B (methyl tert-butyl ether solvate).
Representative peaks from the 13C NMR solid state spectrum of Form B (methyl tert-butyl ether solvate) are shown in the table below. Form B (methyl tert-butyl ether solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.













v(F1)
Intensity


Peak
[ppm]
[rel]

















1
173.2*
55.0


2
169.9
24.91


3
151.1
50.46


4
144.7
20.81


5
129.9*
100.00


6
123.3
47.74


7
118.3*
77.98


8
103.5
41.84


9
92.8
29.78


10
82.4
43.94


11
79.8
88.11


12
74.1
57.28


13
72.3*
20.83


14
68.5*
76.94


15
68.1
67.80


16
50.9
12.62


17
50.3
27.03


18
49.2*
57.83


19
27.1*
61.90


20
22.6
76.64


21
22.2
75.51


22
22.0
16.01


23
21.7
65.44


24
19.5*
52.58





Peaks with an asterisk (*) are major peaks






Representative peaks from the XRPD spectrum of Form B (methyl tert-butyl ether solvate) are shown in the table below. Form B (methyl tert-butyl ether solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.












No.
2-Theta °
Intensity %

















1
5.720*
71.8


2
9.395*
31.2


3
17.042*
100.0


4
26.219*
28.5





Peaks with an asterisk (*) are major peaks






Example 4b
Synthesis of Form B (Cyclohexane Solvate)
To a vial containing 20 mg of Form A was added 200 μL of HPLC grade cyclohexane. The vial was stirred at an intermediate speed (250 rpm) on a stir plate at RT for 3 weeks. The mixture was filtered through a 0.22 μm PVDF filter to provide Form B (cyclohexane solvate).
Representative peaks from the 13C NMR solid state spectrum of Form B (cyclohexane solvate) are shown in the table below. Form B (cyclohexane solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.













v(F1)
Intensity


Peak #
[ppm]
[rel]

















1
172.6
20.01


2
170.3*
26.09


3
150.5*
39.10


4
146.6
15.32


5
144.4
12.23


6
129.8*
31.00


7
126.3
25.02


8
122.6
15.89


9
120.4
26.04


10
118.2*
30.57


11
104.1
18.00


12
102.2
17.34


13
92.8
19.56


14
84.2
16.62


15
79.8*
53.48


16
75.0
22.56


17
73.6
20.49


18
69.5
21.11


19
68.1
19.74


20
66.9
21.59


21
64.0
13.37


22
50.5
20.41


23
40.8
12.34


24
27.2*
21.00


25
21.8*
100.00


26
18.6
15.87





Peaks with an asterisk (*) are major peaks






Representative peaks from the XRPD spectrum of Form B (cyclohexane solvate) are shown in the table below. Form B (cyclohexane solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.












No.
2-Theta °
Intensity %

















1
5.720*
71.8


2
9.395*
31.2


3
17.042*
100.0


4
26.219*
28.5





Peaks with an asterisk (*) are major peaks






Example 5
Synthesis of Form C (Nitromethane Solvate)
To a vial containing 20 mg of Form A was added 100 μL of HPLC grade nitromethane. The vial was stirred at an intermediate speed (250 rpm) on a stir plate at RT for 3 weeks. The mixture was filtered through a 0.22 μm PVDF filter to provide Form C.
Representative peaks from the 13C NMR solid state spectrum of Form C (nitromethane solvate) are shown in the table below. Form C (nitromethane solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.













v(F1)
Intensity


Peak
[ppm]
[rel]

















1
173.7*
72.2


2
163.6
27.15


3
162.7
27.66


4
152.6
33.02


5
151.9*
39.39


6
151.3
17.72


7
150.4
19.06


8
144.1
20.92


9
140.7
19.90


10
129.6
32.86


11
126.7
18.14


12
126.1
20.87


13
125.5
22.15


14
123.3
27.16


15
122.8
35.54


16
103.2*
40.00


17
102.5
24.12


18
101.9
21.60


19
93.3
34.02


20
92.4
35.66


21
83.3*
51.71


22
81.5
57.50


23
80.8*
54.60


24
80.3
75.92


25
73.3*
88.51


26
69.4
39.18


27
68.3
39.61


28
65.5
23.22


29
64.9
26.70


30
63.8*
54.98


31
51.8
21.78


32
50.6
28.73


33
25.1*
71.94


34
20.8
88.14


35
20.1*
100.00


36
18.8
24.24





Peaks with an asterisk (*) are major peaks






Representative peaks from the XRPD spectrum of Form C (nitromethane solvate) are shown in the table below. Form C (nitromethane solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.












No.
2-Theta °
Intensity %

















1
4.980*
27.4


2
6.573*
31.0


3
8.174*
39.0


4
9.151**
47.4


5
9.585**
56.2


6
16.337**
62.7


7
22.340*
28.1





Peaks with an asterisk (*) are major peaks


Peaks with a double asterisk (**) are secondary peaks






Example 6
Synthesis of Form D (Desolvated Acetonitrile Solvate)
To a vial containing 50 mg of Form A was added 100 μL of HPLC grade acetonitrile (ACN) and stirred at RT until all solids dissolved. The vial was then stirred at an intermediate speed (250 rpm) on a stir plate at 5° C. for 3 weeks. The mixture was filtered through a 0.22 μm PVDF filter, and the isolated solid was dried at RT and atmospheric pressure until the solid was substantially desolvated to provide Form D (desolvated acetonitrile solvate).
Representative peaks from the 13C NMR solid state spectrum of Form D (desolvated acetonitrile solvate) are shown in the table below. Form D (desolvated acetonitrile solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.













v(F1)
Intensity


Peak #
[ppm]
[rel]

















1
172.5
31.47


2
170.3
39.91


3
163.0
36.97


4
152.7
57.96


5
150.4
41.72


6
143.3
19.06


7
139.1*
20.55


8
130.9
74.16


9
130.2
33.92


10
125.3*
71.51


11
124.4
39.60


12
120.8*
61.60


13
105.2*
73.13


14
92.3
31.47


15
91.0
29.46


16
81.8
47.28


17
79.9
100.00


18
78.5
65.96


19
73.6
52.41


20
72.8*
51.48


21
69.4
48.17


22
67.5*
45.52


23
63.0*
84.89


24
53.6
23.06


25
50.8
25.81


26
23.7
50.37


27
22.8
89.54


28
22.0
51.17


29
21.3
98.72


30
20.8
54.41


31
18.3
54.61





Peaks with an asterisk (*) are major peaks






Representative peaks from the XRPD spectrum of Form D (desolvated acetonitrile solvate) are shown in the table below. Form D (desolvated acetonitrile solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.












No.
2-Theta °
Intensity %

















1
8.105*
55.6


2
13.357*
44.1


3
14.424**
100.0


4
17.215**
66.0


5
29.590*
29.1


6
35.019*
25.3





Peaks with an asterisk (*) are major peaks


Peaks with a double asterisk (**) are secondary peaks






Example 7
Synthesis of a Mixture of Form E (Dioxane Solvate) and Form A
To a vial containing 40 mg of Form A was added 100 μL of HPLC grade dioxane. The vial was stirred at an intermediate speed (250 rpm) on a stir plate at 5° C. for 24 hours. 100 μL of HPLC grade heptane was then added, and the vial was sonicated in a ultrasonicator for 2 minutes. The mixture was then stirred at 5° C. for an additional 3 weeks. The vial was then uncapped and placed in the open air to evaporate the solvent and provide a solid mixture of Form E (dioxane solvate) and Form A.
Representative peaks from the 13C NMR solid state spectrum of Form E (dioxane solvate) are shown in the table below. Form E (dioxane solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.













v(F1)
Intensity


Peak #
[ppm]
[rel]

















1
173.0*
56.27


2
172.1
10.64


3
170.1
29.76


4
151.3
14.75


5
150.7*
55.30


6
146.7
6.43


7
145.2
17.07


8
144.0
6.43


9
130.2*
78.40


10
126.2
14.42


11
123.7
34.51


12
120.5
15.84


13
118.3*
65.27


14
104.1
11.22


15
103.2
33.55


16
102.2
11.20


17
92.7
28.19


18
84.1
12.31


19
82.4
35.17


20
80.1
73.44


21
79.8
36.49


22
75.0
14.45


23
73.9*
48.37


24
69.2
53.62


25
68.0*
59.07


26
67.0*
32.83


27
50.4
28.84


28
22.0*
100.00


29
21.7
93.59


30
21.4
58.58


31
20.6
18.91


32
19.4
40.73





Peaks with an asterisk (*) are major peaks






Representative peaks from the XRPD spectrum of Form E (dioxane solvate) are shown in the table below. Form E (dioxane solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.












No.
2-Theta °
Intensity %

















1
7.765*
58.9


2
10.563**
22.3


3
12.901*
40.7


4
21.571*
26.4


5
24.466**
51.4


6
25.016*
31.6





Peaks with an asterisk (*) are major peaks


Peaks with a double asterisk (**) are secondary peaks






Example 8
Synthesis of a Mixture of Form F (Tetrahydrofuran Solvate) and Form A
To a vial containing 60 mg of Form A was added 200 μL of HPLC grade tetrahydrofuran (THF). The vial was stirred at an intermediate speed (250 rpm) on a stir plate at RT for 3 weeks. The vial was then uncapped and placed in the open air to evaporate the solvent and provide a solid mixture of Form F (tetrahydrofuran solvate) and Form A.
Representative peaks from the 13C NMR solid state spectrum of Form F (tetrahydrofuran solvate) are shown in the table below. Form F (tetrahydrofuran solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.













v(F1)
Intensity


Peak #
[ppm]
[rel]

















1
173.0
21.53


2
172.0
24.07


3
170.2*
27.88


4
151.3
28.85


5
150.5*
40.71


6
146.6
11.13


7
145.2
6.82


8
143.9
11.03


9
130.4*
33.74


10
126.2
25.38


11
123.1
8.05


12
120.4
29.96


13
104.0
20.89


14
103.2
9.89


15
102.2
20.47


16
92.8
22.77


17
92.2
18.97


18
84.0
21.12


19
81.9
7.45


20
79.7*
71.06


21
75.0
24.15


22
73.5*
30.33


23
69.5
29.78


24
69.2
27.71


25
68.2*
20.78


26
66.9*
34.82


27
50.4
28.03


28
25.7*
7.70


29
21.8*
100.00


30
20.6*
39.64





Peaks with an asterisk (*) are major peaks






Representative peaks from the XRPD spectrum of Form F (tetrahydrofuran solvate) are shown in the table below. Form F (tetrahydrofuran solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.












No.
2-Theta °
Intensity %

















1
6.090*
100.0


2
6.970*
32.4


3
17.538*
30.7


4
18.048*
56.0





Peaks with an asterisk (*) are major peaks






Example 9
Synthesis of Form G (Dichloromethane Solvate)
To a vial containing 50 mg of Amorphous Form O was added 50 μL of HPLC grade dichloromethane (DCM). The vial was stirred at an intermediate speed (250 rpm) on a stir plate at RT for 1 hour. An aliquot ( ̃25 μL) was placed in a capillary tube which was then sealed off at both ends. The capillary tube was placed on an XRPD holder and analyzed (an acquisition time of 600 seconds was used for each frame).
Representative peaks from the 13C NMR solid state spectrum of Form G (dichloromethane solvate) are shown in the table below. Form G (dichloromethane solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.













v(F1)
Intensity


Peak
[ppm]
[rel]

















1
172.9*
47.8


2
172.5
60.77


3
170.1
31.87


4
150.8*
97.73


5
145.6
17.22


6
143.7
10.94


7
130.4*
78.80


8
123.6
13.92


9
122.8
39.28


10
122.2
22.62


11
119.6*
30.97


12
118.7*
83.25


13
103.6
49.34


14
103.2
27.56


15
93.1
34.63


16
92.6
30.12


17
83.1*
44.78


18
82.6
41.59


19
80.2
49.48


20
79.9
89.47


21
79.5
48.95


22
74.4
42.00


23
73.5
36.87


24
73.3
36.16


25
69.0*
46.99


26
68.8
93.22


27
68.5
53.49


28
68.3
50.90


29
68.0
70.75


30
54.2*
17.40


31
50.5
44.46


32
23.4
36.90


33
22.9
82.85


34
22.6
100.00


35
21.8
87.94


36
21.4
85.89


37
20.4*
70.1


38
20.1
39.2





Peaks with an asterisk (*) are major peaks






Representative peaks from the XRPD spectrum of Form G (dichloromethane solvate) are shown in the table below. Form G (dichloromethane solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.












No.
2-Theta °
Intensity %

















1
5.857*
100.0


2
7.498*
41.6


3
7.835*
32.1


4
12.522**
23.5


5
17.733*
53.0


6
18.193**
23.5





Peaks with an asterisk (*) are major peaks


Peaks with a double asterisk (**) are secondary peaks






Example 10
Synthesis of Form H (Acetonitrile Solvate)
To a vial containing 120 mg of Amorphous Form O was added 100 μL of HPLC grade acetonitrile (ACN), and the mixture was stirred at RT until the solids dissolved. The vial was then sonicated in an ultrasonicator for 2 minutes, and the mixture was then stirred at an intermediate speed (250 rpm) on a stir plate at RT for 5 minutes. The mixture was filtered through a 0.22 μm PVDF filter to provide Form H (acetonitrile solvate).
Representative peaks from the 13C NMR solid state spectrum of Form H (acetonitrile solvate) are shown in the table below. Form H (acetonitrile solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.













v(F1)
Intensity


Peak
[ppm]
[rel]

















1
173.4*
70.7


2
164.4
44.87


3
153.4*
31.83


4
152.2*
61.17


5
141.4
42.94


6
129.8*
70.37


7
123.6
53.72


8
119.8*
55.92


9
104.6*
76.16


10
92.3
56.76


11
82.6
35.67


12
81.9
32.74


13
79.4*
100.00


14
73.4
96.98


15
68.9
54.71


16
61.7
73.15


17
53.6
47.24


18
23.4
79.96


19
22.9
86.96


20
21.6
41.15


21
20.6*
90.05


22
2.2*
14.59





Peaks with an asterisk (*) are major peaks






Representative peaks from the XRPD spectrum of Form H (acetonitrile solvate) are shown in the table below. Form H (acetonitrile solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.












No.
2-Theta °
Intensity %

















1
8.132*
81.7


2
14.020*
34.6


3
17.226*
61.7


4
20.902*
27.3





Peaks with an asterisk (*) are major peaks






Example 11
Synthesis of the Isostructural Form I (Isopropyl Acetate Solvate) and Form I (Ethyl Acetate Solvate)
Form I (isopropyl acetate solvate) and Form I (ethyl acetate solvate) were determined to be isostructural by XRPD analysis.
Example 11a
Synthesis of Form I (Isopropyl Acetate Solvate)
To a vial containing 33 mg of Amorphous Form O was added 200 μL of HPLC grade isopropyl acetate (IPAC). The mixture was then stirred at an intermediate speed (250 rpm) on a stir plate at RT for 2 hours. The mixture was filtered through a 0.22 μm PVDF filter to provide Form I (isopropyl acetate solvate).
Representative peaks from the 13C NMR solid state spectrum of Form I (isopropyl acetate solvate) are shown in the table below. Form I (isopropyl acetate solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.













v(F1)
Intensity


Peak
[ppm]
[rel]

















1
174.2
28.4


2
173.0*
35.35


3
170.1
18.49


4
168.4*
18.99


5
152.1*
44.16


6
151.0
35.26


7
144.8
19.59


8
143.5
18.22


9
129.9
26.35


10
126.1*
27.72


11
123.4
33.24


12
122.8
27.21


13
119.6
9.23


14
102.7*
56.58


15
93.2
23.93


16
91.1
24.94


17
81.6
37.12


18
80.5
42.31


19
79.6
73.82


20
74.5*
37.87


21
73.2
37.91


22
71.2*
34.86


23
69.3
62.97


24
68.8
39.70


25
63.3*
34.57


26
51.1
22.87


27
50.3
19.47


28
23.3*
100.00


29
22.8
76.24


30
21.9
75.98


31
21.4
42.76


32
20.4
36.17


33
20.0
38.34





Peaks with an asterisk (*) are major peaks






Representative peaks from the XRPD spectrum of Form I (isopropyl acetate solvate) are shown in the table below. Form I (isopropyl acetate solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.












No.
2-Theta °
Intensity %

















1
6.434*
59.2


2
9.283*
30.8


3
10.831*
55.3


4
11.794*
28.3





Peaks with an asterisk (*) are major peaks






Example 11b
Synthesis of Form I (Ethyl Acetate Solvate)
To a vial containing 33 mg of Amorphous Form O was added 200 μL of HPLC grade ethyl acetate. The mixture was then stirred at an intermediate speed (250 rpm) on a stir plate at RT for 2 hours. The mixture was filtered through a 0.22 μm PVDF filter to provide Form I (ethyl acetate solvate).
Representative peaks from the 13C NMR solid state spectrum of Form I (ethyl acetate solvate) are shown in the table below. Form I (ethyl acetate solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.













v(F1)
Intensity


Peak
[ppm]
[rel]

















1
174.2
27.6


2
173.1*
34.33


3
170.3
20.24


4
168.6*
20.76


5
152.1*
41.55


6
151.1
35.37


7
144.9
20.96


8
143.6
18.23


9
129.4
12.59


10
126.1
23.63


11
123.6*
24.98


12
119.3
10.42


13
102.6*
56.41


14
93.2
22.66


15
91.1
23.83


16
81.7
36.81


17
80.6
41.38


18
79.6
68.17


19
74.3
34.18


20
73.2
33.47


21
71.4*
32.36


22
69.3
33.35


23
68.7
34.79


24
63.5*
32.91


25
61.9*
21.88


26
51.3
22.60


27
50.5
21.35


28
22.4*
100.00


29
20.1
52.23


30
15.5*
16.24









Representative peaks from the XRPD spectrum of Form I (ethyl acetate solvate) are shown in the table below. Form I (ethyl acetate solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.












No.
2-Theta °
Intensity %

















1
6.434*
59.2


2
9.283*
30.8


3
10.831*
55.3


4
11.794*
28.3





Peaks with an asterisk (*) are major peaks






Example 12
Synthesis of Form J
To a vial containing 100 mg of Amorphous Form O was added 150 μL of HPLC grade ethanol. The contents of the vial was stirred at an intermediate speed (250 rpm) on a stir plate at RT overnight. The mixture was filtered through a 0.22 μm PVDF filter to provide Form J.
Representative peaks from the XRPD spectrum of Form J are shown in the table below. Form J can be identified and/or characterized by one or more of the peaks selected from the table below.












No.
2-Theta °
Intensity %

















1
6.1*
69.2


2
7.5*
54.4


3
9.0
21.2


4
9.9
21.2


5
10.8
34.0


6
11.1
44.2


7
11.4
26.5


8
12.1*
100.0


9
12.9
24.6


10
13.3*
31.2


11
14.0*
27.2


12
14.8
28.3


13
15.1
30.2


14
15.4
29.5


15
16.1
33.0


16
16.7
41.0


17
17.6
29.8


18
18.0
54.6


19
18.5*
47.3


20
18.9
25.6


21
19.4
41.6


22
19.6
35.8


23
20.3
43.5


24
20.7
59.8


25
21.1
43.8


26
21.7
35.5


27
22.6**
30.1


28
22.3
24.3


29
23.8
23.1


30
24.7
32.7


31
25.2
23.7


32
25.7
20.8


33
26.6
26.7


34
27.5
24.3


35
27.8
23.6


36
28.3
20.7


37
29.6
22.9


38
32.2
20.3


39
33.2**
21.5


40
34.0**
19.2


41
35.3**
19.3


42
35.4
19.4


43
36.5
19.0





Peaks with an asterisk (*) are major peaks


Peaks with a double asterisk (**) are secondary peaks






Representative peaks from the 13C NMR solid state spectrum of Form J are shown in the table below. Form J can be identified and/or characterized by one or more of the peaks selected from the table below.













v(F1)
Intensity


Peak
[ppm]
[rel]

















1
175.6*
26.8


2
172.6
39.76


3
165.8
13.72


4
162.9
22.43


5
162.5
16.16


6
153.0
15.82


7
152.8
15.88


8
151.5
29.40


9
151.1
11.45


10
150.7
36.85


11
150.1
21.71


12
141.4*
19.34


13
140.1
11.81


14
131.1
29.77


15
129.7
35.60


16
129.5
26.33


17
127.8*
25.20


18
127.1
17.58


19
126.3
27.54


20
123.8
29.09


21
123.4*
32.43


22
122.8
26.21


23
103.1*
37.64


24
101.3
27.86


25
93.8
22.55


26
93.3
16.53


27
91.7
18.80


28
83.5*
35.20


29
81.1*
35.52


30
80.7
100.00


31
79.8
28.76


32
78.6
42.08


33
74.4
37.67


34
73.4
41.04


35
73.1
28.84


36
72.3
39.74


37
70.1
57.8


38
63.7
44.0


39
62.2*
33.4


40
53.1
21.6


41
52.5
16.9


42
50.8
15.9


43
25.6*
36.7


44
23.7
60.6


45
23.0
34.4


46
22.5
64.4


47
22.1
46.4


48
21.7
36.1


49
19.6*
34.5


50
18.8
34.8


51
18.4
29.1





Peaks with an asterisk (*) are major peaks






Example 13
Synthesis of Form K (Chloroform Solvate)
To a vial containing 80 mg of Form J was added 200 μL of HPLC grade chloroform. The vial was sonicated in an ultrasonicator for 1 minute, and the mixture was then stirred at an intermediate speed (250 rpm) on a stir plate at RT overnight. An aliquot ( ̃25 μL) was placed on a holder and analyzed by XRPD.
Representative peaks from the 13C NMR solid state spectrum of Form K are shown in the table below. Form K can be identified and/or characterized by one or more of the peaks selected from the table below.













v(F1)
Intensity


Peak
[ppm]
[rel]

















1
173.9*
40.0


2
173.4*
39.97


3
169.9
23.72


4
168.7
24.10


5
151.8*
45.42


6
150.5*
44.95


7
144.6
27.19


8
144.1
24.43


9
129.8
17.44


10
126.2
30.54


11
125.8
20.97


12
122.5
16.21


13
101.9*
81.01


14
93.4
34.58


15
92.0*
35.25


16
81.6
54.04


17
80.4*
88.61


18
79.7
51.32


19
78.6
62.92


20
73.5*
72.84


21
70.6
49.15


22
69.5
50.72


23
68.1
46.78


24
63.6
47.15


25
50.8
55.38


26
23.2
76.97


27
22.8
67.52


28
22.1*
100.00


29
20.7
68.21


30
20.4*
97.77





Peaks with an asterisk (*) are major peaks






Representative peaks from the XRPD spectrum of Form K are shown in the table below. Form K can be identified and/or characterized by one or more of the peaks selected from the table below.












No.
2-Theta °
Intensity %

















1
22.620*
27.5


2
27.257*
26.7


3
28.272*
25.0


4
31.216*
27.0





Peaks with an asterisk (*) are major peaks






Example 14
Synthesis of Form L (Acetonitrile Solvate)
To a vial containing 80 mg of Form J was added 150 μL of HPLC grade acetonitrile (ACN). The vial was sonicated in an ultrasonicator for 1 minute, and the mixture was then stirred at an intermediate speed (250 rpm) on a stir plate at RT for 2 days. The resulting solid Form L (acetonitrile solvate) in the mixture was analyzed by XRPD as a suspension without isolation of the solid.
Representative peaks from the 13C NMR solid state spectrum of Form L (acetonitrile solvate) are shown in the table below. Form L (acetonitrile solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.













v(F1)
Intensity


Peak
[ppm]
[rel]

















1
173.2*
32.2


2
172.6
13.04


3
164.3
20.50


4
152.9
15.62


5
152.3
18.02


6
151.4*
22.38


7
150.8
10.20


8
150.6
15.53


9
142.9
7.14


10
140.9*
17.32


11
130.3
17.85


12
129.9
17.36


13
125.7
15.60


14
124.7
11.99


15
123.4
12.87


16
118.5*
18.82


17
103.8
8.86


18
103.3
18.66


19
102.9
15.60


20
101.5
12.23


21
92.7
29.36


22
92.3
25.58


23
81.5*
51.96


24
80.1*
100.00


25
73.4*
51.97


26
69.9
17.16


27
69.3
27.18


28
68.0
11.49


29
63.0
15.93


30
61.9
24.74


31
61.6*
32.16


32
54.0
18.79


33
53.0
14.69


34
52.2
16.30


35
23.7
12.59


36
23.3
12.87


37
23.0
28.2


38
22.5
42.2


39
22.0
47.5


40
21.4
43.2


41
20.9*
50.2


42
20.2
17.4


43
19.8
22.2


44
19.2
15.2


45
18.9
14.8


46
1.6*
12.9









Representative peaks from the XRPD spectrum of Form L (acetonitrile solvate) are shown in the table below. Form L (acetonitrile solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.












No.
2-Theta °
Intensity %

















1
5.662*
27.0


2
6.036*
27.2


3
15.174*
100.0


4
16.102*
56.5





Peaks with an asterisk (*) are major peaks






Example 15
Synthesis of Form M
Form L, as produced above, was isolated from the mixture and placed in a vacuum overnight until the solid was substantially desolvated, to provide Form M.
Representative peaks from the 13C NMR solid state spectrum of Form M are shown in the table below. Form M can be identified and/or characterized by one or more of the peaks selected from the table below.













v(F1)
Intensity


Peak
[ppm]
[rel]

















1
174.0*
31.8


2
173.2
13.03


3
172.3
7.89


4
170.5*
25.18


5
163.6
11.98


6
163.0
24.93


7
162.4
16.01


8
152.8
24.75


9
151.8
15.28


10
151.3
19.55


11
150.7
13.04


12
150.3
26.82


13
149.8
8.82


14
149.3
28.40


15
141.0
21.01


16
138.9
14.25


17
131.3
17.74


18
130.3
11.77


19
129.5*
32.91


20
127.0
27.77


21
126.6
24.70


22
124.7
17.32


23
124.0
14.60


24
122.4
15.29


25
121.3
12.07


26
118.5
11.42


27
103.5
34.79


28
102.7
10.83


29
102.2
27.86


30
101.7
8.62


31
92.5
36.95


32
83.2
31.87


33
81.5
45.71


34
80.6
14.75


35
80.1
18.58


36
79.6*
100.00


37
74.3
44.8


38
73.3
44.3


39
70.5
10.0


40
69.7*
44.6


41
67.5
8.1


42
64.5
8.8


43
64.0
9.6


44
63.2*
39.5


45
61.4
8.0


46
53.3
20.6


47
51.8*
33.6


48
24.0*
37.0


49
23.7
47.1


50
23.3
62.9


51
22.4
67.7


52
21.9
44.5


53
21.6
52.4


54
20.5
8.9


55
19.5*
49.4





Peaks with an asterisk (*) are major peaks






Representative peaks from the XRPD spectrum of Form M are shown in the table below. Form M can be identified and/or characterized by one or more of the peaks selected from the table below.












No.
2-Theta °
Intensity %

















1
6.274*
66.2


2
13.200*
40.5


3
22.225*
50.0


4
23.520*
38.7





Peaks with an asterisk (*) are major peaks






Example 16
Synthesis of Form N (Toluene Solvate)
To a vial containing 50 mg of Amorphous Form O was added 200 μL of HPLC grade toluene. The vial was sonicated in an ultrasonicator for 1 minute, and the mixture was then stirred at an intermediate speed (250 rpm) on a stir plate at RT for 3 days. The resulting solid Form N (toluene solvate) in the mixture was analyzed by XRPD (Bruker D8 Discover; 40 kV, 35 mA; single frame registered with an exposure of 120 seconds) as a suspension without isolation of the solid.
Representative peaks from the 13C NMR solid state spectrum of Form N (toluene solvate) are shown in the table below. Form N (toluene solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.













v(F1)
Intensity


Peak
[ppm]
[rel]

















1
172.6*
60.5


2
170.3
21.21


3
169.9
20.31


4
151.5
28.70


5
151.1
40.12


6
150.6
26.12


7
145.2
33.34


8
130.4*
78.13


9
129.5*
87.88


10
129.2*
70.02


11
128.4*
64.31


12
125.5
40.20


13
124.4
31.97


14
124.2
31.70


15
120.8
66.36


16
120.0
74.60


17
103.5
40.76


18
103.2
33.90


19
92.8
37.18


20
82.6
41.88


21
82.2*
37.02


22
79.6
64.84


23
79.3
68.37


24
74.0*
88.74


25
68.6
28.92


26
68.4
57.45


27
68.1
92.39


28
67.7*
51.91


29
50.2
29.20


30
23.0
54.35


31
22.3
18.31


32
21.8
60.50


33
21.3*
100.00


34
21.1
61.99


35
20.6
18.12


36
20.2
58.39


37
19.3
34.4





Peaks with an asterisk (*) are major peaks






Representative peaks from the XRPD spectrum of Form N (toluene solvate) are shown in the table below. Form N (toluene solvate) can be identified and/or characterized by one or more of the peaks selected from the table below.












No.
2-Theta °
Intensity %







1
12.419*
25.7


2
15.310*
41.7


3
17.149*
76.6


4
17.873*
57.0





Peaks with an asterisk (*) are major peaks






Example 17
HCV Replicon Assay
Cells
Huh-7 cells containing the self-replicating, subgenomic HCV replicon with a stable luciferase (LUC) reporter were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 2 mM L-glutamine and supplemented with 10% heat-inactivated fetal bovine serum (FBS), 1% penicillin-streptomyocin, 1% nonessential amino acids, and 0.5 mg/mL G418.
Determination of Anti-HCV Activity
Determination of 50% inhibitory concentration (EC50) of compounds in HCV replicon cells were performed by the following procedure. On the first day, 5,000 HCV replicon cells were plated per well in a 96-well plate. On the following day, test compounds were solubilized in 100% DMSO to 100× the desired final testing concentration. Each compound was then serially diluted (1:3) up to 9 different concentrations. Compounds in 100% DMSO are reduced to 10% DMSO by diluting 1:10 in cell culture media. The compounds were diluted to 10% DMSO with cell culture media, which were used to dose the HCV replicon cells in 96-well format. The final DMSO concentration was 1%. The HCV replicon cells were incubated at 37° C. for 72 hours. At 72 hours, cells were processed when the cells are still subconfluent. Compounds that reduce the LUC signal are determined by Bright-Glo Luciferase Assay (Promega, Madison, Wis.). Percent Inhibition was determined for each compound concentration in relation to the control cells (untreated HCV replicon) to calculate the EC50.
Compound 1 was determined to have an EC50 of less than 1 μM by the above procedure.

## Claims

1. 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Form A.

2. Form A of claim 1, wherein the Form A is characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak from about 6.8 to about 7.2 degrees, a peak from about 8.3 to about 8.7 degrees, a peak from about 15.6 to about 16.0 degrees, a peak from about 21.2 to about 21.6 degrees, a peak from about 21.8 to about 22.2 degrees, a peak from about 22.4 to about 22.8 degrees, and a peak from about 23.1 to about 23.5 degrees.

3. Form A of claim 1, wherein the Form A is characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks is selected from a peak at about 7.0 degrees, a peak at about 8.5 degrees, a peak at about 15.8 degrees, a peak at about 21.4 degrees, a peak at about 22.0 degrees, a peak at about 22.6 degrees, and a peak at about 23.3 degrees.

4. Form A of claim 1, wherein the Form A is characterized by a peak at about 7.0 degrees, a peak at about 8.5 degrees, a peak at about 15.8 degrees, and a peak at about 21.4 degrees in an X-ray powder diffraction pattern.

5. Form A of claim 1, wherein the Form A is characterized by a peak at about 7.0 degrees, a peak at about 8.5 degrees, a peak at about 15.8 degrees, a peak at about 21.4 degrees, a peak at about 22.0 degrees, a peak at about 22.6 degrees, and a peak at about 23.3 degrees in an X-ray powder diffraction pattern.

6. Form A of claim 1, wherein the Form A is characterized by an X-ray powder diffraction pattern of FIG. 1.

7. Form A of claim 1, wherein the Form A is characterized by a melting point of about 138° C.

8. Form A of claim 1, wherein the Form A is characterized by a DSC thermogram of FIG. 2.

9. Form A of claim 1, wherein the Form A is characterized by one or more peaks in a 13C NMR solid state spectrum, wherein the one or more peaks is selected from a peak at about 172.0 ppm, a peak at about 146.6 ppm, a peak at about 130.4 ppm, a peak at about 104.1 ppm, a peak at about 69.5 ppm, a peak at about 66.9 ppm, and a peak at about 20.6 ppm.

10. Form A of claim 1, wherein the Form A is characterized by a peak at about 130.4 ppm, a peak at about 69.5 ppm, a peak at about 66.9 ppm, and a peak at about 20.6 ppm in a 13C NMR solid state spectrum.

11. Form A of claim 1, wherein the Form A is characterized by a peak at about 172.0 ppm, a peak at about 146.6 ppm, a peak at about 130.4 ppm, a peak at about 104.1 ppm, a peak at about 69.5 ppm, a peak at about 66.9 ppm, and a peak at about 20.6 ppm in a 13C NMR solid state spectrum.

12. Form A of claim 1, wherein the Form A is characterized by a 13C NMR solid state spectrum of FIG. 3.

13. 2′-C-methyluridine-5′-(O-phenyl-N—(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate characterized as Amorphous Form O.

14. Amorphous Form O of claim 13, wherein the Amorphous Form O contains less than about 30% crystallinity.

15. Amorphous Form O of claim 13, wherein the Amorphous Form O contains less than about 15% crystallinity.

16. Amorphous Form O of claim 13, wherein the Amorphous Form O contains less than about 1.0% crystallinity.

17. A process for producing the compound of claim 1, comprising:
a) contacting Compound 1, having the structure





with first amount of ethyl acetate to form a mixture;
b) heating the mixture until the solids are dissolved;
c) cooling the mixture to allow precipitation of a solid;
d) optionally adding a second amount of ethyl acetate and repeating steps a, b and c; and
e) isolating the solid Form A from said mixture.

18. The process of claim 17, wherein the temperature in step b) is about 60° C.

19. The process of claim 17, wherein the second amount of ethyl acetate in step d) is approximately equal to the first amount of ethyl acetate used in step a).

20. A pharmaceutical composition comprising the compound of claim 1.

21. A method of ameliorating or treating a HCV infection comprising administering to a subject suffering from the HCV infection an amount of the compound of claim 1.

22. A method for inhibiting replication of a hepatitis C virus comprising contacting a cell infected with the hepatitis C virus with the compound of claim 1.

23. A method for ameliorating or treating a HCV infection comprising contacting a cell infected with the hepatitis C virus with the compound of claim 1.

24. The method of claim 21, further comprising administering one or more agents selected from the group consisting of an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (BB)



or a pharmaceutically acceptable salt thereof, wherein BBB1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; XBB can be O (oxygen) or S (sulfur); RBB1 can be selected from —ZBB—RBB9, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; ZBB can be selected from O (oxygen), S (sulfur) and N(RBB10); RBB2 and RBB3 can be independently selected from hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C1-6 haloalkyl and an optionally substituted aryl(C1-6 alkyl); or RBB2 and RBB3 can be taken together to form a group selected from an optionally substituted C3-6 cycloalkyl, an optionally substituted C3-6 cycloalkenyl, an optionally substituted C3-6 aryl and an optionally substituted C3-6 heteroaryl; RBB4 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl and an optionally substituted allenyl; RBB5 can be hydrogen or an optionally substituted C1-6 alkyl; RBB6 can be selected from hydrogen, halogen, azido, amino, cyano, an optionally substituted C1-6 alkyl, —ORBB11 and —OC(═O)RBB12; RBB7 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, —ORBB13 and —OC(═O)RBB14; RBB8 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, —ORBB15 and —OC(═O)RBB16; RBB9 can be selected from an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C1-6alkyl), an optionally substituted heteroaryl(C1-6alkyl) and an optionally substituted heterocyclyl(C1-6alkyl); RBB10 can be selected from hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C1-6alkyl), an optionally substituted heteroaryl(C1-6alkyl) and an optionally substituted heterocyclyl(C1-6alkyl); RBB11, RBB13 and RBB15 can be independently hydrogen or an optionally substituted C1-6 alkyl; and RBB12, RBB14 and RBB16 can be independently an optionally substituted C1-6 alkyl or an optionally substituted C3-6 cycloalkyl;
and a compound of Formula (DD)




or a pharmaceutically acceptable salt thereof, wherein each  can be independently a double or single bond; ADD1 can be selected from C (carbon), O (oxygen) and S (sulfur); BDD1 can be an optionally substituted heterocyclic base or a derivative thereof; DDD1 can be selected from C═CH2, CH2, O (oxygen), S (sulfur), CHF, and CF2; RDD1 can be hydrogen, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aralkyl, dialkylaminoalkylene, alkyl-C(═O)—, aryl-C(═O)—, alkoxyalkyl-C(═O)—, aryloxyalkyl-C(═O)—, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl,





an —O-linked amino acid, diphosphate, triphosphate or derivatives thereof; RDD2 and RDD3 can be each independently selected from hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl and an optionally substituted C1-6 haloalkyl, provided that at least one of RDD2 and RDD3 cannot be hydrogen; or RDD2 and RDD3 are taken together to form a group selected from among C3-6 cycloalkyl, C3-6 cycloalkenyl, C3-6 aryl, and a C3-6 heteroaryl; RDD4 and RDD9 can be independently selected from hydrogen, halogen, —NH2, —NHRDDa1, NRDDa1RDDb1, —ORDDa1, —SRDDa1, —CN, —NC, —N3, —NO2, —N(RDDc1)—NRDDa1RDDb1, —N(RDDc1)—ORDDa1, —S—SRDDa1, —C(═O)RDDa1, —C(═O)ORDDa1, —C(═O)NRDDa1RDDb1, —O—(C═O)RDDa1, —O—C(═O)ORDDa1, —O—C(═O)NRDDa1RDDb1, —N(RDDc1)—C(═O)NRDDa1RDDb1, —S(═O)RDDa1, S(═O)2RDDa1, —O—S(═O)2NRDDa1RDDb1, —N(RDDc1)—S(═O)2NRDDa1RDDb1, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted aralkyl and an —O-linked amino acid; RDD5, RDD6 and RDD7 can be independently absent or selected from hydrogen, halogen, —NH2, —NHRDDa1, NRDDa1RDDb1, —ORDDa1, —SRDDa1, —CN, —NC, —N3, —NO2, —N(RDDc1)—NRDDa1RDDb1, —N(RDDc1)—ORDDa1, —S—SRDDa1, —C(═O)RDDa1, —C(═O)ORDDa1, —C(═O)NRDDa1RDDb1, —O—(C═O)RDDa1, —O—C(═O)ORDDa1, —O—C(═O)NRDDa1RDDb1, —N(RDDc1)—C(═O)NRDDa1RDDb1, —S(═O)RDDa1, S(═O)2RDDa1, —O—S(═O)2NRDDa1RDDb1, —N(RDDc1)—S(═O)2NRDDa1RDDb1, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted aralkyl and an —O-linked amino acid; or RDD6 and RDD7 taken together form —O—C(═O)—O—; RDD8 can be absent or selected from the group consisting of hydrogen, halogen, —NH2, —NHRDDa1, NRDDa1RDDb1, —ORDDa1, —SRDDa1, —CN, —NC, —N3, —NO2, —N(RDDc1)—NRDDa1RDDb1, —N(RDDc1)—ORDDa1, —S—SRDDa1, —C(═O)RDDa1, —C(═O)ORDDa1, —C(═O)NRDDa1RDDb1, —O—C(═O)ORDDa1, —O—C(═O)NRDDa1RDDb1, —N(RDDc1)—C(═O)NRDDa1RDDb1, —S(═O)RDDa1, S(═O)2RDDa1, —O—S(═O)2NRDDa1RDDb1, —N(RDDc1)—S(═O)2NRDDa1RDDb1, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted haloalkyl, an optionally substituted hydroxyalkyl and an —O-linked amino acid, or when the bond to RDD7 indicated by  is a double bond, then RDD7 is a C2-6 alkylidene and RDD8 is absent; RDDa1, RDDb1 and RDDc1 can be each independently selected from hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl and a optionally substituted heteroaryl(C1-6 alkyl); RDD10 can be selected from O−, —OH, an optionally substituted aryloxy or aryl-O—,




alkyl-C(═O)—O—CH2—O—, alkyl-C(═O)—S—CH2CH2—O— and an —N-linked amino acid; RDD11 can be selected from O−, —OH, an optionally substituted aryloxy or aryl-O—,




alkyl-C(═O)—O—CH2—O—, alkyl-C(═O)—S—CH2CH2—O— and an —N-linked amino acid; each RDD12 and each RDD13 can be independently —C≡N or an optionally substituted substituent selected from C1-8 organylcarbonyl, C1-8 alkoxycarbonyl and C1-8 organylaminocarbonyl; each RDD14 can be hydrogen or an optionally substituted C1-6-alkyl; each mDD can be independently 1 or 2, and if both RDD10 and RDD11 are




each RDD12, each RDD13, each RDD14 and each mDD can be the same or different;
or a pharmaceutically acceptable salt any of the aforementioned compounds.

25. The method of claim 24, wherein the one or more agents are selected from the group consisting of Compounds 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065, 1066, 8001, 8002, 8003, 8004, 8005, 8006, 8007, 8008, 8009, 8010, 8011 and 8012, or a pharmaceutically acceptable salt of any of the aforementioned compounds, as provided in FIG. 32.

26. The method of claim 24, wherein the one or more additional agents is selected from Pegylated interferon-alpha-2a, ribavirin, Pegylated interferon-alpha-2b, a HCV protease inhibitor, a HCV polymerase inhibitor, and a NS5A inhibitor.

27. The method of claim 24, wherein the one or more agents is a compound of Formula (BB).

28. The method of claim 24, wherein the one or more agents is a compound of Formula (DD).

29. The method of claim 24, wherein the one or more agents is




or a pharmaceutically acceptable salt thereof.

30. The method of claim 24, wherein the one or more agents is




or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition comprising the compound of claim 13.

32. A method of ameliorating or treating a HCV infection comprising administering to a subject suffering from the HCV infection an amount of the compound of claim 13.

33. A method for inhibiting replication of a hepatitis C virus comprising contacting a cell infected with the hepatitis C virus with the compound of claim 13.

34. A method for ameliorating or treating a HCV infection comprising contacting a cell infected with the hepatitis C virus with the compound of claim 13.

35. The method of claim 32, further comprising administering one or more agents selected from the group consisting of an interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a compound of Formula (BB)



or a pharmaceutically acceptable salt thereof, wherein BBB1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; XBB can be O (oxygen) or S (sulfur); RBB1 can be selected from —ZBB—RBB9, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; ZBB can be selected from O (oxygen), S (sulfur) and N(RBB10); RBB2 and RBB3 can be independently selected from hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C1-6 haloalkyl and an optionally substituted aryl(C1-6 alkyl); or RBB2 and RBB3 can be taken together to form a group selected from an optionally substituted C3-6 cycloalkyl, an optionally substituted C3-6 cycloalkenyl, an optionally substituted C3-6 aryl and an optionally substituted C3-6 heteroaryl; RBB4 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl and an optionally substituted allenyl; RBB5 can be hydrogen or an optionally substituted C1-6 alkyl; RBB6 can be selected from hydrogen, halogen, azido, amino, cyano, an optionally substituted C1-6 alkyl, —ORBB11 and —OC(═O)RBB12; RBB7 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, —ORBB13 and —OC(═O)RBB14; RBB8 can be selected from hydrogen, halogen, azido, cyano, an optionally substituted C1-6 alkyl, —ORBB15 and —OC(═O)RBB16; RBB9 can be selected from an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C1-6alkyl), an optionally substituted heteroaryl(C1-6alkyl) and an optionally substituted heterocyclyl(C1-6alkyl); RBB10 can be selected from hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C1-6alkyl), an optionally substituted heteroaryl(C1-6alkyl) and an optionally substituted heterocyclyl(C1-6alkyl); RBB11, RBB13 and RBB15 can be independently hydrogen or an optionally substituted C1-6 alkyl; and RBB12, RBB14 and RBB16 can be independently an optionally substituted C1-6 alkyl or an optionally substituted C3-6 cycloalkyl;
and a compound of Formula (DD)




or a pharmaceutically acceptable salt thereof, wherein each  can be independently a double or single bond; ADD1 can be selected from C (carbon), O (oxygen) and S (sulfur); BDD1 can be an optionally substituted heterocyclic base or a derivative thereof; DDD1 can be selected from C═CH2, CH2, O (oxygen), S (sulfur), CHF, and CF2; RDD1 can be hydrogen, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aralkyl, dialkylaminoalkylene, alkyl-C(═O)—, aryl-C(═O)—, alkoxyalkyl-C(═O)—, aryloxyalkyl-C(═O)—, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl,





an —O-linked amino acid, diphosphate, triphosphate or derivatives thereof; RDD2 and RDD3 can be each independently selected from hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl and an optionally substituted C1-6 haloalkyl, provided that at least one of RDD2 and RDD3 cannot be hydrogen; or RDD2 and RDD3 are taken together to form a group selected from among C3-6 cycloalkyl, C3-6 cycloalkenyl, C3-6 aryl, and a C3-6 heteroaryl; RDD4 and RDD9 can be independently selected from hydrogen, halogen, —NH2, —NHRDDa1, NRDDa1RDDb1, —ORDDa1, —SRDDa1, —CN, —NC, —N3, —NO2, —N(RDDc1)—NRDDa1RDDb1, —N(RDDc1)—ORDDa1, —S—SRDDa1, —C(═O)RDDa1, —C(═O)ORDDa1, —C(═O)NRDDa1RDDb1, —O—(C═O)RDDa1, —O—C(═O)ORDDa1, —O—C(═O)NRDDa1RDDb1, —N(RDDc1)—C(═O)NRDDa1RDDb1, —S(═O)RDDa1, S(═O)2RDDa1, —O—S(═O)2NRDDa1RDDb1, —N(RDDc1)—S(═O)2NRDDa1RDDb1, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted aralkyl and an —O-linked amino acid; RDD5, RDD6 and RDD7 can be independently absent or selected from hydrogen, halogen, —NH2, —NHRDDa1, NRDDa1RDDb1, —ORDDa1, —SRDDa1, —CN, —NC, —N3, —NO2, —N(RDDc1)—NRDDa1RDDb1, —N(RDDc1)—ORDDa1, —S—SRDDa1, —C(═O)RDDa1, —C(═O)ORDDa1, —C(═O)NRDDa1RDDb1, —O—(C═O)RDDa1, —O—C(═O)ORDDa1, —O—C(═O)NRDDa1RDDb1, —N(RDDc1)—C(═O)NRDDa1RDDb1, —S(═O)RDDa1, S(═O)2RDDa1, —O—S(═O)2NRDDa1RDDb1, —N(RDDc1)—S(═O)2NRDDa1RDDb1, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted aralkyl and an —O-linked amino acid; or RDD6 and RDD7 taken together form —O—C(═O)—O—; RDD8 can be absent or selected from the group consisting of hydrogen, halogen, —NH2, —NHRDDa1, NRDDa1RDDb1, —ORDDa1, —SRDDa1, —CN, —NC, —N3, —NO2, —N(RDDc1)—NRDDa1RDDb1, —N(RDDc1)—ORDDa1, —S—SRDDa1, —C(═O)RDDa1, —C(═O)ORDDa1, —C(═O)NRDDa1RDDb1, —O—C(═O)ORDDa1, —O—C(═O)NRDDa1RDDb1, —N(RDDc1)—C(═O)NRDDa1RDDb1, —S(═O)RDDa1, S(═O)2RDDa1, —O—S(═O)2NRDDa1RDDb1, —N(RDDc1)—S(═O)2NRDDa1RDDb1, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted haloalkyl, an optionally substituted hydroxyalkyl and an —O-linked amino acid, or when the bond to RDD7 indicated by  is a double bond, then RDD7 is a C2-6 alkylidene and RDD8 is absent; RDDa1, RDDb1 and RDDc1 can be each independently selected from hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl and an optionally substituted heteroaryl(C1-6 alkyl); RDD10 can be selected from O−, —OH, an optionally substituted aryloxy or aryl-O—,




alkyl-C(═O)—O—CH2—O—, alkyl-C(═O)—S—CH2CH2—O— and an —N-linked amino acid; RDD11 can be selected from O−, —OH, an optionally substituted aryloxy or aryl-O—,




alkyl-C(═O)—O—CH2—O—, alkyl-C(═O)—S—CH2CH2—O— and an —N-linked amino acid; each RDD12 and each RDD13 can be independently —C≡N or an optionally substituted substituent selected from C1-8 organylcarbonyl, C1-8 alkoxycarbonyl and C1-8 organylaminocarbonyl; each RDD14 can be hydrogen or an optionally substituted C1-6-alkyl; each mDD can be independently 1 or 2, and if both RDD10 and RDD11 are




each RDD12, each RDD13, each RDD14 and each mDD can be the same or different;
or a pharmaceutically acceptable salt any of the aforementioned compounds.

36. The method of claim 35, wherein the one or more agents are selected from the group consisting of Compounds 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065, 1066, 8001, 8002, 8003, 8004, 8005, 8006, 8007, 8008, 8009, 8010, 8011 and 8012, or a pharmaceutically acceptable salt of any of the aforementioned compounds, as provided in FIG. 32.

37. The method of claim 35, wherein the one or more additional agents is selected from Pegylated interferon-alpha-2a, ribavirin, Pegylated interferon-alpha-2b, a HCV protease inhibitor, a HCV polymerase inhibitor, and a NS5A inhibitor.

38. The method of claim 35, wherein the one or more agents is a compound of Formula (BB).

39. The method of claim 35, wherein the one or more agents is a compound of Formula (DD).

40. The method of claim 35, wherein the one or more agents is




or a pharmaceutically acceptable salt thereof.

41. The method of claim 35, wherein the one or more agents is




or a pharmaceutically acceptable salt thereof.

42. The method of claim 24, wherein the one or more agents is selected from the group consisting of daclatasvir, PPI-461, ACH-2928, GS-5885, BMS-824393, ABT 267, ACH-3102, AZD-7295, IDX719, PPI-668, MK8742 and GSK805, or a pharmaceutically acceptable salt of the foregoing.

43. The method of claim 32, wherein the one or more agents is selected from the group consisting of daclatasvir, PPI-461, ACH-2928, GS-5885, BMS-824393, ABT 267, ACH-3102, AZD-7295, IDX719, PPI-668, MK8742 and GSK805, or a pharmaceutically acceptable salt of the foregoing.