HK40016048B

HK40016048B - Novel crystalline forms

Info

Publication number: HK40016048B
Application number: HK62020006146.8A
Authority: HK
Inventors: K·布拉克; E·A·卡拉; L·V·休曼; N·劳森
Original assignee: 吉利德科学公司
Priority date: 2017-05-01
Filing date: 2018-04-27
Publication date: 2023-05-12

Description

Novel crystalline forms

Cross Reference to Related Applications

This application claims priority to U.S. provisional application No. 62/492,364, filed on 2017, month 5,1, the entire contents of which are incorporated herein for all purposes.

Technical Field

The present invention relates to novel crystalline forms of (S) -2- (((S) - (((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester, pharmaceutical formulations thereof, and their therapeutic use in the treatment of viral infections.

Background

Methods of prevention and treatment of certain arenaviridae, coronavirus, filoviridae, flaviviridae, and paramyxoviridae viruses present challenges due to the lack of vaccines or post-exposure treatment modalities for preventing or controlling infection by these viruses. In some cases, patients will only receive supportive and resource intensive treatment, such as treatment of electrolyte and fluid balance, oxygen, blood pressure maintenance, or secondary infections. Thus, there is a need for antiviral treatments with broad antiviral activity.

The compound (S) -2- (((S) - (((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester, referred to herein as compound 1 or formula I, is known to exhibit antiviral properties against viruses of the arenaviridae, coronaviridae, filoviridae, and paramyxoviridae families, as described in Warren, t. et al, nature (2016) 531-381-385, and antiviral activity against viruses of the flaviviridae family, as described in co-pending U.S. provisional patent application No. 62/325,419, filed 4/20/2016.

(S) -2- (((S) - (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester or ((S) - ((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [ 3536 ] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine 2-ethylbutyl ester, (formula I) having the following structure:

it is desirable to have a physically stable form of the compound suitable for therapeutic use and manufacturing processes.

Brief description of the invention

In some embodiments, the present invention relates to novel forms of formula I.

In some embodiments, the invention relates to crystalline forms of (S) -2- (((S) - (((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester.

In some embodiments, the invention relates to (S) -2- (((S) - (((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester form I (formula I form I).

In some embodiments, the invention relates to (S) -2- (((S) - (((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester form II (formula I form II).

In some embodiments, the invention relates to (S) -2- (((S) - (((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester form III (formula I form III).

In some embodiments, the invention relates to (S) -2- (((S) - (((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester form IV (formula I form IV).

In some embodiments, the invention relates to a mixture of crystalline forms of (S) -2- (((S) - (((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester (formula I mixture).

In some embodiments, the invention relates to a mixture of (S) -2- (((S) - (((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester form II and (S) -2- (((S) - ((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester form IV (a mixture of form II and form IV of formula I).

In some embodiments, the invention relates to a mixture of crystalline forms of (S) -2- (((S) - (((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester (mixture I).

In some embodiments, the invention relates to a mixture of crystalline forms of (S) -2- (((S) - (((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester (mixture II).

In some embodiments, the invention relates to a mixture of crystalline forms of (S) -2- (((S) - (((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester (mixture III).

In some embodiments, the invention relates to (S) -2- (((S) - (((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester maleate form I (formula I maleate form I).

In some embodiments, the present invention relates to methods of treating an arenaviridae, coronavirus, filoviridae, flaviviridae or paramyxoviridae viral infection by administering a compound of formula I provided herein.

Brief Description of Drawings

FIG. 1 XRPD pattern of form I of formula I.

FIG. 2 DSC of form I of formula I.

Figure 3 TGA of form I of formula I.

FIG. 4 DVS of form I of formula I.

FIG. 5 XRPD pattern of form II of formula I.

FIG. 6 DSC of form II of formula I.

Figure 7 TGA of form I, form II.

FIG. 8, form II of DVS of formula I.

Figure 9 a calculated XRPD pattern of form III of formula I.

FIG. 10 is an XRPD pattern for form IV of formula I.

FIG. 11, DSC of form IV of formula I.

Figure 12 TGA of form IV of formula I.

FIG. 13 XRPD patterns of a mixture of form I of formula I form II and form I form IV of formula I (mixture I).

FIG. 14 DSC of a mixture of form II of formula I and form IV of formula I (mixture I).

Figure 15 TGA of a mixture of form I of formula I form II and form I IV (mixture I).

FIG. 16 XRPD patterns of form I of formula I and a mixture of form IV of formula I (mixture II).

FIG. 17 DSC of form II of formula I and a mixture of form IV of formula I (mixture II).

Figure 18 TGA of a mixture of form I of formula I form II and form IV of formula I (mixture II).

FIG. 19 XRPD patterns of a mixture of form I of formula I form II and form I form IV of formula I (mixture III).

FIG. 20 DSC of a mixture of form II of formula I and form IV of formula I (mixture III). DSC GS5734 Material 02 lots 6662-102-36.

Figure 21 TGA of a mixture of form I of formula I form II and form I IV (mixture III).

Figure 22 XRPD pattern of maleate form I of formula I.

FIG. 23 DSC of maleate form I of formula I.

Figure 24 TGA of maleate form I of formula I.

FIG. 25 DVS of maleate form I of formula I.

FIG. 26 is an XRPD pattern for form IV of formula I.

FIG. 27 solid state NMR of form II of formula I.

FIG. 28 solid state NMR of mixtures of form II and form IV of formula I (top), mixture III (middle) and mixture I (bottom).

FIG. 29 solid state NMR of mixture III (top), mixture of form II and form IV of formula I (middle) and mixture II (bottom).

Detailed Description

I. General description of the invention

In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these details. The following description of several embodiments is provided with the understanding that the present disclosure is to be considered an example of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments shown. Headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the claims in any way. Embodiments shown under any heading may be combined with embodiments shown under any other heading.

Definition of

Throughout the specification and claims, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" are to be interpreted in an open, inclusive sense, i.e., "including but not limited to".

Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

Embodiments referring to "compound of formula I" throughout the specification include crystalline, salt, co-crystal, and solvate forms of the compounds and/or formulae disclosed herein. Thus, the appearance of the phrase "compound of formula I" includes crystalline forms I-IV and derivatives thereof, mixtures I-III, and maleate form I of formula I.

The invention disclosed herein is also intended to include all pharmaceutically acceptable compounds of formula I that are isotopically labeled by substituting one or more atoms with atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as ² H、 ³ H、 ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹³ N、 ¹⁵ N、 ¹⁵ O、 ¹⁷ O、 ¹⁸ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F、 ³⁶ Cl、 ¹²³ I and ¹²⁵ I. these radiolabeled compounds may be used to help determine or measure the effectiveness of a compound, for example, by characterizing the site or mode of action, or binding affinity to a pharmacologically important site of action. Certain isotopically-labeled compounds of formula I, for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. Radioactive isotopes tritium (i.e. for the detection of radioactive isotopes), in view of their ease of incorporation and ready availability as detection means ³ H) And carbon-14 (i.e. ¹⁴ C) Particularly suitable for this purpose.

With heavier isotopes such as deuterium (i.e. ² H) Substitution may provide certain therapeutic advantages resulting from greater metabolic stability. For example, the in vivo half-life may be increased or the dosage requirements may be decreased. Thus, in some cases, heavier isotopes may be preferred.

Using positron-emitting isotopes (e.g. of the type ¹¹ C、 ¹⁸ F、 ¹⁵ O and ¹³ n) substitution can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically-labelled compounds of formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the examples below, using an appropriate isotopically-labelled reagent in place of the unlabelled reagent previously used.

"stable compound" and "stable structure" are intended to mean that the compound is sufficiently robust to withstand isolation to a useful degree of purity from a reaction mixture, and formulation into an effective therapeutic agent.

"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and the description includes both substituted aryl and unsubstituted aryl.

"pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. food and drug administration as acceptable for use in humans or livestock.

"pharmaceutical composition" refers to a formulation of a compound of the present invention and a vehicle generally accepted in the art for delivering biologically active compounds to a mammal (e.g., a human). Such vehicles include all pharmaceutically acceptable excipients therefor.

An "effective amount" or "therapeutically effective amount" refers to an amount of a compound according to the present invention that, when administered to a patient in need thereof, is sufficient to effect treatment of a disease state, condition, or disorder for which the compound has utility. Such an amount will be sufficient to elicit the biological or medical response of the tissue system or patient sought by the researcher or clinician. The amount of a compound according to the invention that constitutes a therapeutically effective amount will vary depending on factors such as: the compound and its biological activity, the composition for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease state or condition being treated and its severity, the drugs used in combination or in concert with the compounds of the invention, and the age, weight, general health, sex, and diet of the patient. Such therapeutically effective amounts can be routinely determined by those of ordinary skill in the art based on their own knowledge, prior art, and the present disclosure.

The term "treating" as used herein, unless otherwise indicated, refers to reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which this term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein refers to the act of treating, as "treating" is as described immediately above. In certain embodiments, the term "treating" is intended to mean administering a compound or composition according to the present invention to reduce or eliminate symptoms of an arenaviridae viral infection and/or to reduce the viral load in a patient. In some embodiments, the term "treating" as used herein is further or alternatively intended to mean administering a compound or composition according to the present invention to reduce or eliminate symptoms of a coronavirus infection and/or reduce the viral load in a patient. In some embodiments, the term "treating" as used herein is further or alternatively intended to mean administering a compound or composition according to the present invention to reduce or eliminate symptoms of filoviridae virus infection and/or reduce viral load in a patient. In some embodiments, the term "treating" as used herein is further or alternatively intended to mean administering a compound or composition according to the present invention to reduce or eliminate symptoms of a flaviviridae viral infection and/or reduce the viral load in a patient. In some embodiments, the term "treating" as used herein is further or alternatively intended to mean administering a compound or composition according to the present invention to reduce or eliminate symptoms of paramyxoviridae virus infection and/or reduce viral load in a patient. In some embodiments, the term "treating" as used herein is further or alternatively intended to mean administering a therapeutically effective amount of a compound or composition according to the invention to maintain a reduced viral load in a patient.

"prevention" (prevention) refers to any treatment of a disease or disorder that results in the failure to develop clinical symptoms of the disease or disorder. The term "preventing" also includes administering a therapeutically effective amount of a compound or composition according to the invention prior to exposure of the individual to the virus (e.g., pre-exposure prevention) to prevent the onset of symptoms of the disease and/or to prevent the virus from reaching detectable levels in the blood.

The term "subject" or "patient" refers to an animal, such as a mammal (including a human), who has been or will be the object of treatment, observation or experiment. The methods described herein can be used for human therapy and/or veterinary applications. In some embodiments, the subject is a mammal (or patient). In some embodiments, the subject (or patient) is a human, a livestock animal (e.g., dogs and cats), a farm animal (e.g., cows, horses, sheep, goats, and pigs), and/or a laboratory animal (e.g., mice, rats, hamsters, guinea pigs, rabbits, dogs, and monkeys). In some embodiments, the subject (or patient) is a human. "a human (or patient) in need thereof" refers to a human who may have or is suspected of having a disease or condition that would benefit from some treatment; for example, treatment with a compound disclosed herein is in accordance with the present application.

The term "antiviral agent" as used herein is intended to mean an agent (compound or biologic) effective to inhibit the formation and/or replication of a virus in a human, including, but not limited to, agents that interfere with host or viral mechanisms necessary for the formation and/or replication of a virus in a human.

The term "arenaviridae virus replication inhibitor" as used herein is intended to mean an agent capable of reducing or eliminating the ability of an arenaviridae virus to replicate in a host cell, whether in vitro, ex vivo or in vivo.

The term "inhibitor of coronavirus virus replication" as used herein is intended to mean an agent capable of reducing or eliminating the ability of a virus of the family coronaviridae to replicate in a host cell (whether in vitro, ex vivo or in vivo).

The term "inhibitor of filoviridae virus replication" as used herein is intended to mean an agent capable of reducing or eliminating the ability of a filoviridae virus to replicate in a host cell, whether in vitro, ex vivo or in vivo.

The term "flaviviridae viral replication inhibitor" as used herein is intended to mean an agent capable of reducing or eliminating the ability of a flaviviridae virus to replicate in a host cell, whether in vitro, ex vivo or in vivo.

The term "inhibitor of paramyxoviridae virus replication" as used herein is intended to mean an agent capable of reducing or eliminating the ability of a paramyxoviridae virus to replicate in a host cell (whether in vitro, ex vivo or in vivo).

"tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. The invention includes tautomers of any of the compounds.

Reference herein to a "value or parameter" about "includes (and describes) embodiments directed to that value or parameter per se. For example, a description referring to "about X" includes a description of "X". In addition, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.

"pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

A "unit dosage form" is a physically discrete unit suitable as a unit dose for a subject (e.g., human subjects and other mammals), each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

The term "substantially as shown in.. When referring to, for example, an XRPD pattern, DSC thermogram, DVS pattern, or TGA pattern, includes patterns, thermograms, or patterns that are not necessarily identical to those described herein, but fall within the limits of experimental error or deviation when considered by one of ordinary skill in the art. Mixtures I-III are understood to have different ratios of form II of formula I to form IV of formula I (form II of formula I: form IV of formula I). Thus, one of ordinary skill in the art will appreciate that there may be other mixtures of form II and form IV of formula I having data substantially as shown in the XRPD pattern, DSC thermogram or TGA pattern provided herein, wherein "substantially as shown in.

In some embodiments, the term "substantially pure" or "substantially free" with respect to a particular crystalline form of a compound means that the composition comprising that crystalline form contains less than 99%, less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% by weight of other materials, including other crystalline forms and/or impurities. In some embodiments, "substantially pure" or "substantially free" refers to a material that is free of other materials, including other crystalline forms and/or impurities. For example, impurities may include by-products or residual reagents from chemical reactions, contaminants, degradation products, other crystalline forms, water, and solvents.

Crystalline form

A. Formula I

It is desirable to develop crystalline forms of formula I that can be used in the synthesis of compounds of formula I. The crystalline form of formula I may be an intermediate in the synthesis of formula I. A crystalline form may have properties that may be suitable for medical or pharmaceutical use, such as bioavailability, stability, purity, and/or manufacturability, under certain conditions.

The crystalline forms of formula I, including both substantially pure forms and mixtures of substantially pure forms, may provide bioavailability and stability advantages and are suitable for use as the active ingredient in pharmaceutical compositions. Changes in the crystal structure of a drug substance or active ingredient can affect the dissolution rate of the drug product or active ingredient (which can affect bioavailability, etc.), manufacturability (e.g., ease of handling, ability to consistently prepare doses of known strength), and stability (e.g., thermostability, shelf life, etc.). Such variations may affect the preparation or formulation of pharmaceutical compositions in different dosages or delivery forms (e.g., solutions or solid oral dosage forms, including tablets and capsules). Crystalline forms may provide desirable or appropriate hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield and/or process control as compared to other forms, such as amorphous or amorphous forms. Thus, the crystalline form of formula I may provide advantages such as: improve the stability or storability of the active agent in the form of a pharmaceutical product of the compound or active ingredient, and/or have suitable bioavailability and/or stability as an active agent.

It has been found that the use of certain solvents and/or processes results in different crystalline forms of formula I as described herein, which may exhibit one or more of the advantageous characteristics described above. The methods of preparing the crystalline forms described herein and the characterization of these crystalline forms are described in detail below.

The compound names provided above are named according to IUPAC rules or using chembidraw Ultra, and one skilled in the art will appreciate that other well-recognized naming systems and symbols can be used to name or identify the compound structure. For example, a compound may be named or identified by a common name, system or non-system name. Commonly accepted nomenclature systems and symbols in the chemical arts include, but are not limited to, the Chemical Abstracts Service (CAS) and the International Union of Pure and Applied Chemistry (IUPAC). Thus, the compound structures provided above may also be named or identified by IUPAC nomenclature as (S) -2- (((S) - (((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester, by ChemBioDraw Ultra nomenclature or as ((S) - ((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine 2-ethylbutyl ester, and by CAS accession number 34-zft 34-37-zft 353-3.

In a particular embodiment, a crystalline form of formula I is disclosed.

Form I of the formula I

In some embodiments, there is provided crystalline form I of formula I (crystalline form I), wherein the crystalline structure exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in figure 1. The crystalline form I of formula I may exhibit a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 2. Crystalline form I of formula I can exhibit a thermogravimetric analysis (TGA) profile substantially as shown in figure 3. The crystalline form I of formula I can exhibit a dynamic gas phase adsorption (DVS) profile substantially as shown in figure 4.

In some embodiments of the crystalline form I of formula I, at least one, at least two, at least three, at least four, or all of the following (a) - (d) apply: (a) Crystalline form I having an XRPD pattern substantially as shown in figure 1; (b) The crystalline form I of formula I has a DSC thermogram substantially as shown in figure 2; (c) Crystalline form I of formula I has a TGA profile substantially as shown in figure 3; (d) The crystalline form I of formula I has a DVS profile substantially as shown in figure 4.

In some embodiments, the crystalline form I of formula I has the following characteristics:

(a) An XRPD pattern substantially as shown in figure 1;

(b) A DSC thermogram substantially as shown in figure 2;

(c) A TGA profile substantially as shown in figure 3; and

(d) A DVS plot substantially as shown in figure 4.

In some embodiments, the crystalline form I has an XRPD pattern that exhibits at least two, at least three, at least four, at least five, or at least six ° 2 Θ -reflections at maximum intensity, such as the XRPD pattern substantially as shown in figure 1.

In some embodiments, the crystalline form I of formula I has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 5.3 °,20.6 ° and 22.7 °. In some embodiments, the crystalline form I of formula I has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 5.3 °,20.6 ° and 22.7 ° and one or more ° 2 θ -reflections (+/-0.2 ° 2 θ) at 17.1 ° and 20.0 °. In some embodiments, the crystalline form I of formula I has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 5.3 °,20.6 ° and 22.7 ° and one ° 2 Θ -reflection (+/-0.2 ° 2 Θ) at 17.1 ° and 20.0 °. In some embodiments, the crystalline form I of formula I has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 5.3 °,20.6 ° and 22.7 ° and two ° 2 θ -reflections (+/-0.2 ° 2 θ) at 17.1 ° and 20.0 °. In some embodiments, the crystalline form I of formula I has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 5.3 °,20.6 °,22.7 °,17.1 °, and 20.0 °. In some embodiments, the crystalline form I of formula I has an XRPD pattern comprising any three ° 2 Θ -reflections (+/-0.2 ° 2 Θ) selected from 5.3 °,20.6 °,22.7 °,17.1 °, and 20.0 °.

In some embodiments, the crystalline form I of formula I has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 5.3 °,20.6 °,22.7 °,17.1 ° and 20.0 ° and one or more ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 17.6 °,16.3 ° and 13.7 °. In some embodiments, the crystalline form I of formula I has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 5.3 °,20.6 °,22.7 °,17.1 ° and 20.0 ° and one ° 2 Θ -reflection (+/-0.2 ° 2 Θ) at 17.6 °,16.3 ° and 13.7 °. In some embodiments, the crystalline form I of formula I has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 5.3 °,20.6 °,22.7 °,17.1 ° and 20.0 ° and two ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 17.6 °,16.3 ° and 13.7 °. In some embodiments, the crystalline form I of formula I has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 5.3 °,20.6 °,22.7 °,17.1 °,20.0 °,17.6 °,16.3 ° and 13.7 °. In some embodiments, the crystalline form I of formula I has an XRPD pattern comprising any three ° 2 Θ -reflections (+/-0.2 ° 2 Θ) selected from 5.3 °,20.6 °,22.7 °,17.1 °,20.0 °,17.6 °,16.3 °, and 13.7 °.

Form II of formula I

In some embodiments, there is provided crystalline form II of formula I (crystalline form I form II), wherein the crystalline structure exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in figure 5. The crystalline form I, form II, may exhibit a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 6. The crystalline form I, form II, can exhibit a thermogravimetric analysis (TGA) profile substantially as shown in figure 7. The crystalline form I form II can exhibit a dynamic gas phase sorption (DVS) profile substantially as shown in figure 8.

The crystalline form I form II may have, for example, the formula I or II may be crystalline or crystalline, such as by mono-crystallizationUnit cell of the following dimensions determined by X-ray crystallography:α =90 °; β =100.105 (7) °; and γ =90 °.

In some embodiments of the crystalline form I, form II, at least one, at least two, at least three, at least four, at least five, or all of the following (a) - (e) apply: (a) Crystalline form I form II has a unit cell with the following dimensions as determined by crystalline X-ray crystallography at a temperature of 100K:α =90 °; β =100.105 (7) °; and γ =90 °; (b) Crystalline form I form II having an XRPD pattern substantially as shown in figure 5; (c) Crystalline form I form II having a DSC thermogram substantially as shown in figure 6; (d) The crystalline form I form II has a TGA profile substantially as shown in figure 7; (e) Crystalline form I form II has a DVS profile substantially as shown in figure 8. In some embodiments of the crystalline form I, form II, at least one, at least two, at least three, at least four, at least five, or all of the following (a) - (f) apply: (a) Crystalline form I, form II, has a unit cell with the following dimensions as determined by crystalline X-ray crystallography at a temperature of 100K:α =90 °; β =100.105 (7) °; and γ =90 °; (b) Crystalline form I form II having an XRPD pattern substantially as shown in figure 5; (c) Crystalline form I form II having a DSC thermogram substantially as shown in figure 6; (d) The crystalline form I form II has a TGA profile substantially as shown in figure 7; (e) The crystalline form I form II has a DVS profile substantially as shown in figure 8; (f) Crystalline form I, form II, has a solid state NMR substantially as shown in figure 27.

In some embodiments, the crystalline form I form II has the following characteristics:

(a) Unit cell of the following dimensions as determined by crystallographic X-ray crystallography at a temperature of 100K:α =90 °; β =100.105 (7) °; and γ =90 °;

(b) An XRPD pattern substantially as shown in figure 5;

(c) A DSC thermogram substantially as shown in figure 6;

(d) A TGA profile substantially as shown in figure 7; and

(e) A DVS plot substantially as shown in figure 8.

(b) An XRPD pattern substantially as shown in figure 5;

(c) A DSC thermogram substantially as shown in figure 6;

(d) A TGA profile substantially as shown in figure 7;

(e) A DVS plot substantially as shown in figure 8; and

(f) Solid state NMR substantially as shown in figure 27.

an X-ray powder diffraction (XRPD) pattern having peaks at about 22.3 °,16.9 °,16.2 °,13.8 °,12.7 °,22.5 °,10.6 ° and 14.5 ° 2-theta ± 0.2 ° 2-theta;

a Differential Scanning Calorimetry (DSC) thermogram peak at 138 ℃; and

unit cells of the following dimensions as determined by single crystal X-ray crystallography:α =90 °; β =100.105 (7) °; and γ =90 °.

In some embodiments, the crystalline form I form II has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, or at least six ° 2 Θ -reflections at maximum intensity, such as the XRPD pattern substantially as shown in figure 5.

In some embodiments, the crystalline form I form II has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 22.3 °,16.9 °, and 16.2 °. In some embodiments, the crystalline form I form II has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 22.3 °,16.9 ° and 16.2 ° and one or more ° 2 θ -reflections (+/-0.2 ° 2 θ) at 13.8 ° and 12.7 °. In some embodiments, the crystalline form I form II has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 22.3 °,16.9 ° and 16.2 ° and one ° 2 Θ -reflection (+/-0.2 ° 2 Θ) at 13.8 ° and 12.7 °. In some embodiments, the crystalline form I form II has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 22.3 °,16.9 ° and 16.2 ° and two ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 13.8 ° and 12.7 °. In some embodiments, the crystalline form I form II has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 22.3 °,16.9 °,16.2 °,13.8 ° and 12.7 °. In some embodiments, the crystalline form I form II has an XRPD pattern comprising any three ° 2 Θ -reflections (+/-0.2 ° 2 Θ) selected from 22.3 °,16.9 °,16.2 °,13.8 °, and 12.7 °.

In some embodiments, the crystalline form I form II has an XRPD pattern further comprising ° 2 Θ -reflections at 22.5 °,10.6 °, and 14.5 ° (/ -0.2 ° 2 Θ). In some embodiments, the crystalline form I form II has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 22.3 °,16.9 °,16.2 °,13.8 ° and 12.7 ° and one or more ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 22.5 °,10.6 ° and 14.5 °. In some embodiments, the crystalline form I form II has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 22.3 °,16.9 °,16.2 °,13.8 ° and 12.7 ° and one ° 2 Θ -reflection (+/-0.2 ° 2 Θ) at 22.5 °,10.6 ° and 14.5 °. In some embodiments, the crystalline form I form II has an XRPD pattern comprising ° 2 Θ -reflections at 22.3 °,16.9 °,16.2 °,13.8 °, and 12.7 ° (+/-0.2 ° 2 Θ) and two ° 2 Θ -reflections at 22.5 °,10.6 °, and 14.5 ° (+/-0.2 ° 2 Θ). In some embodiments, the crystalline form I form II has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 22.3 °,16.9 °,16.2 °,13.8 °,12.7 °,22.5 °,10.6 °, and 14.5 °. In some embodiments, the crystalline form I form II has an XRPD pattern comprising any three ° 2 Θ -reflections (+/-0.2 ° 2 Θ) selected from 22.3 °,16.9 °,16.2 °,13.8 °,12.7 °,22.5 °,10.6 °, and 14.5 °.

Form III of formula I

In some embodiments, there is provided a crystalline form III of formula I (crystalline form I form III), wherein the crystalline structure exhibits a calculated powder pattern substantially as shown in fig. 9.

Crystalline form I form III may have a unit cell with the following dimensions as determined by single crystal X-ray crystallography:α =90 °; β =92.500 (3) °; and γ =90 °.

In some embodiments of the crystalline form I form III, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all of the following (a) - (g) apply: (a) Crystalline form III has a calculated powder pattern substantially as shown in figure 9; (b) Crystalline form I form III has a unit cell with the following dimensions as determined by crystalline X-ray crystallography at a temperature of 100K:α =90 °; β =92.500 (3) °; and γ =90 °; (c) crystalline form III of formula I has a monoclinic system; (d) Crystalline form I, form III, and crystalline forms thereofP21 space group is present; (e) Crystalline form III of formula I havingThe volume of (a); (f) crystalline form III of formula I has a Z value of 2; and (g) crystalline form III of formula I having 1.348Mg/m ³ The density of (c).

In some embodiments, the crystalline form I form III has the following characteristics:

(a) A calculated powder map substantially as shown in figure 9; and

(b) Unit cell of the following dimensions as determined by crystallographic X-ray crystallography at a temperature of 100K:α =90 °; β =92.500 (3) °; and γ =90 °;

in some embodiments, crystalline form I form III has a calculated powder pattern that exhibits at least two, at least three, at least four, at least five, or at least six ° 2 Θ -reflections at maximum intensity, such as a calculated powder pattern substantially as shown in figure 9.

In some embodiments, the crystalline form I form III has a calculated powder pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 4.1 °,8.2 °,17.1 °, and 23.8 °. In some embodiments, the crystalline form I form III has a calculated powder pattern comprising any three ° 2 Θ -reflections (+/-0.2 ° 2 Θ) selected from 4.1 °,8.2 °,17.1 °, and 23.8 °.

In some embodiments, the crystalline form I form III has a calculated powder pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 4.1 °,8.2 °,17.1 ° and 23.8 ° and one or more ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 16.9 °,14.4 ° and 25.6 °. In some embodiments, the crystalline form I form III has a calculated powder pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 4.1 °,8.2 °,17.1 ° and 23.8 ° and one ° 2 Θ -reflection (+/-0.2 ° 2 Θ) at 16.9 °,14.4 ° and 25.6 °. In some embodiments, the crystalline form I form III has a calculated powder pattern comprising ° 2 Θ -reflections at 4.1 °,8.2 °,17.1 °, and 23.8 ° (+/-0.2 ° 2 Θ) and two ° 2 Θ -reflections at 16.9 °,14.4 °, and 25.6 ° (+/-0.2 ° 2 Θ). In some embodiments, the crystalline form I form III has a calculated powder pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 4.1 °,8.2 °,17.1 °,23.8 °,16.9 °,14.4 °, and 25.6 °.

Form IV of formula I

In some embodiments, there is provided crystalline form IV of formula I (crystalline form I IV), wherein the crystalline structure exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in figure 10. The crystalline form I, form IV, may exhibit a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 11. Crystalline form I, form IV, can exhibit a thermogravimetric analysis (TGA) profile substantially as shown in figure 12.

In some embodiments of the crystalline form I IV, at least one, at least two, or all of the following (a) - (c) apply: (a) Crystalline form I form IV has an XRPD pattern substantially as shown in figure 10; (b) Crystalline form IV of formula I has a DSC thermogram substantially as shown in figure 11; (c) The crystalline form I form IV has a TGA profile substantially as shown in figure 12.

In some embodiments, the crystalline form I IV has the following characteristics:

(a) An XRPD pattern substantially as shown in figure 10;

(b) A DSC thermogram substantially as shown in figure 11; and

(c) A TGA profile substantially as shown in figure 12.

In some embodiments, the crystalline form I form IV has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, or at least six ° 2 Θ -reflections at maximum intensity, such as the XRPD pattern substantially as shown in figure 10.

In some embodiments, the crystalline form I form IV has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 22.6 °,19.9 °, and 14.1 °. In some embodiments, the crystalline form I form IV has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 22.6 °,19.9 ° and 14.1 ° and one or more ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 17.4 °,8.0 ° and 12.5 °. In some embodiments, the crystalline form I form IV has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 22.6 °,19.9 ° and 14.1 ° and one ° 2 θ -reflections (+/-0.2 ° 2 θ) at 17.4 °,8.0 ° and 12.5 °. In some embodiments, the crystalline form I form IV has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 22.6 °,19.9 ° and 14.1 ° and two ° 2 θ -reflections (+/-0.2 ° 2 θ) at 17.4 °,8.0 ° and 12.5 °. In some embodiments, the crystalline form I form IV has an XRPD pattern comprising ° 2 θ -reflections at 22.6 °,19.9 °, and 14.1 ° (/ -0.2 ° 2 θ) and three ° 2 θ -reflections at 17.4 °,8.0 °, and 12.5 ° (/ -0.2 ° 2 θ). In some embodiments, the crystalline form I form IV has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 22.6 °,19.9 °,14.1 °,17.4 °,8.0 ° and 12.5 °. In some embodiments, the crystalline form I form IV has an XRPD pattern comprising any three ° 2 Θ -reflections (+/-0.2 ° 2 Θ) selected from 22.6 °,19.9 °,14.1 °,17.4 °,8.0 °, and 12.5 °.

B. Mixtures of forms of formula I

Mixture I

In some embodiments, a mixture of forms II and IV of formula I (mixture I) is provided, wherein the crystalline structure exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in figure 13. Mixture I may exhibit a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 14. Mixture I can exhibit a thermogravimetric analysis (TGA) profile substantially as described in figure 15.

In some embodiments of mixture I, at least one, at least two, or all of the following (a) - (c) apply: (a) Mixture I has an XRPD pattern substantially as shown in figure 13; (b) Mixture I has a DSC thermogram substantially as shown in figure 14; (c) Mixture I has a TGA profile substantially as shown in figure 15.

In some embodiments, mixture I has the following characteristics:

(a) An XRPD pattern substantially as shown in figure 13;

(b) A DSC thermogram substantially as shown in figure 14; and

(c) A TGA profile substantially as shown in figure 15.

In some embodiments, mixture I has an XRPD pattern that exhibits at least two, at least three, or at least four ° 2 Θ -reflections at maximum intensity, such as the XRPD pattern substantially as shown in figure 13.

In some embodiments, mixture I has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 15.9 °,22.6 ° and 14.1 °. In some embodiments, mixture I has an XRPD pattern comprising ° 2 θ -reflections at 15.9 °,22.6 ° and 14.1 ° (/ -0.2 ° 2 θ) and ° 2 θ -reflections at 12.5 ° (/ -0.2 ° 2 θ). In some embodiments, mixture I has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 15.9 °,22.6 °,14.1 ° and 12.5 °. In some embodiments, mixture I has an XRPD pattern comprising any three ° 2 Θ -reflections (+/-0.2 ° 2 Θ) selected from 15.9 °,22.6 °,14.1 °, and 12.5 °.

Mixture II

In some embodiments, a mixture of forms II and IV of formula I (mixture II) is provided, wherein the crystalline structure exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in figure 16. Mixture II may exhibit a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 17. Mixture II can exhibit a thermogravimetric analysis (TGA) profile substantially as described in figure 18.

In some embodiments of mixture II, at least one, at least two, or all of the following (a) - (c) apply: (a) Mixture II has an XRPD pattern substantially as shown in figure 16; (b) Mixture II has a DSC thermogram substantially as shown in figure 17; (c) Mixture II has a TGA profile substantially as shown in figure 18.

In some embodiments, mixture II has the following characteristics:

(a) An XRPD pattern substantially as shown in figure 16;

(b) A DSC thermogram substantially as shown in figure 17; and

(c) A TGA profile substantially as shown in figure 18.

In some embodiments, mixture II has an XRPD pattern that exhibits at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve ° 2 Θ -reflections at maximum intensity, such as the XRPD pattern substantially as shown in figure 16.

In some embodiments, mixture II has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 16.1 °,22.4 °, and 12.7 °. In some embodiments, mixture II has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 16.1 °,22.4 ° and 12.7 ° and one or more ° 2 θ -reflections (+/-0.2 ° 2 θ) at 24.2 °,16.8 ° and 8.1 °. In some embodiments, mixture II has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 16.1 °,22.4 ° and 12.7 ° and one ° 2 θ -reflection (+/-0.2 ° 2 θ) at 24.2 °,16.8 ° and 8.1 °. In some embodiments, mixture II has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 16.1 °,22.4 ° and 12.7 ° and two ° 2 θ -reflections (+/-0.2 ° 2 θ) at 24.2 °,16.8 ° and 8.1 °. In some embodiments, mixture II has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 16.1 °,22.4 ° and 12.7 ° and three ° 2 θ -reflections (+/-0.2 ° 2 θ) at 24.2 °,16.8 ° and 8.1 °. In some embodiments, mixture II has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 16.1 °,22.4 °,12.7 °,24.2 °,16.8 ° and 8.1 °. In some embodiments, mixture II has an XRPD pattern comprising any three ° 2 Θ -reflections (+/-0.2 ° 2 Θ) selected from 16.1 °,22.4 °,12.7 °,24.2 °,16.8 °,8.1 °,13.9 °,17.5 °,11.1 °,10.7 °,14.7 °, and 19.8 °.

Mixture III

In some embodiments, a mixture of forms II and IV of formula I (mixture III) is provided, wherein the crystalline structure exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in figure 19. Mixture III may exhibit a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 20. Mixture III can exhibit a thermogravimetric analysis (TGA) profile substantially as depicted in figure 21.

In some embodiments of mixture III, at least one, at least two, or all of the following (a) - (c) apply: (a) Mixture III has an XRPD pattern substantially as shown in figure 19; (b) Mixture III has a DSC thermogram substantially as shown in figure 20; (c) Mixture III has a TGA profile substantially as shown in figure 21.

In some embodiments, mixture III has the following characteristics:

(a) An XRPD pattern substantially as shown in figure 19;

(b) A DSC thermogram substantially as shown in figure 20; and

(c) A TGA profile substantially as shown in figure 21.

In some embodiments, mixture III has an XRPD pattern that exhibits at least two, at least three, at least four, or at least five ° 2 Θ -reflections at maximum intensity, such as the XRPD pattern substantially as shown in figure 19.

In some embodiments, mixture III has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 16.7 °,12.6 °, and 17.2 °. In some embodiments, mixture III has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 16.7 °,12.6 ° and 17.2 ° and one or more ° 2 θ -reflections (+/-0.2 ° 2 θ) at 19.6 ° and 14.1 °. In some embodiments, mixture III has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 16.7 °,12.6 ° and 17.2 ° and one ° 2 θ -reflection (+/-0.2 ° 2 θ) at 19.6 ° and 14.1 °. In some embodiments, mixture III has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 16.7 °,12.6 ° and 17.2 ° and two ° 2 θ -reflections (+/-0.2 ° 2 θ) at 19.6 ° and 14.1 °. In some embodiments, mixture III has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 16.7 °,12.6 °,17.2 °,19.6 °, and 14.1 °. In some embodiments, mixture III has an XRPD pattern comprising any three ° 2 Θ -reflections (+/-0.2 ° 2 Θ) selected from 16.7 °,12.6 °,17.2 °,19.6 °, and 14.1 °.

C. Maleate form I of formula I

In some embodiments, a crystalline maleate salt of formula I (crystalline maleate salt form I) is provided, wherein the crystalline structure exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in figure 22. The crystalline maleate salt form I of formula I may exhibit a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 23. Crystalline maleate form I of formula I can exhibit a thermogravimetric analysis (TGA) profile substantially as shown in figure 24. The crystalline maleate salt form I of formula I can exhibit a dynamic gas phase adsorption (DVS) profile substantially as shown in figure 25.

In some embodiments of crystalline maleate form I of formula I, at least one, at least two, at least three, or all of the following (a) - (d) apply: (a) Crystalline maleate form I of formula I has an XRPD pattern substantially as shown in figure 22; (b) Crystalline maleate form I of formula I having a DSC thermogram substantially as shown in figure 23; (c) Crystalline maleate form I of formula I has a TGA profile substantially as shown in figure 24; and (d) the crystalline maleate form I of formula I has a DVS profile substantially as shown in figure 25.

In some embodiments, the crystalline maleate form I of formula I has the following characteristics:

(a) An XRPD pattern substantially as shown in figure 22;

(b) A DSC thermogram substantially as shown in figure 23;

(c) A TGA profile substantially as shown in figure 24; and

(d) A DVS plot substantially as shown in figure 25.

In some embodiments, the crystalline maleate form I of formula I has an XRPD pattern that exhibits at least two, at least three, at least four, at least five, or at least six ° 2 Θ -reflections at maximum intensity, such as the XRPD pattern substantially as shown in figure 22.

In some embodiments, the crystalline maleate form I of formula I has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 16.3 °,4.6 °, and 9.0 °. In some embodiments, the crystalline maleate form I of formula I has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 16.3 °,4.6 ° and 9.0 ° and one or more ° 2 θ -reflections (+/-0.2 ° 2 θ) at 6.2 ° and 7.3 °. In some embodiments, the crystalline maleate form I of formula I has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 16.3 °,4.6 ° and 9.0 ° and one ° 2 θ -reflection (+/-0.2 ° 2 θ) at 6.2 ° and 7.3 °. In some embodiments, the crystalline maleate form I has an XRPD pattern comprising ° 2 θ -reflections at 16.3 °,4.6 °, and 9.0 ° (/ -0.2 ° 2 θ) and two ° 2 θ -reflections at 6.2 ° and 7.3 ° (/ -0.2 ° 2 θ). In some embodiments, the crystalline maleate form I of formula I has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 16.3 °,4.6 °,9.0 °,6.2 ° and 7.3 °. In some embodiments, the crystalline maleate form I of formula I has an XRPD pattern comprising any three ° 2 Θ -reflections (+/-0.2 ° 2 Θ) selected from 16.3 °,4.6 °,9.0 °,6.2 °, and 7.3 °.

In some embodiments, the crystalline maleate form I of formula I has an XRPD pattern comprising ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 16.3 °,4.6 °,9.0 °,6.2 ° and 7.3 ° and one or more ° 2 Θ -reflections (+/-0.2 ° 2 Θ) at 17.8 °,15.1 ° and 14.7 °. In some embodiments, the crystalline maleate form I has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 16.3 °,4.6 °,9.0 °,6.2 °, and 7.3 ° and one ° 2 θ -reflection (+/-0.2 ° 2 θ) at 17.8 °,15.1 °, and 14.7 °. In some embodiments, the crystalline maleate form I of formula I has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 16.3 °,4.6 °,9.0 °,6.2 ° and 7.3 ° and two ° 2 θ -reflections (+/-0.2 ° 2 θ) at 17.8 °,15.1 ° and 14.7 °. In some embodiments, the crystalline maleate form I has an XRPD pattern comprising ° 2 θ -reflections (+/-0.2 ° 2 θ) at 16.3 °,4.6 °,9.0 °,6.2 °,7.3 °,17.8 °,15.1 ° and 14.7 °. In some embodiments, the crystalline maleate form I of formula I has an XRPD pattern comprising any three ° 2 Θ -reflections (+/-0.2 ° 2 Θ) selected from 16.3 °,4.6 °,9.0 °,6.2 °,7.3 °,17.8 °,15.1 °, and 14.7 °.

Pharmaceutical compositions

For administration purposes, in some embodiments, the compounds described herein are administered as raw chemicals or formulated into pharmaceutical compositions. The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of formula I (including forms thereof), and a pharmaceutically acceptable excipient. The compound of formula I is present in the composition in an amount effective to treat the particular disease or disorder of interest. The activity of a compound of formula I can be determined by one skilled in the art, e.g., as described herein. One skilled in the art can readily determine the appropriate therapeutically effective concentration and dosage. In some embodiments, the compound of formula I is present in the pharmaceutical composition in an amount from about 5mg to about 300 mg. In some embodiments, the compound of formula I is present in the pharmaceutical composition in an amount from about 100mg to about 200 mg. In some embodiments, the compound of formula I is present in the pharmaceutical composition in an amount from about 5mg to about 100 mg. In some embodiments, the compound of formula I is present in the pharmaceutical composition in an amount from about 5mg to about 20 mg. In some embodiments, the compound of formula I is present in the pharmaceutical composition in an amount from about 130mg to about 160 mg. In some embodiments, the compound of formula I is present in the pharmaceutical composition in an amount of about 5mg,10mg,25mg,50mg,75, mg,100mg,150mg,200mg,250mg, or about 300 mg. In some embodiments, the compound of formula I is present in the pharmaceutical composition in an amount of about 10 mg. In some embodiments, the compound of formula I is present in the pharmaceutical composition in an amount of about 150 mg. In some embodiments, the compound of formula I is present in the pharmaceutical composition in an amount of about 10 mg. In some embodiments, the compound of formula I is present in the pharmaceutical composition in an amount of about 150 mg.

Administration of the compounds of the present invention in pure form or in suitable pharmaceutical compositions may be by any acceptable mode of administration for providing agents of similar utility. The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with an appropriate pharmaceutically acceptable excipient, and can be formulated into preparations in the form of solid, semisolid, liquid, or gas, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. The pharmaceutical compositions of the present invention may be prepared by combining a compound of the present invention with suitable pharmaceutically acceptable excipients, and may be formulated into preparations in solid, semi-solid, liquid or gaseous form, such as solid dispersions and solid solutions. Typical routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal and intranasal. In some embodiments, the pharmaceutical composition is prepared for parenteral administration. In one embodiment, the pharmaceutical composition is a solution. The pharmaceutical compositions of the present invention are formulated so as to provide bioavailability of the active ingredient contained therein when the composition is administered to a patient. The composition to be administered to a subject or patient takes the form of one or more dosage units, where for example a tablet may be a single dose unit and a container of a compound of the invention in aerosol form may contain a plurality of dosage units. The actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, remington, the Science and Practice of Pharmacy, 20 th edition (Philadelphia College of Pharmacy and Science, 2000). In any event, the composition to be administered will contain a therapeutically effective amount of a compound of the invention for treating a disease or condition of interest in accordance with the teachings of the present invention.

The pharmaceutical compositions of the present invention may be prepared by methods well known in the pharmaceutical arts. For example, a pharmaceutical composition intended for administration by injection may be prepared by mixing a compound of the present invention with sterile distilled water to form a solution. Alternatively, a pharmaceutical composition intended for administration by injection may be prepared by mixing a compound of the invention with sterile reverse osmosis water to form a solution. Surfactants or other solubilizing excipients may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compounds of the present invention to facilitate dissolution or uniform suspension of the compounds in an aqueous delivery system.

In other embodiments, a solid pharmaceutical composition intended for oral administration may be prepared by: a therapeutically effective amount of a compound of the present invention is mixed with at least one suitable pharmaceutically acceptable excipient to form a solid preformulation composition, which can then be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. Thus, in some embodiments, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable excipient.

The compounds of the present invention are administered in therapeutically effective amounts, which will vary depending on a variety of factors, including the activity of the particular compound employed; metabolic stability and length of action of the compound; the age, weight, general health, sex, and diet of the patient; mode and time of administration; the rate of excretion; a pharmaceutical composition; the severity of the particular disease or disorder; and the subject receiving the treatment. In some embodiments, the compounds of the present invention may be administered alone or in combination with other antiviral agents, once a day, or twice a day, or three times a day, or four times a day, as long as the patient is infected, latently infected, or to prevent infection (e.g., for many years, months, weeks, or days).

The compositions of the present invention may comprise the compound of formula I in any suitable purity. For example, the purity of the compound of formula I may be at least 99.0%, or at least 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or at least 99.9%. In some embodiments, the present invention provides compositions having a compound of formula I with a purity of at least 99.1%. In some embodiments, the present invention provides compositions having a compound of formula I with a purity of at least 99.3%. In some embodiments, the present invention provides compositions having a compound of formula I with a purity of at least 99.5%. In some embodiments, the present invention provides compositions having a compound of formula I with a purity of at least 99.7%.

Impurities present in the compositions of the present invention may include unreacted starting materials, undesirable by-products, and other materials. Representative impurities include impurity a:

impurity a may be present in the compositions of the present invention in an amount of less than about 0.5% (w/w), or less than about 0.45%,0.40,0.35,0.30, 0.25,0.20,0.15,0.10,0.09,0.08,0.07,0.06,0.05,0.04,0.03, 0.02, or less than about 0.01% (w/w). In some embodiments, the composition of the compound of formula I comprises less than 0.10% (w/w) of impurity a. In some embodiments, the composition of the compound of formula I comprises less than 0.05% (w/w) of impurity a.

In some embodiments, a composition of a compound of formula I may have a purity of at least 99.1%, wherein the composition comprises less than 0.10% (w/w) of impurity a. In some embodiments, a composition of a compound of formula I may have a purity of at least 99.1%, wherein the composition comprises less than 0.05% (w/w) of impurity a. In some embodiments, a composition of a compound of formula I may have a purity of at least 99.1%, wherein the composition comprises less than 0.04% (w/w) of impurity a. In some embodiments, a composition of a compound of formula I may have a purity of at least 99.5%, wherein the composition comprises less than 0.04% (w/w) of impurity a. In some embodiments, a composition of a compound of formula I may have a purity of at least 99.5%, wherein the composition comprises less than 0.04% (w/w) of impurity a.

Formula I

Also provided are compositions comprising at least one, at least two, at least three, or all of the crystalline forms of formula I as described herein. In a particular embodiment, there is provided a composition comprising one of the compounds of formula I as described herein. In a particular embodiment, there is provided a composition comprising two crystalline compounds of formula I as described herein. In a particular embodiment, there is provided a composition comprising three crystalline compounds of formula I as described herein. In a particular embodiment, there is provided a composition comprising four crystalline compounds of formula I as described herein. In a particular embodiment, a composition comprises a mixture of crystalline form I form II and form I form IV described herein. In other embodiments, the compositions described herein may comprise a substantially pure crystalline form, or may be substantially free of other crystalline forms and/or impurities.

In some embodiments, the composition comprises a crystalline form of formula I. In some embodiments, there is provided a composition comprising a crystalline form as described herein, wherein the compound of formula I in the composition is substantially pure (i.e., substantially pure compound of formula I as described herein). In particular embodiments of the composition comprising the crystalline form of formula I, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the formula I present in the composition is one of the crystalline forms disclosed herein. In some embodiments, the composition comprises at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of one of the crystalline forms of formula I.

In other embodiments of the compositions comprising the crystalline forms disclosed herein, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of the formula I present in the composition is other amorphous or crystalline forms of formula I and/or impurities.

In other embodiments of the compositions comprising the crystalline forms disclosed herein, the impurities comprise less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of the total mass relative to the mass of the crystalline form present. For example, impurities may include by-products from the synthesis of formula I, contaminants, degradation products, other crystalline forms, amorphous forms, water, and solvents. In some embodiments, the impurities comprise by-products from the process of synthesizing formula I. In some embodiments, the impurities comprise contaminants from the process of synthesizing formula I. In some embodiments, the impurity comprises a degradation product of formula I. In some embodiments, the impurities comprise other crystalline forms of formula I. In some embodiments, the impurities comprise water or a solvent. In some embodiments of the compositions comprising the crystalline forms disclosed herein, the impurities are selected from the group consisting of byproducts, contaminants, degradation products, other crystalline forms, water, solvents, and combinations thereof from the synthesis of formula I.

Combination therapy

In some embodiments, there is provided a method for treating an arenaviridae virus infection in a human, comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In some embodiments, there is provided a method for treating a lassa virus infection in a human comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In some embodiments, there is provided a method for treating a hookeri virus infection in a human comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

In some embodiments, the present invention provides a method for treating an arenaviridae virus infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating an arenaviridae virus infection. In some embodiments, the present invention provides a method for treating a lassa virus infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating an arenaviridae virus infection. In some embodiments, the present invention provides a method for treating a lassa virus infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents useful for treating a lassa virus infection. In some embodiments, the present invention provides a method for treating a hookeri virus infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating an arenaviridae virus infection. In some embodiments, the present invention provides a method for treating a virus infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating a virus infection.

Some embodiments provide a method of treating a viral infection in a human having an arenaviridae viral infection with a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. Some embodiments provide a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents for use in a method of treating a viral infection in a human suffering from a lassa virus infection. Some embodiments provide a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents for use in a method of treating a viral infection in a human suffering from a junin viral infection. Some embodiments provide a therapeutically effective amount of a compound disclosed herein for use in a method of treating a viral infection in a human having an arenaviridae viral infection, wherein the compound is administered in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. Some embodiments provide a compound disclosed herein for use in a method of treating a viral infection in a human suffering from a lassa virus infection, wherein a therapeutically effective amount of the compound is administered in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. Some embodiments provide a compound disclosed herein for use in a method of treating a viral infection in a human suffering from a junin virus infection, wherein a therapeutically effective amount of the compound is administered in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In some embodiments, the present invention provides methods of using the compounds disclosed herein in the treatment of arenaviridae virus infections, in combination with one or more additional therapeutic agents suitable for treating arenaviridae virus infections. In some embodiments, the present invention provides a compound disclosed herein for use in a method of treating an arenaviridae viral infection, wherein a therapeutically effective amount of the compound is administered in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating an arenaviridae viral infection. In some embodiments, the present invention provides a compound disclosed herein in combination with one or more additional therapeutic agents useful for treating a lassa virus infection for use in a method of treating a lassa virus infection. In some embodiments, the present invention provides a compound disclosed herein for use in a method of treating a lassa virus infection, wherein a therapeutically effective amount of the compound is administered in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating a lassa virus infection. In some embodiments, the present invention provides methods of using the compounds disclosed herein in the treatment of a junin virus infection in combination with one or more additional therapeutic agents useful in the treatment of a junin virus infection. In some embodiments, the present invention provides a compound disclosed herein for use in a method of treating a huning virus infection, wherein a therapeutically effective amount of the compound is administered in combination with a therapeutically effective amount of one or more additional therapeutic agents useful in treating a huning virus infection.

In some embodiments, there is provided a method for treating a coronavirus infection in a human, comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In some embodiments, there is provided a method for treating a SARS virus infection in a human comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In some embodiments, there is provided a method for treating a MERS virus infection in a human comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

In some embodiments, the present invention provides a method for treating a coronaviridae viral infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents useful for treating a coronaviridae viral infection. In some embodiments, the present invention provides methods for treating a SARS virus infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating a coronavirus infection. In some embodiments, the present invention provides methods for treating a SARS virus infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating a SARS virus infection. In some embodiments, the present invention provides a method for treating MERS virus infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating coronavirus infection. In some embodiments, the present invention provides a method for treating MERS virus infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating MERS virus infection.

Some embodiments provide a method of treating a viral infection in a human afflicted with a coronaviridae viral infection by a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. Some embodiments provide a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents for use in a method of treating a viral infection in a human suffering from a SARS viral infection. Some embodiments provide a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents for use in a method of treating a viral infection in a human having a MERS viral infection. Some embodiments provide a therapeutically effective amount of a compound disclosed herein for use in a method of treating a viral infection in a human having a coronavirus infection, wherein the compound is administered in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. Some embodiments provide a method of using a compound disclosed herein for treating a viral infection in a human having a SARS viral infection, wherein a therapeutically effective amount of the compound is administered in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. Some embodiments provide a compound disclosed herein for use in a method of treating a viral infection in a human having a MERS viral infection, wherein a therapeutically effective amount of the compound is administered in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In some embodiments, the present invention provides methods of treating a coronaviridae viral infection with a compound disclosed herein in combination with one or more additional therapeutic agents suitable for treating a coronaviridae viral infection. In some embodiments, the present invention provides a compound disclosed herein for use in a method of treating a coronaviridae viral infection, wherein a therapeutically effective amount of the compound is administered in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating a coronaviridae viral infection. In some embodiments, the present invention provides methods for treating a SARS virus infection using the compounds disclosed herein in combination with one or more additional therapeutic agents suitable for treating a SARS virus infection. In some embodiments, the invention provides a method of using a compound disclosed herein for treating a SARS virus infection, wherein a therapeutically effective amount of the compound is administered in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating a SARS virus infection. In some embodiments, the present invention provides methods of using the compounds disclosed herein in the treatment of MERS virus infection in combination with one or more additional therapeutic agents suitable for use in the treatment of MERS virus infection. In some embodiments, the present invention provides a compound disclosed herein for use in a method of treating a MERS virus infection, wherein a therapeutically effective amount of the compound is administered in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating a MERS virus infection.

In some embodiments, there is provided a method for treating a filoviridae virus infection in a human comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In some embodiments, there is provided a method for treating ebola virus infection in a human comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

In some embodiments, the present invention provides a method for treating a filoviridae viral infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating a filoviridae viral infection. In some embodiments, the present invention provides a method for treating ebola virus infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents useful for treating ebola virus infection.

Some embodiments provide a method of treating a viral infection in a human having a filoviridae viral infection with a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. Some embodiments provide a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents for use in a method of treating a viral infection in a human suffering from an ebola virus infection. Some embodiments provide a therapeutically effective amount of a compound disclosed herein for use in a method of treating a viral infection in a human having a filoviridae viral infection, wherein the compound is administered in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. Some embodiments provide a compound disclosed herein for use in a method of treating a viral infection in a human having an ebola virus infection, wherein a therapeutically effective amount of the compound is administered in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In some embodiments, the present invention provides methods of treating filoviridae virus infections with a compound disclosed herein in combination with one or more additional therapeutic agents suitable for treating filoviridae virus infections. In some embodiments, the present invention provides a compound disclosed herein for use in a method of treating a filoviridae viral infection, wherein a therapeutically effective amount of the compound is administered in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating a filoviridae viral infection.

In some embodiments, there is provided a method for treating a flaviviridae viral infection in a human comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In some embodiments, there is provided a method for treating a zika virus infection in a human comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

In some embodiments, the present invention provides methods for treating a flaviviridae viral infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents useful for treating a flaviviridae viral infection. In some embodiments, the present invention provides a method for treating zika virus infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating zika virus infection.

Some embodiments provide methods of using a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents for treating a viral infection in a human having a flaviviridae viral infection. Some embodiments provide a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents for use in a method of treating a viral infection in a human having a zika virus infection. Some embodiments provide a therapeutically effective amount of a compound disclosed herein for use in a method of treating a viral infection in a human having a flaviviridae viral infection, wherein the compound is administered in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. Some embodiments provide a compound disclosed herein for use in a method of treating a viral infection in a human having a zika virus infection, wherein a therapeutically effective amount of the compound is administered in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In some embodiments, the present invention provides methods of using the compounds disclosed herein in the treatment of flaviviridae viral infections in combination with one or more additional therapeutic agents suitable for the treatment of flaviviridae viral infections. In some embodiments, the present invention provides a method of treating a flaviviridae viral infection with a compound disclosed herein, wherein a therapeutically effective amount of the compound is administered in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating a flaviviridae viral infection.

In some embodiments, there is provided a method for treating a paramyxoviridae virus infection in a human comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In some embodiments, there is provided a method for treating an RSV viral infection in a human comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

In some embodiments, the present invention provides a method for treating a paramyxoviridae viral infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating a paramyxoviridae viral infection. In some embodiments, the present invention provides methods for treating RSV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating RSV infection.

Some embodiments provide a method of treating a viral infection in a human having a paramyxoviridae viral infection with a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. Some embodiments provide a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents for use in a method of treating a viral infection in a human suffering from a RSV infection. Some embodiments provide a therapeutically effective amount of a compound disclosed herein for use in a method of treating a viral infection in a human having a paramyxoviridae viral infection, wherein the compound is administered in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. Some embodiments provide a method of using a compound disclosed herein for treating an infection in a human suffering from a RSV infection, wherein a therapeutically effective amount of the compound is administered in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In some embodiments, the present invention provides methods of using the compounds disclosed herein in the treatment of a paramyxoviridae virus infection in combination with one or more additional therapeutic agents suitable for use in the treatment of a paramyxoviridae virus infection. In some embodiments, the present invention provides a compound disclosed herein for use in a method of treating a paramyxoviridae viral infection, wherein a therapeutically effective amount of the compound is administered in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating a paramyxoviridae viral infection.

A therapeutically effective amount of a compound of formula I as disclosed herein can be combined with a therapeutically effective amount of one or more additional therapeutic agents in any dosage amount of the compound of formula I (e.g., 5mg to 300mg of the compound).

In some embodiments, pharmaceutical compositions are provided that comprise a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents, and a pharmaceutically acceptable excipient.

In some embodiments, combination medicaments are provided that comprise a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

In some embodiments, kits are provided that comprise a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

In some embodiments, the additional therapeutic agent for use in combination with the compounds disclosed herein is effective against a viral infection.

In some embodiments, the additional therapeutic agent for use in combination with the compounds disclosed herein is effective against arenaviridae virus infections (particularly lassa virus and junin virus infections).

In some embodiments, a therapeutically effective amount of a compound of formula I is formulated as a solution, which may optionally contain a therapeutically effective amount of one or more other compounds useful for treating an arenaviridae virus infection. In some embodiments, the solution may contain another active ingredient for treating an arenaviridae virus infection.

In some embodiments, the additional therapeutic agents used in combination with the compounds disclosed herein are active against coronavirus infection, particularly SARS virus and MERS virus infection.

In some embodiments, a therapeutically effective amount of a compound of formula I is formulated as a solution, which may optionally contain a therapeutically effective amount of one or more other compounds useful for treating a coronavirus infection. In some embodiments, the solution may contain another active ingredient for treating a coronavirus infection.

In some embodiments, the additional therapeutic agent used in combination with the compounds disclosed herein has activity against filoviridae virus infection, particularly marburg virus, ebola virus, and/or Cueva virus infectionAnd (4) activity. Non-limiting examples of such other active therapeutic agents are ribavirin, palivizumab, motavizumab, RSV-IGIV (R) ((R))) MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, ebola Convalescent Plasma (ECP), TKM-100201, BCX4430 ((2S, 3S,4R, 5R) -2- (4-amino-5H-pyrrolo [3,2-d)]Pyrimidin-7-yl) -5- (hydroxymethyl) pyrrolidine-3,4-diol), farragir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N, 7-N-bis [3- (dimethylamino) propyl ] phosphate]-3,9-dimethylquinolino [8,7-h]Quinolone-1,7-diamine), JK-05, TKM-Ebola, ZMAP, rNAPc2, VRC-EBOADC076076-00-VP, OS-2966, MVA-BN filo, brincidovir, ebola vaccine based on Vaxart adenovirus vector 5, ad26-ZEBOV, filoVax vaccine, GOVX-E301, GOVX-E302, ebola virus entry inhibitor (NPC 1 inhibitor) and rVSV-EBOV, and mixtures thereof. The compounds and compositions of the invention may also be used in combination with Phosphoramide Morpholino Oligomer (PMO), which is a synthetic antisense oligonucleotide analog intended to interfere with translation processes by forming base pair duplexes with specific RNA sequences. Examples of PMOs include AVI-7287, AVI-7288, AVI-7537, AVI-7539, AVI-6002, and AVI-6003. The compounds and compositions of the present invention may also be used with general care provided to patients with filoviridae virus infections, including parenteral fluids (including dextrose saline and ringer's lactic acid) and nutraceuticals, antibiotics (including metronidazole and cephalosporin antibiotics, such as ceftriaxone and cefuroxime) and/or antifungal prophylaxis, fever and pain killers, antiemetics (such as metoclopramide) and/or antidiarrheals, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), analgesics and other common disease drugs in the patient population, for example antimalarial drugs (including artemether and artesunate-benzfluorenol combination therapy), typhoid fever (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporins such as ceftriaxone, or aminopenicillin such as cillin) or will, including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycinHegellosis.

In some embodiments, a therapeutically effective amount of a compound of formula I is formulated as a solution, which may optionally contain a therapeutically effective amount of one or more other compounds useful for treating filoviridae virus infections. In some embodiments, the solution may contain another active ingredient for treating filoviridae virus infection.

In some embodiments, the additional therapeutic agent used in combination with the compounds disclosed herein has activity against flaviviridae virus infections, particularly zika virus infections. Non-limiting examples of these other active therapeutic agents are amodiaquine, chloroquine, ribavirin, interferon alpha, BCX4430, NITD008 and monoclonal antibodies.

In some embodiments, a therapeutically effective amount of a compound of formula I is formulated as a solution, which may optionally contain a therapeutically effective amount of one or more other compounds useful for treating flaviviridae viral infections. In some embodiments, the solution may contain another active ingredient for treating a flaviviridae virus infection.

In some embodiments, the additional therapeutic agent used in combination with the compounds disclosed herein has activity against a paramyxoviridae virus infection, particularly a RSV infection. Non-limiting examples of these other active therapeutic agents are ribavirin, salbutamol, epinephrine, and palivizumab.

In some embodiments, a therapeutically effective amount of a compound of formula I is formulated as a solution, which may optionally contain a therapeutically effective amount of one or more other compounds useful for treating a paramyxoviridae viral infection. In some embodiments, the solution may contain another active ingredient for treating a paramyxoviridae virus infection.

In some embodiments, when a compound disclosed herein is combined with one or more additional therapeutic agents as described above, the components of the composition are administered in a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.

In some embodiments, a therapeutically effective amount of a compound disclosed herein is combined with a therapeutically effective amount of one or more additional therapeutic agents in a unit dosage form for simultaneous administration to a patient, e.g., as a solid dosage form for oral administration.

In some embodiments, a therapeutically effective amount of a compound disclosed herein is administered with one or more additional therapeutic agents. Co-administration of a therapeutically effective amount of a compound disclosed herein with a therapeutically effective amount of one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents such that both a therapeutically effective amount of a compound disclosed herein and one or more additional therapeutic agents are present in the body of the patient.

Co-administration includes administering a unit dose comprising a therapeutically effective amount of one or more compounds disclosed herein before or after administering a unit dose of a therapeutically effective amount of one or more additional therapeutic agents, e.g., a compound disclosed herein can be administered within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed by administration of a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents after a period of several hours (e.g., 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of a compound disclosed herein after a period of several hours (e.g., 1-12 hours).

Methods of treatment

In some embodiments, the present invention relates to methods of treating a virus selected from the group consisting of arenaviridae, coronaviridae, filoviridae, flaviviridae, and paramyxoviridae.

In some embodiments, the invention relates to methods of treating an arenaviridae virus infection by administering a compound of formula I provided herein. In some embodiments, the present invention relates to methods of treating an arenaviridae species infection selected from the group consisting of: allpahuayo virus (ALLV), amapari virus (AMAV), bear canyon virus (BCNV), katalana virus, chapare virus, cupiqui virus (CPXV), danton nong virus, flexal virus (FLEV), guarantor virus (GTOV), ipyv virus (IPPYV), junin virus (JUNV), kodoko virus, lassa virus (LASV), leidiro virus (LATV), lymphocytic choriomeningitis virus (LCMV), lujo virus, machupo virus (MACV), mobala virus (MOBV), mooro virus, mopelia virus (MOPV), oliveros virus (OLV), parana virus (PARV), pichimede virus (PICV), pinhal virus, pirital virus (PIRV), saurua virus (SABV), spyiba virus (TCAV), tabace virus (TCAV), atara virus (TCAV), and Woo virus (WW MV). In some embodiments, the invention relates to methods of treating a lassa virus infection by administering a compound of formula I provided herein. In some embodiments, the present invention relates to methods of treating a junin virus infection by administering a compound of formula I provided herein.

In some embodiments, the invention relates to methods of treating a coronaviridae viral infection by administering a compound of formula I provided herein. In some embodiments, the invention relates to methods of treating Middle East Respiratory Syndrome (MERS) infection by administering a compound of formula I provided herein. In some embodiments, the invention relates to methods of treating Severe Acute Respiratory Syndrome (SARS) infection by administering a compound of formula I provided herein.

In some embodiments, the present invention relates to methods of treating filoviridae virus infections by administering a compound of formula I provided herein. In some embodiments, the invention relates to methods of treating ebola virus infection by administering a compound of formula I provided herein. In some embodiments, the invention relates to methods of treating ebola virus infection selected from the group consisting of: zaire (i.e., ebola virus, EBOV), sudan, forest (Tai Forest), bundbjg and reston. In some embodiments, the invention relates to methods of treating marburg virus infection by administering a compound of formula I provided herein.

In some embodiments, the invention relates to methods of treating flaviviridae viral infections by administering a compound of formula I provided herein. In some embodiments, the invention relates to methods of treating zika virus infection by administering a compound of formula I provided herein.

In some embodiments, the present invention relates to methods of using the compounds of formula I provided herein for the treatment of arenaviridae virus infections. In some embodiments, the present invention relates to a method of treating an infection of an arenaviridae species selected from the group consisting of: allpahuayo virus (ALLV), amapari virus (AMAV), bear canyon virus (BCNV), katalana virus, chapare virus, cupiqui virus (CPXV), danton nong virus, flexal virus (FLEV), guarantor virus (GTOV), ipyv virus (IPPYV), junin virus (JUNV), kodoko virus, lassa virus (LASV), leidiro virus (LATV), lymphocytic choriomeningitis virus (LCMV), lujo virus, machupo virus (MACV), mobala virus (MOBV), mooro virus, mopelia virus (MOPV), oliveros virus (OLV), parana virus (PARV), pichimede virus (PICV), pinhal virus, pirital virus (PIRV), saurua virus (SABV), spyiba virus (TCAV), tabace virus (TCAV), atara virus (TCAV), and Woo virus (WW MV). In some embodiments, the present invention relates to methods of using the compounds of formula I provided herein for the treatment of lassa virus infection. In some embodiments, the present invention relates to methods of using the compounds of formula I provided herein for the treatment of a junin virus infection.

In some embodiments, the present invention relates to methods of using the compounds of formula I provided herein for the treatment of infections with viruses of the family coronaviridae. In some embodiments, the present invention relates to methods of using a compound of formula I provided herein for treating Middle East Respiratory Syndrome (MERS) infection. In some embodiments, the present invention relates to methods of using the compounds of formula I provided herein for the treatment of Severe Acute Respiratory Syndrome (SARS) infection.

In some embodiments, the present invention relates to methods of using the compounds of formula I provided herein for the treatment of filoviridae virus infections. In some embodiments, the present invention relates to methods of using the compounds of formula I provided herein for the treatment of ebola virus infections. In some embodiments, the present invention relates to methods of treating ebola virus infection selected from the group consisting of: zaire (i.e., ebola virus, EBOV), sudan, forest (Tai Forest), bundibugi, and reston. In some embodiments, the present invention relates to a method of treating marburg virus infection with a compound of formula I provided herein.

In some embodiments, the present invention relates to methods of using the compounds of formula I provided herein for the treatment of flaviviridae viral infections. In some embodiments, the present invention relates to methods of using a compound of formula I provided herein for treating zika virus infection.

In some embodiments, the present invention relates to the use of a compound of formula I provided herein for the preparation of a medicament for the treatment of an arenaviridae virus infection. In some embodiments, the present invention relates to the use of a compound of formula I provided herein for the manufacture of a medicament for the treatment of an infection by an arenaviridae species selected from: allpahuayo virus (ALLV), amapari virus (AMAV), bear canyon virus (BCNV), catarina virus, chapare virus, cupiqui virus (CPXV), danton nong virus, flexal virus (FLEV), guanitoryto virus (GTOV), ippyV, jun virus (JUNV), kodoko virus, lassa virus (LASV), latiuer virus (LATV), lymphocytic pleximeningitis virus (LCMV), lujo virus, machupo virus (MACV), mobala virus (MOBV), momooro virus, moia virus (MOPV), oliveros virus (OL), parana virus (PARV), pichimurid virus (PICV), pinhal virus, pirital virus (PIRV), sapbeyia virus (SABV), spibave virus (TCRV), care virus (TCRV), attaAV), and Atara virus (WWAV). In some embodiments, the present invention relates to the use of a compound of formula I provided herein for the preparation of a medicament for the treatment of a lassa virus infection. In some embodiments, the present invention relates to the use of a compound of formula I provided herein for the manufacture of a medicament for the treatment of a junin virus infection.

In some embodiments, the present invention relates to the use of a compound of formula I provided herein for the preparation of a medicament for the treatment of an infection of the coronaviridae family. In some embodiments, the present invention relates to the use of a compound of formula I provided herein for the manufacture of a medicament for the treatment of MERS infections. In some embodiments, the present invention relates to the use of a compound of formula I provided herein for the preparation of a medicament for the treatment of SARS infection.

In some embodiments, the present invention relates to the use of a compound of formula I provided herein for the preparation of a medicament for the treatment of filoviridae virus infections. In some embodiments, the present invention relates to the use of a compound of formula I provided herein for the preparation of a medicament for the treatment of ebola virus infection. In some embodiments, the present invention relates to the use of a compound of formula I provided herein for the manufacture of a medicament for the treatment of an ebola virus infection selected from: zaire (i.e., ebola virus, EBOV), sudan, forest (Tai Forest), bundibugi, and reston. In some embodiments, the present invention relates to the use of a compound of formula I provided herein for the manufacture of a medicament for the treatment of marburg virus infection.

In some embodiments, the present invention relates to the use of a compound of formula I provided herein for the preparation of a medicament for the treatment of a flaviviridae viral infection. In some embodiments, the present invention relates to the use of a compound of formula I provided herein in the manufacture of a medicament for treating zika virus infection.

Xrpd data, vi.

In some embodiments, the crystalline form is characterized by intercrystalline spacing as determined by X-ray powder diffraction pattern (XRPD). The diffraction pattern of an XRPD is typically represented by a graph plotting the intensity of the peak versus the position of the peak, i.e., the diffraction angle in degrees, 2 θ (2- θ). The characteristic peaks of a given XRPD can be selected according to their position and their relative intensity to conveniently distinguish that crystal structure from other crystal structures.

Those skilled in the art recognize that the measurement of XRPD peak position and/or intensity for a given crystalline form of the same compound will vary within a margin of error. The value of 2 theta allows for a suitable error range. Typically, the error range is denoted "±". For example, a ° 2 θ of about "8.7 ± 0.3" represents a range of about 8.7 ± 0.3 (i.e., about 9.0) to about 8.7-0.3 (i.e., about 8.4). Depending on the sample preparation technique, calibration techniques applied to the instrument, human handling variations, etc., one skilled in the art recognizes that a suitable error range for XRPD may be ± 0.5; plus or minus 0.4; plus or minus 0.3; plus or minus 0.2; plus or minus 0.1; plus or minus 0.05; or smaller. In some embodiments of the invention, the XRPD error range is ± 0.2. In some embodiments of the invention, the XRPD error range is ± 0.5.

Additional details of the methods and apparatus for XRPD analysis are described in the examples section.

The XRPD peaks of crystalline form I of formula I are shown in table 1A below.

TABLE 1A XRPD peaks for crystalline form I of formula I

The XRPD peaks of crystalline form I, form II are shown in table 1B below.

TABLE 1B XRPD peaks of crystalline form I form II

The calculated powder pattern peaks for crystalline form I form III are shown in table 1C below.

TABLE 1C calculated powder pattern peaks for crystalline form I form III

The XRPD peaks of crystalline form I, form IV are shown in table 1D below.

TABLE 1D XRPD peaks for crystalline form I IV

The XRPD peaks of a mixture of form II and form IV of formula I (mixture I) prepared by a process comprising combining formula I with a solvent wherein the solvent is isopropyl acetate are shown in table 1E below.

TABLE 1E XRPD peaks for a mixture of form II and form IV of formula I (mixture I) prepared by a process comprising combining formula I with a solvent wherein the solvent is isopropyl acetate

The XRPD peaks of the mixture of form II and form IV of formula I (mixture II) prepared by the process comprising combining formula I with a solvent wherein the solvent is isopropyl acetate are in table 1F below.

TABLE 1F XRPD peaks for a mixture of form II and form IV of formula I (mixture II) prepared by a process comprising combining formula I with a solvent wherein the solvent is isopropyl acetate

The XRPD peaks of the mixture of form II and form IV of formula I (mixture III) prepared by a process comprising combining formula I with a solvent at a temperature wherein the solvent is isopropanol and water and the temperature is 20 ℃ are in table 1G below.

TABLE 1G XRPD peaks for a mixture of form II and form IV of formula I (mixture III) prepared by a process comprising combining formula I with a solvent at a temperature wherein the solvent is isopropanol and water and the temperature is 20 ℃

The XRPD peaks of the crystalline maleate form I of formula I are in table 1H below.

TABLE 1H XRPD peaks of crystalline form I maleate salt of formula I

Preparation of crystalline forms

A. Formula I

A method of synthesizing 2-ethylbutyl (S) -2- (((S) - (((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoate (e.g., a compound of formula I) has been previously described in co-pending U.S. patent application No. 14/926,062, and the related co-pending PCT patent application No. US2015/057933 entitled "method for treating filoviridae infections" filed 10, 29. This reference is incorporated herein by reference in its entirety, and particularly with respect to the synthesis of 2-ethylbutyl (S) -2- (((S) - (((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoate.

For example, in one aspect, a method of producing a composition comprising one or more crystalline forms of the compound of formula I is provided, wherein the method comprises combining the compound of formula I with a suitable solvent or a mixture of suitable solvents to produce the composition comprising one or more crystalline forms of the compound of formula I. In another aspect, another method of producing a composition comprising one or more crystalline forms of formula I is provided, wherein the method comprises combining formula I with a suitable solvent or a mixture of suitable solvents.

The selection of a particular solvent or combination of solvents or methods of combining solvents will affect the relative favorability of one crystalline form of formula I over the formation of another crystalline form. Solvents suitable for crystal formation may include, for example, water, isopropyl ether, isopropyl acetate, isopropanol, ethanol, dichloromethane, 2-methyltetrahydrofuran, methyl tert-butyl ether, heptane, acetonitrile, and any mixture thereof.

The presence of impurities can affect the formation of one crystalline form of formula I in a relatively favorable manner with respect to the formation of another crystalline form. In some embodiments, the form is prepared by a process comprising formula I with impurities. In another embodiment, the form is prepared by a process comprising substantially pure formula I.

In another aspect, there is also provided one or more crystalline forms of formula I produced according to any of the methods described herein.

It is understood that the methods described herein for preparing crystalline forms (including any one or more of crystalline forms I through IV and/or mixtures I, II and/or III) can produce quantitative and quality differences compared to methods produced on a laboratory scale for preparing formula I.

Form I of the formula I

In some embodiments, there is provided a method of producing a composition comprising crystalline form I, wherein the method comprises combining formula I with a solvent to produce a composition comprising crystalline form I, wherein the solvent is isopropyl ether.

Crystalline form I of formula I produced by combining formula I with a solvent, wherein the solvent is isopropyl ether, is provided.

Form II of formula I

In some embodiments, there is provided a method of producing a composition comprising crystalline form I form II, wherein the method comprises combining formula I with a solvent to produce the composition comprising crystalline form I form II, wherein the solvent is ethanol and water.

There is provided crystalline form II of formula I produced by combining formula I with a solvent, wherein the solvent is ethanol and water.

In some embodiments, there is provided a method of producing a composition comprising crystalline form I form II, wherein the method comprises combining formula I with a solvent at a temperature to produce the composition comprising crystalline form I form II, wherein the solvent is isopropanol and water, and the temperature is 50 ℃.

There is provided crystalline form II of formula I produced by combining formula I with a solvent at a temperature, wherein the solvent is isopropanol and water, and the temperature is 50 ℃.

In some embodiments, there is provided a process for producing crystalline form I form II by contacting formula I of the present invention with a solvent mixture of isopropanol and water under conditions suitable to produce crystalline form I form II, wherein formula I remains substantially insoluble in the solvent mixture. The formula I used in the process of the invention may be crystalline formula I, for example crystalline form I, crystalline form II, crystalline form III, crystalline form IV, or mixtures thereof, for example mixture I, mixture II or mixture III. In some embodiments, formula I can be crystalline formula I. In some embodiments, formula I may be a mixture of formula I form II and formula I form IV. In some embodiments, formula I can be mixture I, mixture II, or mixture III. In some embodiments, formula I can be mixture II. In some embodiments, form II is prepared substantially free of form IV. In some embodiments, formula I comprises a mixture of form II and form IV, and the solvent mixture comprises isopropanol and water, wherein formula I remains substantially insoluble in the solvent mixture, thereby producing crystalline form II substantially free of crystalline form IV.

The isopropanol and the water may be present in the solvent mixture in any suitable ratio, wherein the volume of water is at least equal to the volume of the isopropanol. Representative ratios of isopropanol to water include 1:1 to about 1:5 (V/V), or 1:1 to about 1:4 (V/V), or 1:1 to about 1:3 (V/V), or 1:1 to about 1:2 (V/V), or about 1.5 to about 1:2 (V/V). Representative ratios of isopropanol to water include at least 1:1 (V/V), and 1.1,1, 1.3,1, 1.4,1, 1.5, 1. Other ratios of isopropanol to water include 2,2, 3,2. In some embodiments, the solvent mixture comprises isopropanol and water in a ratio of 1:1 to about 1:2 (V/V). In some embodiments, the solvent mixture comprises isopropanol and water in a ratio of about 2:3 to about 1:2 (V/V). In some embodiments, the solvent mixture comprises isopropanol and water in a ratio of at least 1:1 (V/V), wherein the water is present in a volume that is not less than the volume of the isopropanol. In some embodiments, the solvent mixture comprises isopropanol and water in a ratio of about 3:4 (V/V). In some embodiments, the solvent mixture comprises isopropanol and water in a ratio of about 3:5 (V/V). In some embodiments, the solvent mixture comprises isopropanol and water in a ratio of about 1:2 (V/V).

The process for preparing crystalline form I, form II may be carried out at any suitable temperature. Representative temperatures for preparing crystalline form I, form II, are about 20 ℃, or 25, 30, 35, 40, 45, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 65, 70, 75, or about 80 ℃. Representative temperature ranges include 20 ℃ to 80 ℃, or 25 ℃ to 70 ℃,30 ℃ to 60 ℃, 40 ℃ to 60 ℃,45 ℃ to 60 ℃, or 45 ℃ to 55 ℃. In some embodiments, the contacting step is performed at a temperature of about 30 ℃ to about 60 ℃. In some embodiments, the contacting step is performed at a temperature of about 45 ℃ to about 60 ℃. In some embodiments, the contacting step is performed at a temperature of about 50 ℃.

In some embodiments, the contacting step is carried out at a temperature of about 30 ℃ to about 60 ℃, wherein the solvent mixture comprises isopropanol and water in a ratio of at least 1:1 (V/V), wherein the water is present in a volume that is not less than the volume of the isopropanol. In some embodiments, the contacting step is conducted at a temperature of about 45 ℃ to about 60 ℃, wherein the solvent mixture comprises isopropanol and water in a ratio of 1:1 to about 1:3 (V/V). In some embodiments, the contacting step is carried out at a temperature of about 45 ℃ to about 60 ℃, wherein the solvent mixture comprises isopropanol and water in a ratio of about 2:3 to about 2:5 (V/V). In some embodiments, the contacting step is carried out at a temperature of about 45 ℃ to about 60 ℃, wherein the solvent mixture comprises isopropanol and water in a ratio of about 3:4 (V/V). In some embodiments, the contacting step is carried out at a temperature of about 45 ℃ to about 60 ℃, wherein the solvent mixture comprises isopropanol and water in a ratio of about 3:5 (V/V). In some embodiments, the contacting step is performed at a temperature of about 50 ℃, wherein the solvent mixture comprises isopropanol and water in a ratio of about 1:2 (V/V).

In some embodiments, the crystalline form II is prepared substantially free of form IV. In some embodiments, mixture II comprises formula I form II and formula I form IV, such that crystalline form II is prepared substantially free of formula I form IV.

In some embodiments, there is provided a method of producing crystalline form II comprising contacting formula I with a solvent mixture, wherein formula I comprises form II and form IV, wherein the solvent mixture comprises isopropanol and water in a ratio of about 3:5 (V/V) and is at a temperature of about 50 ℃, and wherein formula I remains substantially insoluble in the solvent mixture, thereby producing crystalline form II substantially free of crystalline form IV.

In some embodiments, there is provided a method of producing a composition comprising crystalline form I form II, wherein the method comprises combining formula I with a solvent to produce the composition comprising crystalline form I form II, wherein the solvent is 1-propanol.

There is provided crystalline form II of formula I produced by combining formula I with a solvent, wherein the solvent is 1-propanol.

In some embodiments, there is provided a method of producing a composition comprising crystalline form I form II, wherein the method comprises combining formula I with a solvent to produce the composition comprising crystalline form I form II, wherein the solvent is tetrahydrofuran.

There is provided crystalline form II of formula I produced by combining formula I with a solvent, wherein the solvent is tetrahydrofuran.

In some embodiments, a method of producing a composition comprising crystalline form I form II is provided, wherein the method comprises combining formula I with a solvent to produce the composition comprising crystalline form I form II, wherein the solvent is 2-propanol.

There is provided crystalline form II of formula I produced by combining formula I with a solvent, wherein the solvent is 2-propanol.

In some embodiments, there is provided a method of producing a composition comprising crystalline form I form II, wherein the method comprises combining formula I with a solvent to produce the composition comprising crystalline form I form II, wherein the solvent is acetonitrile.

There is provided crystalline form II of formula I produced by combining formula I with a solvent, wherein the solvent is acetonitrile.

In some embodiments, a method of producing a composition comprising crystalline form I form II is provided, wherein the method comprises combining formula I with a solvent to produce the composition comprising crystalline form I form II, wherein the solvent is dichloromethane.

There is provided crystalline form II of formula I produced by combining formula I with a solvent, wherein the solvent is dichloromethane.

In some embodiments, there is provided a method of producing a composition comprising crystalline form I form II, wherein the method comprises combining formula I with a solvent to produce the composition comprising crystalline form I form II, wherein the solvent is ethanol.

There is provided crystalline form II of formula I produced by combining formula I with a solvent, wherein the solvent is ethanol.

In some embodiments, there is provided a method of producing a composition comprising crystalline form I form II, wherein the method comprises combining formula I with a solvent to produce the composition comprising crystalline form I form II, wherein the solvent is methyl tert-butyl ether.

There is provided crystalline form II of formula I produced by combining formula I with a solvent, wherein the solvent is methyl tert-butyl ether.

In some embodiments, there is provided a method of producing a composition comprising crystalline form I form II, wherein the method comprises combining formula I with a solvent to produce the composition comprising crystalline form I form II, wherein the solvent is 2-methyltetrahydrofuran.

There is provided crystalline form II of formula I produced by combining formula I with a solvent, wherein the solvent is 2-methyltetrahydrofuran.

In some embodiments, there is provided a method of producing a composition comprising crystalline form I form II, wherein the method comprises combining formula I with a solvent to produce the composition comprising crystalline form I form II, wherein the solvent is ethyl acetate and water.

There is provided crystalline form II of formula I produced by combining formula I with a solvent, wherein the solvent is ethyl acetate and water.

In some embodiments, there is provided a method of producing a composition comprising crystalline form I form II, wherein the method comprises combining formula I with a solvent to produce the composition comprising crystalline form I form II, wherein the solvent is methyl ethyl ketone.

There is provided crystalline form II of formula I produced by combining formula I with a solvent, wherein the solvent is methyl ethyl ketone.

Form III of formula I

In some embodiments, there is provided a method of producing a composition comprising crystalline form III, wherein the method comprises combining formula I with a solvent to produce the composition comprising crystalline form III, wherein the solvent is dichloromethane.

Provided is crystalline form III produced by combining formula I with a solvent, wherein the solvent is dichloromethane.

Form IV of formula I

In some embodiments, a method of producing a composition comprising crystalline form I IV is provided, wherein the method comprises combining formula I with a solvent to produce the composition comprising crystalline form I IV, wherein the solvent is 2-methyltetrahydrofuran and methyl tert-butyl ether.

There is provided crystalline form IV of formula I produced by combining formula I with a solvent, wherein the solvent is 2-methyltetrahydrofuran and methyl tert-butyl ether.

In some embodiments, a method of producing a composition comprising crystalline form I IV is provided, wherein the method comprises combining formula I with a solvent to produce the composition comprising crystalline form I IV, wherein the solvent is 2-methyltetrahydrofuran and heptane.

There is provided crystalline form IV of formula I produced by combining formula I with a solvent, wherein the solvent is 2-methyltetrahydrofuran and heptane.

B. Mixtures of forms of formula I

In some embodiments, the invention relates to a mixture of (S) -2- (((S) - ((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester form II and (S) -2- (((S) - ((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethyl form IV.

In some embodiments, the present invention relates to a mixture of crystalline forms of (S) -2- (((S) - ((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester prepared by a process comprising combining formula I with a solvent, wherein the solvent is selected from isopropyl acetate and a mixture of isopropyl alcohol and water. In some embodiments, the invention relates to a mixture of (S) -2- (((S) - ((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester form II and (S) -2- (((S) - ((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester form IV prepared by a process comprising combining formula I with a solvent, wherein the solvent is isopropyl acetate and isopropyl acetate. In some embodiments, the present invention relates to a mixture of (S) -2- (((S) - ((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester form II and (S) -2- (((S) - ((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester form IV prepared by a process comprising combining formula I with a solvent, wherein the solvent is isopropyl acetate. In some embodiments, the present invention relates to 2-ethylbutyl (S) -2- (((S) - ((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoate form II and (S) -2- (((S) - ((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoate form IV prepared by a process comprising combining formula I with a solvent, wherein the solvent is a mixture of isopropyl alcohol and water.

Mixtures of form ii and form iv of formula I may be prepared by using a variety of solvents or mixtures thereof. Representative solvents include, but are not limited to, water, isopropanol (IPA), isopropyl acetate (IPAc), tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), methyl tert-butyl ether (MTBE), and combinations thereof. Mixtures of form II and form IV can result in form II and form IV being present in different amounts. Representative mixtures of form II and form IV include mixture I, mixture II and mixture III, and the like.

In some embodiments, there is provided a process for producing a mixture of form ii and form iv, wherein the process comprises combining formula i with a solvent, wherein the solvent is isopropyl acetate.

Provided is a mixture of form II and form IV produced by combining formula I with a solvent, wherein the solvent is isopropyl acetate. Provided are mixtures of form II and form IV produced by combining formula I with a solvent, wherein the solvent is a mixture of isopropanol and water. There is provided a mixture of form II and form IV produced by combining formula I with a solvent, wherein the solvent is a mixture of 2-methyltetrahydrofuran and methyl-tert-butyl ether.

When the solvent comprises a solvent mixture, the solvent mixture may comprise a solvent suitable for dissolving the starting materials and an anti-solvent substantially incapable of dissolving the starting materials. The solvent and antisolvent may be present in any suitable ratio. Representative ratios of solvent and anti-solvent include 10 to 1, or 5:1 to 1,1 to 4,3 to 1:3, or 2:1 to 1:2 (V/V). The ratio of solvent to anti-solvent can also be varied during crystallization, for example the starting ratio of solvent to anti-solvent is 10. In some embodiments, the initial ratio of solvent to anti-solvent may be about 3:1 (V/V) and the final ratio of solvent to anti-solvent may be about 1:2 (V/V). In some embodiments, the initial ratio of isopropanol to water may be about 3:1 (V/V) and the final ratio may be about 1:2 (V/V). In some embodiments, the initial ratio of solvent to anti-solvent may be about 8:1 (V/V) and the final ratio of solvent to anti-solvent may be about 1:2 (V/V). In some embodiments, the initial ratio of 2-methyltetrahydrofuran (MeTHF) to methyl tert-butyl ether (MTBE) may be about 8:1 (V/V), and the final ratio may be about 1:2 (V/V).

Mixture I

In some embodiments, a process for producing mixture I is provided, wherein the process comprises combining formula I with a solvent, wherein the solvent is isopropyl acetate.

Provided is a mixture I produced by combining formula I with a solvent, wherein the solvent is isopropyl acetate.

Mixture II

In some embodiments, a method of producing mixture II is provided, wherein the method comprises combining formula I with a solvent, wherein the solvent is isopropyl acetate.

Provided is mixture II produced by combining formula I with a solvent, wherein the solvent is isopropyl acetate.

Mixture III

In some embodiments, a method of producing mixture III is provided, wherein the method comprises combining formula I with a solvent at a temperature, wherein the solvent is isopropanol and water, and the temperature is about 20 ℃.

Provided is a mixture III produced by combining formula I with a solvent at a temperature, wherein the solvent is isopropanol and water, and the temperature is about 20 ℃.

C. Maleic acid salt of formula I

In some embodiments, there is provided a method of producing a composition comprising crystalline maleate form I of formula I, wherein the method comprises combining formula I with maleic acid in a solvent to produce a composition comprising crystalline maleate form I of formula I, wherein the solvent is methanol and isopropyl acetate.

Provided is maleate salt form I of formula I produced by combining formula I with maleic acid in a solvent to produce a composition comprising crystalline maleate salt of formula I, wherein the solvent is methanol and isopropyl acetate.

Use of pharmaceutical products

Also provided is the use of the crystalline forms described herein in the manufacture of a pharmaceutical product. One or more compounds of formula I described herein may be used as intermediates in manufacturing processes to produce pharmaceutical products.

In some embodiments, the compounds of formula I are used in the manufacture of an active pharmaceutical ingredient. In some embodiments, form I of formula I is used in the manufacture of an active pharmaceutical ingredient. In some embodiments, formula I form II is used in the manufacture of an active pharmaceutical ingredient. In some embodiments, form III of formula I is used in the manufacture of an active pharmaceutical ingredient. In some embodiments, form IV of formula I is used in the manufacture of an active pharmaceutical ingredient. In some embodiments, the mixture of forms of formula I is used in the manufacture of an active pharmaceutical ingredient. In some embodiments, a mixture of formula I form II and formula I form IV is used to manufacture the active pharmaceutical ingredient. In some embodiments, mixture I is used in the manufacture of an active pharmaceutical ingredient. In some embodiments, mixture II is used to manufacture an active pharmaceutical ingredient. In some embodiments, mixture III is used to produce an active pharmaceutical ingredient. In some embodiments, the maleate form I of formula I is used in the manufacture of an active pharmaceutical ingredient.

IX. articles and kits

Compositions comprising one or more compounds of formula I as described herein and formulated in one or more pharmaceutically acceptable excipients or other ingredients may be prepared, placed in a suitable container, and labeled for treatment of a designated condition. Thus, an article of manufacture is also contemplated, such as a container containing one or more compounds of formula I as described herein in dosage form and a label containing instructions for use of the compound.

In some embodiments, the article of manufacture is a container containing one or more compounds of formula I described herein in dosage form, and one or more pharmaceutically acceptable excipients or other ingredients. In some embodiments of the articles described herein, the dosage form is a solution.

Kits are also contemplated. For example, a kit may comprise a dosage form of a pharmaceutical composition and a package insert comprising instructions for use of the composition in treating a medical condition. In another embodiment, a kit may comprise a plurality of separate dosage forms, each dosage form comprising a therapeutically effective amount of a compound as described herein, together with instructions for administering them to a human in need thereof. Each individual dosage form may comprise a therapeutically effective amount of a compound as described herein in combination with at least one pharmaceutically effective excipient. The individual dosage forms may be in the form of, for example, solutions, tablets, pills, capsules, sachets, sublingual medication, lyophilized powder, spray-dried powder or liquid compositions for oral, parenteral or topical administration. The instructions used in the kit may be for treating an arenaviridae virus infection, a coronaviridae virus infection, a filoviridae virus infection, a flaviviridae virus infection, or a paramyxoviridae virus infection, including each of the species described herein. In some embodiments, the instructions used in the kit can be for use in treating a lassa virus infection in a human. In some embodiments, the instructions for use in the kit can be for treating a huinin virus infection in a human. In some embodiments, the instructions used in the kit can be for use in treating a SARS virus infection in a human. In some embodiments, the instructions used in the kit can be for treating MERS virus infection in a human. In some embodiments, the instructions used in the kit can be for treating an ebola virus infection in a human. In some embodiments, the instructions for use in the kit can be instructions for treating a zika virus infection in a human. In some embodiments, the instructions for use in the kit can be for treating RSV infection in a human. The instructions may be directed to any of the viral infections and methods described herein. The instructions may be for preventing or treating an existing viral infection.

In some embodiments, the crystalline or salt forms described herein may potentially exhibit improved properties. For example, in some embodiments, the crystalline or salt forms described herein may potentially exhibit improved stability. Such improved stability may have potentially beneficial effects on the preparation of compounds of formula I, such as the ability to provide long term storage of process intermediates. Improved stability may also be beneficial in compositions or pharmaceutical compositions of compounds of formula I. In some embodiments, the crystals or salts described herein may also potentially lead to increased yields of the compound of formula I, or may lead to improved quality of the compound of formula I. In some embodiments, the crystalline, salt, and solvate forms described herein may also exhibit improved pharmacokinetic properties and/or potentially improved bioavailability.

X. Process

Example 1 form I of formula I

Formula I (56.2 mg) was added to a glass vial. Isopropyl ether (about 0.5 mL) was added, the vial was capped, and the suspension was stirred at about 21 ℃ for about 4 days. Form I of formula I in solid form was isolated from the suspension by centrifugation/filtration and characterized as described below.

Example 2 form II of formula I

Formula I (0.03 to 0.07 g) was added to the reaction vessel and about 0.1 to 0.4g of ethanol and water mixture was added thereto, the water activity ranged from 0.2 to 0.8. The vessel was sealed and stirred at room temperature for about two weeks. Form II of formula I was isolated and characterized as described below.

In another method, formula I (3.7 g) is added to a reaction vessel. Isopropanol (about 11 mL) and water (about 4 mL) were added and the suspension was heated to about 50 ℃ until dissolution was achieved. Water (about 2 mL) was added over about 1 hour at about 50 ℃ followed by about 37 mg of formula I form II seed crystals. Water (about 6 mL) was added at about 50 ℃ over about 2.5 hours and the suspension was stirred at about 50 ℃ for about 1.5 hours. Water (about 11 mL) was added over about 6 hours and the suspension was stirred at about 50 ℃ for about 9 hours. The suspension was cooled to about 20 ℃ over about 6 hours and the suspension was stirred at about 20 ℃ for about 17 hours. Form II of formula I in solid form was isolated from the suspension by filtration and characterized as described below.

In another method, crystalline formula I (7.0 g) is added to a reaction vessel. Isopropanol (about 21 mL) and water (about 35 mL) were added and the suspension was heated to about 50 ℃. The suspension was stirred at about 50 ℃ for about 18 hours, then cooled to about 20 ℃ over about 3 hours and stirred at about 20 ℃ for about 3 hours. Form II of formula I in solid form was isolated from the suspension by filtration and characterized as described below.

Example 3 form III of formula I

Formula I (41.2 mg) was dissolved in a flask with dichloromethane (97.9 mg) at about 21 ℃. The flask was capped for several days. Form III of formula I was observed.

Example 4 form IV of formula I

MeTHF/MTBE

A crude solution of formula I (8.0 g) in 2-methyltetrahydrofuran (32 mL) was stirred in a reaction vessel at about 20 deg.C and methyl tert-butyl ether (4 mL) was added over about 1 hour. Seeds containing a mixture of form II and form IV were added and the suspension was stirred at about 20 ℃. Methyl tert-butyl ether (64 mL) was added over a period of about 5 days at about 20 deg.C, and the suspension was stirred for 2 days at about 20 deg.C. Form IV of formula I in solid form is isolated from the suspension by filtration and dried.

MeTHF/MTBE

(3aR, 4R,6R, 6aR) -4- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6- (hydroxymethyl) -2,2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxole-4-carbonitrile (10 g, 30mmol), ((S) - (4-nitrophenoxy) (phenoxy) phosphoryl) -L-alanine 2-ethylbutyl ester (14g, 32mmol) and magnesium chloride (4.4g, 46mmol) were added to the reaction vessel. At about 25 deg.C, tetrahydrofuran (about 100 mL) was added followed by N, N-diisopropylethylamine (13 mL, 76mmol). After about 3h, the reaction mixture was added to a pre-cooled (about 10 ℃ C.) mixture of methyl tert-butyl ether (about 100 mL) and aqueous citric acid (10 wt%, about 100 mL). The organic and aqueous layers were separated and the organic layer was washed with aqueous potassium carbonate (10 wt%, about 150 mL), aqueous potassium carbonate (10 wt%, twice about 100 mL), aqueous ammonium chloride (10 wt%, about 100 mL) and aqueous sodium chloride (15 wt%, about 100 mL). The solvent of the organic layer was exchanged for acetonitrile and the volume was adjusted to about 100mL. The acetonitrile solution was cooled to about 0 ℃ and concentrated hydrochloric acid (about 20 mL) was added. After about 3h, the reaction mixture was added to a pre-cooled (about 10 ℃) mixture of 2-methyltetrahydrofuran (about 100 mL) and aqueous potassium bicarbonate (20 wt%, about 100 mL) and was washed forward with 2-methyltetrahydrofuran (about 50 mL). The organic and aqueous layers were separated and the organic layer was washed with aqueous potassium bicarbonate (20 wt%, about 40 mL) and aqueous sodium chloride (15 wt%, about 100 mL). The organic layer was concentrated to about 50mL and 2-methyltetrahydrofuran (about 50 mL) was added. The organic layer was then washed with aqueous sodium chloride (15 wt%, ca. 50 mL). The organic layer was concentrated and distilled from 2-methyltetrahydrofuran until the solution reached a target water content of no more than 0.2%. The 2-methyltetrahydrofuran solution (about 200 mL) was polish filtered, and then a portion (about one third) of the 2-methyltetrahydrofuran solution was concentrated to about 23mL. Form I IV seed crystals (about 40 mg) were added at about 20 deg.C and methyl tert-butyl ether (about 43 mL) was added over about 8 h. The suspension was stirred at about 20 ℃ for about one week. Form IV of formula I in solid form was isolated from the suspension by filtration and characterized as described below.

MeTHF/heptane

In another method, (3aR, 4R,6R, 6aR) -4- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6- (hydroxymethyl) -2,2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxole-4-carbonitrile (3.0g, 9.0mmol), ((S) - (4-nitrophenoxy) (phenoxy) phosphoryl) -L-alanine 2-ethylbutyl ester (4.3g, 9.5mmol) and magnesium chloride (1.3 g, 14 mmol) were added to a reaction vessel. Tetrahydrofuran (about 30 mL) was added at about 25 ℃ followed by N, N-diisopropylethylamine (3.9 mL, 23mmo). After about 16h, the reaction mixture was added to a pre-cooled (about 3 ℃) mixture of 2-methyltetrahydrofuran (about 30 mL) and aqueous citric acid (10 wt%, about 30 mL). The organic layer and the aqueous layer were separated, and the organic layer was washed with an aqueous potassium carbonate solution (10 wt%, about 45 mL), an aqueous potassium carbonate solution (10 wt%, twice about 30 mL) and an aqueous ammonium chloride solution (10 wt%, about 30 mL). The solvent of the organic layer was exchanged for acetonitrile and the volume was adjusted to about 32mL. The acetonitrile solution was cooled to about 0 ℃ and concentrated hydrochloric acid (about 6 mL) was added. After about 2h, the reaction mixture was added to a pre-cooled (about 12 ℃ C.) mixture of 2-methyltetrahydrofuran (about 30 mL) and aqueous potassium bicarbonate (20 wt%, about 30 mL). The organic and aqueous layers were separated and the organic layer was washed with aqueous potassium bicarbonate (20 wt%, about 12 mL) and aqueous sodium chloride (15 wt%, about 30 mL). The organic layer was concentrated to about 12mL and 2-methyltetrahydrofuran (about 15 mL) was added. The organic layer was then washed with aqueous sodium chloride (15 wt%, ca. 15 mL). The organic layer was concentrated and distilled from 2-methyltetrahydrofuran until the solution reached a target water content of no more than 0.2%. The 2-methyltetrahydrofuran solution (about 60 mL) was polish filtered, then concentrated to about 24mL and the solution was stirred at about 20 ℃. Seed crystals (about 30 mg) containing a mixture of form II and form IV were added and heptane (about 18 mL) was slowly added to the suspension. The suspension was stirred at about 21 ℃ for about 1 day, then after about 2 weeks, form IV of formula I was isolated as a solid from the suspension by filtration and characterized as described below.

Example 5 mixture of mixture I, form II and form IV

(3aR, 4R,6R, 6aR) -4- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6- (hydroxymethyl) -2,2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxole-4-carbonitrile (20 g, 60mmol), ((S) - (4-nitrophenoxy) (phenoxy) phosphoryl) -L-alanine 2-ethylbutyl ester (32g, 72mmol), and magnesium chloride (8.6g, 90mmol) were added to the reaction vessel. At about 20 deg.C, tetrahydrofuran (about 200 mL) was added followed by N, N-diisopropylethylamine (26 mL, 151mmol). After about 3h, the reaction mixture was added to a pre-cooled (about 15 ℃) mixture of 2-methyltetrahydrofuran and aqueous citric acid (10 wt%). The organic and aqueous layers were separated and the organic layer was washed with aqueous potassium carbonate (10 wt%, about 300 mL), aqueous potassium carbonate (10 wt%, twice about 200 mL), aqueous ammonium chloride (10 wt%,200 mL) and aqueous sodium chloride (15 wt%, about 200 mL). The solvent of the organic layer was exchanged for acetonitrile and the volume was adjusted to about 200mL. The acetonitrile solution was cooled to about 0 ℃ and concentrated hydrochloric acid (about 40 mL) was added. After about 3h, the reaction mixture was cooled to about-10 ℃ and added to a pre-cooled (about 10 ℃) mixture of 2-methyltetrahydrofuran (about 200 mL) and aqueous potassium bicarbonate (20 wt%, about 200 mL). The organic and aqueous layers were separated and the organic layer was washed with aqueous potassium bicarbonate (20 wt%, about 100 mL) and aqueous sodium chloride (15 wt%, about 200 mL). The organic layer was concentrated to about 140mL and washed with aqueous sodium chloride (15 wt%, about 100 mL). The organic layer was concentrated and distilled from 2-methyltetrahydrofuran until the solution reached a target water content of no more than 0.2%. The 2-methyltetrahydrofuran solution (about 400 mL) was polish filtered and the solvent exchanged for isopropyl acetate. The isopropyl acetate solution (about 100 mL) was stirred at about 21 ℃. Seed crystals (about 40 mg) containing a mixture of form II and form IV were added and the suspension was stirred at about 21 ℃ for about 3 days. The crystalline form I containing a mixture of form II and form IV in solid form is isolated from the suspension by filtration and characterized as described below.

Example 6 mixture II, form II and form IV

(3aR, 4R,6R, 6aR) -4- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6- (hydroxymethyl) -2,2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxole-4-carbonitrile (20 g, 60mmol), ((S) - (4-nitrophenoxy) (phenoxy) phosphoryl) -L-alanine 2-ethylbutyl ester (29g, 63mmol) and magnesium chloride (8.6g, 90mmol) were added to the reaction vessel. At about 20 deg.C, tetrahydrofuran (about 200 mL) was added followed by N, N-diisopropylethylamine (26 mL, 151mmol). After about 4h, the reaction mixture was added to a pre-cooled (about 10 ℃) mixture of methyl tert-butyl ether (about 200 mL) and aqueous citric acid (10 wt%, about 200 mL). The organic and aqueous layers were separated and the organic layer was washed with aqueous potassium carbonate (10 wt%, about 300 mL), aqueous potassium carbonate (10 wt%, twice about 200 mL), aqueous ammonium chloride (10 wt%,200 mL) and aqueous sodium chloride (15 wt%, about 200 mL). The solvent of the organic layer was exchanged for acetonitrile and the volume was adjusted to about 200mL. The acetonitrile solution was cooled to about 0 ℃ and concentrated hydrochloric acid (about 40 mL) was added. After about 3h, the reaction mixture was cooled to about-10 ℃ and added to a pre-cooled (about 10 ℃) mixture of 2-methyltetrahydrofuran (about 200 mL) and aqueous potassium bicarbonate (20 wt%, about 200 mL). The organic and aqueous layers were separated and the organic layer was washed with aqueous potassium bicarbonate (20 wt%, about 80 mL) and aqueous sodium chloride (15 wt%, about 200 mL). The organic layer was concentrated to about 100mL and washed with aqueous sodium chloride (15 wt%, about 100 mL). The organic layer was concentrated and distilled from 2-methyltetrahydrofuran until the solution reached a target water content of no more than 0.2%. The 2-methyltetrahydrofuran solution (about 400 mL) was polish filtered and the solvent exchanged for isopropyl acetate. The isopropyl acetate solution (about 100 mL) was stirred at about 20 ℃. Seed crystals (about 40 mg) containing a mixture of form II and form IV were added and the suspension was stirred at about 20 ℃ for about 3 days. The crystalline form I containing a mixture of form II and form IV in solid form is isolated from the suspension by filtration and characterized as described below.

Example 7 mixture of mixture III, form II and form IV

Formula I (14.0 g) was added to the reaction vessel. Isopropanol (42 mL) and water (14 mL) were added and the suspension was heated to about 50 ℃ until dissolution was achieved. The solution was cooled to about 20 ℃ and about 14mg of seed crystals containing a mixture of form II and form IV were added. Water (70 mL) was added at about 20 ℃ over about 3 hours, and the suspension was stirred at about 20 ℃ for about 17 hours. The crystalline form I containing a mixture of form II and form IV in solid form is isolated from the suspension by filtration and characterized as described below.

Example 8 maleate form I of formula I

0.58g (2S, 3R,4R, 5R) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3,4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-carbonitrile was dissolved in 5mL isopropyl acetate (IPAc) using a stir bar in a 20mL vial. In a second vial 4mL IPAc and 0.25mL ethanol were added to 150mg maleic acid and the maleic acid was dissolved. The contents of the second vial were added to a 20mL vial with stirring. After stirring for about 1 hour, the suspension was filtered, and the filtrate was washed with 2.5mL of IPAc and air dried to isolate (2S, 3R,4R, 5R) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3,4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-carbonitrile maleate.

The mixture of the form of formula I (3.31 g) and isopropyl acetate (about 20 mL) was added to the first reaction vessel, capped and magnetically stirred at high speed. Maleic acid (0.72 g) was added to the second reaction vessel. To the second reaction vessel was added isopropyl acetate (about 20 mL). Methanol (about 5 mL) was added to the second reaction vessel. Methanol (about 5 mL) was added to the first reaction vessel. The contents of the second reaction vessel are added to the first reaction vessel. The first reaction vessel was stirred at about 21 ℃ for about 5 minutes and then seeded with (2S, 3R,4R, 5R) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3,4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-carbonitrile maleate. The first reaction vessel was capped and stirred at about 21 ℃ for about 18 hours. The maleate salt form I of formula I in solid form was isolated from the suspension by centrifugation/filtration and characterized as described below.

Characterization of the crystalline form

The crystalline forms of the present invention are characterized by various analytical techniques including X-ray powder diffraction (XRPD), differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA) and dynamic gas phase adsorption (DVS) using the procedures described below.

X-ray powder diffraction: copper radiation (Cu K alpha,) XRPD analysis was performed on a diffractometer (panalytical XPERT-PRO, panalytical b.v., almelo, the netherlands). By depositing a powdered sampleThe samples for analysis were prepared in the center of a steel holder equipped with a zero background plate. The generator was operated at a voltage of 45kV and a current of 40 mA. The slit used was Soller 0.02rad, anti-scatter 1.0 ° and divergence. The sample rotation speed was 2 revolutions per second. The scan was performed from 2 to 40 deg. 2 theta in 5 minutes with a step size of 0.008 deg. 2 theta. Data analysis was performed by X 'Pert Date Viewer version 2.2c (PANALYTIC B.V., almelo, netherlands) and X' Pert Data Viewer version 1.2d (PANALYTIC B.V., almelo, netherlands).

The XRPD pattern of form I of formula I is shown in figure 1.

The XRPD pattern of form II of formula I is shown in figure 5.

The calculated XRPD pattern of form III of formula I shown in figure 9 was calculated by using Mercury 3.1Development (Build RC 5). The single crystal data for form III of formula I was entered into Mercury 3.1 to calculate the XRPD pattern for form III of formula I.

The XRPD pattern of form IV of formula I is shown in figure 10.

The XRPD pattern of compound I of formula I is shown in figure 13.

The XRPD pattern of compound II of formula I is shown in figure 16.

The XRPD pattern of compound III of formula I is shown in figure 19.

The XRPD pattern of maleate form I of formula I is shown in figure 22.

The XRPD pattern of form IV of formula I is shown in figure 26.

Differential scanning calorimetry: thermal performance was evaluated using a Differential Scanning Calorimetry (DSC) instrument (TA Q1000, TA Instruments, new Castle, DE, USA). For each experiment, approximately 1 to 10mg of solid sample was placed in a standard aluminum pan with a pinhole and heated at a rate of 5 to 10 ℃ per minute under a 50 mL/min nitrogen purge. Data Analysis was performed using a Universal Analysis 2000.7A edition (TA Instruments, new Castle, DE, USA).

The DSC of form I of formula I is shown in figure 2.

The DSC of form II of formula I is shown in figure 6.

A DSC of form IV of formula I is shown in figure 11.

The DSC of compound I of formula I is shown in figure 14.

The DSC of compound II of formula I is shown in figure 17.

The DSC of compound III of formula I is shown in figure 20.

DSC of maleate form I of formula I is shown in figure 23.

Thermogravimetric analysis: thermogravimetric analysis (TGA) was performed on a TGA instrument (TA Q500, TA Instruments, new Castle, DE, USA). For each experiment, approximately 1 to 10mg of the solid sample was placed in an open aluminum pan and heated at a rate of 5 to 10 ℃/min under a nitrogen purge of 60 mL/min. Data Analysis was performed using a Universal Analysis 2000.7A edition (TA Instruments, new Castle, DE, USA).

TGA of form I of formula I is shown in figure 3.

The TGA of form I, form II is shown in figure 7.

The TGA of form I, form IV is shown in figure 12.

TGA of formula I mixture I is shown in figure 15.

TGA of formula I mixture II is shown in figure 18.

TGA of formula I mixture III is shown in figure 21.

TGA of maleate form I of formula I is shown in figure 24.

Dynamic gas phase adsorption: hygroscopicity was assessed at room temperature using a dynamic gas phase sorption (DVS) instrument (TGA Q5000 TA Instruments, new Castle, DE). At 25 ℃, the adsorption and desorption of water was studied as a function of the range of Relative Humidity (RH) from 0 to 90%. The relative humidity within the chamber was increased by 10% rh and held until the solids and atmosphere reached equilibrium. The equilibration test was continued until either 5 or 10 hours had passed and expired. At this point, the RH was increased by 10%, and the process was repeated until 90% RH was reached and equilibrium was reached. During this time, the water absorption was monitored. For desorption, the relative humidity was reduced in a similar manner to measure the entire adsorption/desorption cycle. The cycle is optionally repeated. All experiments were run in dm/dt mode (mass over time) to determine the equilibrium end point. About 5-10mg of solid was used. Data Analysis was performed using a Universal Analysis 2000.7A edition (TA Instruments, new Castle, DE, USA).

The DVS of form I of formula I is shown in figure 4.

The DVS of form II of formula I is shown in figure 8.

DVS of maleate form I of formula I is shown in figure 25.

In the presence of Mo K _α Single crystal X-ray diffraction studies were performed on a Bruker APEX II Ultra diffractometer on radiation (e.g. Wavelength). The crystals of the subject compound were cut into sections of 0.22x0.18x0.04mm and fixed on Cryoloop with a Paratone-N oil. Data were collected under nitrogen flow at specific temperatures (e.g., 100 (2) K or 200 (2) K) as shown in the table below. The total number of reflections covering the index is collected (e.g., -9)<＝h<＝10，-13<＝k<＝16， -37<＝l<= 36). Some of the reflections were found to be symmetrically independent, with R _int The value is obtained. Graduation and unit cell refinement indicate crystal systems (e.g., monoclinic, triclinic, or orthorhombic). Spatial clusters (e.g., P1, P2 (1), C2, and P21212) uniquely defined by a systematic deficiency in the data are found. Data were integrated using the Bruker SAINT software program and measurements were performed using the SADABS software program. Solving by a direct method (SHELXT) yields a complete phase model that is compatible with the proposed architecture.

All non-hydrogen atoms (SHELXL-2014) were anisotropically refined by the full matrix least squares method. All hydrogen atoms were placed using a riding model. Their position is restricted relative to their parent atom using the appropriate HFIX command in SHELXL-2014. The crystallographic data are summarized in the table below. The absolute stereochemistry was set to correspond to a sample of the same compound previously studied.

Single crystal X-ray crystallographic data for form II of formula I are summarized in table 2A below.

TABLE 2A Single Crystal data for form II of formula I

Single crystal X-ray crystallographic data for form III of formula I are summarized in table 2B below.

TABLE 2B Single Crystal data for form III of formula I

The purity profiles of the various forms of formula I are summarized in table 3 below,

TABLE 3 purity profile

¹ Prepared at 20 ℃ using iPAc. ² Prepared from entry 2 by: dissolved in IPA/water (3V/V) at 50 ℃, then water (5V) was added and the final solvent mixture was IPA/water (3. ³ Prepared from entry 1 in IPA/water (1.

Wherein impurity A is (2R, 3R,4S, 5R) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile:

in some embodiments of the invention, formula I is hydrated. In some embodiments, the ratio of formula I to water molecules is 1:1.

Solid state NMR: solid State NMR (SSNMR) experiments were performed on a Bruker Avance I spectrometer (Bruker, billerica, mass.), ¹³ c is operated at 100.51MHz, ¹ the operation of H is at 399.66 MHz. Data were acquired using a chemagetics (Ft. Collins, CO) Apex probe modified with a 7mm magic angle rotation (MAS) system (withdrawal NMR, ft. Collins, CO). Each sample was loaded into a 7mm zirconia rotor. All experiments were obtained using cross-polarization and magic angle spinning (CP/MAS). The magic angle spinning speed is typically 5kHz. Chemical shifts were recorded relative to TMS by secondary reference of the methyl peak of 3-methylglutaric acid at 18.84ppm with an accuracy of ± 0.2ppm. The rotating sidebands are eliminated using total sideband suppression (TOSS). Saturation recovery for measurement ¹ H T ₁ The relaxation time.

Data collection was performed at a nominal temperature of 8.5 ℃. Acquisition parameters included a cross-polarization time of 1.5ms, an acquisition time of-50 ms, and about 2 times that of ¹ H T ₁ (3.2 seconds). Using-64 kHz during acquisition ¹ H is decoupled. Data in Bruker TopspinAnd processing in a software package. The free induction decay is subjected to fourier transform, phasing and baseline correction.

Solid state NMR of form II of formula I is shown in figure 27.

Solid state NMR of mixtures of form II and form IV of formula I (top), mixture III (middle), and mixture I (bottom) are shown in fig. 28.

Solid state NMR of mixture III (top), mixture of form I, form II and form IV (middle), and mixture II (bottom) is shown in fig. 29.

Competition experiment

Several experiments were performed which demonstrated that form I, form II, is a more stable form.

Formula I was mixed with the corresponding solvent and mixed at room temperature by a stirrer without a stir bar.

XRPD of the isolated solid was obtained after two weeks.

Competition experiments between form I of formula I and form II of formula I were performed by mixing form I of formula I with isopropyl acetate and then adding mixture II (a mixture of form II of formula I and form IV of formula I).

Competition experiments between form II of formula I and form IV of formula I were performed by combining mixture II of formula I with IPA/water (3/6V/V) at 50 ℃ for several days. All experiments showed conversion to form II of formula I.

Each reference, including all patents, patent applications, and publications cited in this application, is hereby incorporated by reference in its entirety as if each were individually incorporated. Furthermore, it will be appreciated that certain changes or modifications may be made by those skilled in the art in light of the above teachings of the invention, and that such equivalents will be within the scope of the invention as defined in the following claims. Each reference, including all patents, patent applications, and publications cited in this application, is hereby incorporated by reference in its entirety as if each were individually incorporated. Furthermore, it will be appreciated that certain changes or modifications may be made by those skilled in the art in light of the above teachings of the invention, and that such equivalents will still be within the scope of the invention as defined by the appended claims.

Claims

1. A crystalline form of (S) -2- (((S) - (((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester, wherein said crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 22.3 °,16.9 ° and 16.2 ° 2- Θ ± 0.2 ° 2- Θ.

2. The crystalline form of claim 1, wherein the X-ray powder diffraction (XRPD) pattern has additional peaks at 13.8 ° and 12.7 ° 2-theta ± 0.2 ° 2-theta.

3. The crystalline form of claim 1, wherein the X-ray powder diffraction (XRPD) pattern has additional peaks at 22.5 °,10.6 ° and 14.5 ° 2-theta ± 0.2 ° 2-theta.

4. The crystalline form of claim 1, wherein the X-ray powder diffraction (XRPD) pattern has peaks at 22.3 °,16.9 °,16.2 °,13.8 °,12.7 °,22.5 °,10.6 °, and 14.5 ° 2-theta ± 0.2 ° 2-theta.

5. The crystalline form of claim 1, characterized by a unit cell of the following dimensions as determined by single crystal X-ray crystallography:α =90 °; β =100.105 (7) °; and γ =90 °.

6. The crystalline form of claim 1, characterized by a Differential Scanning Calorimetry (DSC) thermogram peak at 138 ℃.

7. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 6 and a pharmaceutically acceptable excipient.

8. Use of a therapeutically effective amount of the crystalline form of any one of claims 1 to 6 in the manufacture of a medicament for treating a viral infection in a human, wherein the viral infection is caused by a virus selected from the group consisting of: arenaviridae, coronaviridae, filoviridae, flaviviridae and paramyxoviridae.

9. A method of preparing a crystalline form of (S) -2- (((S) - ((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester (formula I) of any of claims 1 to 6, comprising

Contacting said formula I with a solvent mixture comprising isopropanol and water, wherein said formula I remains substantially insoluble in said solvent mixture under conditions suitable to produce a crystalline form.

10. A composition comprising a crystalline form of (S) -2- (((S) - (((2r, 3s,4r, 5r) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester of any of claims 1 to 6 having a purity of at least 99.1%.

11. The composition of claim 10, wherein the composition comprises less than 0.05% (w/w) of impurity a having the structural formula:

12. the use of claim 8, wherein the viral infection is selected from the group consisting of Middle East Respiratory Syndrome (MERS) infection and Severe Acute Respiratory Syndrome (SARS) infection.

13. The use of claim 8, wherein the viral infection is an Ebola virus infection or a Marburg virus infection.

14. The use of claim 8, wherein the viral infection is a Zika virus infection.

15. The use of claim 8, wherein the medicament comprises one or more additional therapeutic agents.

16. The method of claim 9, wherein the crystalline form is prepared substantially free of form IV characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 22.6 °,19.9 °, and 14.1 ° 2-theta ± 0.2 ° 2-theta.

17. The method of claim 9 or 16, wherein the solvent mixture comprises isopropanol and water in a ratio of at least 1:1 (V/V), wherein the water is present in a volume not less than the volume of isopropanol.

18. The method of claim 9 or 16, wherein the contacting step is performed at a temperature of 30 ℃ to 60 ℃.