NZ719970B2 - Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof - Google Patents

Abstract

Provided herein are solid forms comprising {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid, compositions comprising the solid forms, methods of making the solid forms and methods of their use for the treatment of various diseases and/or disorders.

Description

SOLID FORMS OF {[5-(3-CHLOROPHENYL)—3-HYDROXYPYRIDINE CARBONYL]AMINO}ACETIC ACID, COMPOSITIONS, AND USES THEREOF This application claims the benefit ofUS. Provisional Application No. ,803, filed November 15, 2013, the entire contents of which are incorporated herein by reference. 1. FIELD OF THE INVENTION Provided herein are solid forms of -chlorophenyl)hydroxypyridine carbonyl]amino}acetic acid, itions comprising one or more solid forms, methods of making the solid forms and methods of their use for the treatment of various or symptoms thereof. 2. BACKGROUND OF THE INVENTION The fication and selection of a solid form of a pharmaceutical nd (I) is complex, given that a change in solid form may affect a variety of physical and chemical ties, which may provide benefits or drawbacks in processing, ining, storage, formulation, ity and bioavailability, among other important pharmaceutical characteristics.

Potential pharmaceutical solids include lline solids, amorphous solids, and es thereof. Amorphous solids are characterized by a lack of long-range ural order, whereas crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solid depends upon the specific application; amorphous solids are sometimes selected on the basis of, e. g., an enhanced dissolution profile, while crystalline solids may be desirable for ties such as, e.g., physical or chemical stability (See, e.g., S. R. Vippagunta et al., Adv.

Drug. Deliv. Rev., (2001) 483-26; L. Yu, Adv. Drug. Deliv. Rev, (2001) 48:27-42).

Whether crystalline or amorphous, potential solid forms of a pharmaceutical Compound (I) include single-component and multiple-component solids. Single-component solids consist essentially of the pharmaceutical Compound (I) in the absence of other compounds. Variety among single-component crystalline materials may potentially arise from the phenomenon of polymorphism, wherein multiple three-dimensional arrangements exist for a particular pharmaceutical compound (See, e.g., S. R. Bym et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). The importance of discovering polymorphs was underscored by the case of Ritonavir, an HIV protease inhibitor that was formulated as soft gelatin capsules.

About two years after the product was launched, the unanticipated precipitation of a new, less soluble rph in the formulation necessitated the awal of the product from the market until a more consistent formulation could be developed (See S. R. Chemburkar et al., Org.

Process Res. Dev., (2000) 4:413-417).

Additional diversity among the potential solid forms of a pharmaceutical nd may arise from the possibility of multiple-component . Crystalline solids comprising two or more ionic species are termed salts (See, e.g., Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, Eds., (2002), Wiley, Weinheim). Additional types of le-component solids that may potentially offer other property improvements for a pharmaceutical compound or salt thereof include, e.g., hydrates, solvates, co-crystals and clathrates, among others (See, e.g., S. R. Bym et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). Moreover, le-component crystal forms may potentially be susceptible to polymorphism, wherein a given le-component composition may exist in more than one three-dimensional lline arrangement. The discovery of solid forms is of great importance in the development of a safe, effective, stable and marketable pharmaceutical nd.

A new class of prolyl hydroxylase tors and their use to treat or prevent diseases ameliorated by modulation of hypoxia-inducible factor (HIF) prolyl hydroxylase are described in US. Patent No. 7,81 1,595, which is incorporated herein by reference in its entirety.

The sis of such prolyl hydroxylase inhibitors is described in US. Patent Publication No. 2012/0309977, which is incorporated herein by reference in its entirety. Such compounds t HIF prolyl hydroxylase, thereby izing HIFu. As a consequence of stabilizing HIFu, endogenous erythropoietin (EPO) production is increased. One such compound is{[5-(3- chlorophenyl)hydroxypyridinecarbonyl]amino}acetic acid ("Compound (1)") and methods ofmaking the compound were disclosed in US. Pat. No. 7,811,595, filed June 26, 2007 (See inter alia Schemes I and II and accompanying synthetic procedures in columns 15-17, and 25) and US. Publication 2012-0309977 (US. Pat. Appl. No. 13/488,554), filed in June 5, 2012 (See inter alia paragraphs [0254] — [267]), the entireties of each of which are incorporated by reference herein. 3. SUMMARY OF THE INVENTION Provided herein are solid forms comprising -chlorophenyl) hydroxypyridinecarbonyl]amino}acetic acid ("Compound (I)"). In certain embodiments, the solid forms may be single-component crystal forms Compound (I). In certain alternative embodiments, the solid forms may be multiple-component crystal forms, including, but not limited to, salts, co-crystals, solvates, hydrates of Compound (I). In other ments, the solid forms are single-component amorphous forms of the free acid of Compound (I). In other embodiments, the solid forms are multiple-component amorphous forms, including, but not d to, salts of Compound (I). Also provided herein are ceutical compositions comprising the solid forms and methods of their use for the treatment or tion of anemia (e.g., anemia secondary to or associated with chronic kidney disease, anemia secondary to chronic heart disease, idiopathic anemia of aging, anemia of chronic disease, myelodysplastic syndrome, bone marrow fibrosis, other aplastic or dysplastic anemias, herapy induced anemia (including chemotherapy for ng cancer, hepatitis C, or other chronic drug therapy that reduces bone marrow production), anemia resulting from blood loss, anemia resulting from iron deficiency, anemia ing from n B12 deficiency, sickle cell disease, or thalassemia). Certain embodiments are provided herein including solid forms of Compound (1) including, but not limited to, polymorphs of the unsolvated, free acid, salts, and other useful solid forms.

In certain embodiments, the invention s to Form A of Compound (I): CI \ N o / wkOH OH 0 which has an X-ray powder diffraction pattern as shown in In certain embodiments, Form A of Compound (I) has an X-ray powder diffraction pattern comprising one, two, three, four, or five peaks at approximately 18.1, 20.3, 22.9, 24.0, and 26.3 c’20; and wherein the crystalline Compound (I) is substantially free of any other crystalline form of Compound (I).

In certain embodiments, Form A of Compound (I) has a peak maximum temperature in a DSC gram at about l75.8°C. In particular embodiments, the thermal event at about 175.8 CC is a melting event. In certain embodiments, Form A of Compound (I) melts at about 175.8 °C.

In certain embodiments, Form A of Compound (1) comprises less than about 15%, less than about 10%, or less than about 5% by weight of any other crystalline nd (I).

In certain embodiment, the invention relates to Form A of Compound (I): CI \ N o / "QkOH OH O which has an X-ray powder diffraction pattern comprising one, two, three, four, or five peaks at approximately 18.1, 20.3, 22.9, 24.0, and 26.3 c’20; and n the crystalline Compound (I) is substantially free of amorphous Compound (I).

In n embodiments, Form A of Compound (I) has a peak in a DSC thermogram at about 175.8°C. In particular embodiments, the thermal event at about 175.8 °C is a melting event. In certain embodiments, the crystalline Compound (I) melts at about 175.8 CC.

In certain embodiments, Form A of Compound (1) ses less than about 15%, less than about 10% or less than about 5% by weight of amorphous Compound (I).

In certain ments, the invention relates to a crystalline Compound (I), such as Form A of Compound (1): CI \ N o / HJxOH OH O n the crystalline Compound (I), such as Form A of Compound (I) is substantially free of a compound of Formula (II): as ined by GC/MS. In certain embodiments, the crystalline compound comprises less than about 100 ppm, less than about 50 ppm, less than about 10 ppm, or less than 1 ppm of a compound of Formula (II) as determined by GC/MS. In certain embodiments, crystalline Compound (I), such as Form A of Compound (I) comprises an amount of Formula (II) that is less than a detectable amount by GC/MS.

In certain embodiments, Form A of Compound (I) has an X-ray powder diffraction pattern comprising one, two, three, four, or five peaks at approximately 18. l , 20.3, 22.9, 24.0, and 26.3 C’20.

In certain embodiments, Form A of nd (I) has a peak in a DSC thermogram at aboutl75.8°C. In particular embodiments, the thermal event at about 1758 °C is a melting event. In certain embodiments, the crystalline Compound (I) melts at about 1758 CC.

In certain embodiments, the invention relates to Form A of Compound (I): CI \ N o / HdkOH OH O wherein Form A of Compound (I) is at least 99.5% pure as ed by HPLC.

In certain embodiments, Form A of Compound (I) has an X-ray powder diffraction n sing one, two, three, four, or five peaks at approximately 18. l , 20.3, 22.9, 24.0, and 26.3 020.

In certain embodiments, Form A of Compound (I)has a peak in a DSC thermogram at l75.8°C. In particular ments, the thermal event at about 1758 °C is a melting event. In certain embodiments, Form A of Compound (I) melts at about 175.8 0C.

In certain embodiments, Form A of Compound (I) is at least about 99.6% pure, at least about 99.7% pure, at least about 99.8% pure, or at least about 99.9% pure. In certain embodiments, the purity may be determined e.g., by HPLC.

In certain embodiments, Form A of Compound (I) is substantially free of a compound of Formula (II): as determined by GC/MS. In certain embodiments, the lline compound comprises less than about 100 ppm, less than about 50 ppm, less than about 10 ppm, or less than 1 ppm of a compound of Formula (II) as determined by GC/MS. In n embodiments, Form A of Compound (I) comprises an amount of Formula (II) that is less than a detectable amount by GC/MS.

In certain embodiments, the invention relates to Form B of Compound (I): CI \ N o / "AOH OH O which has an X-ray powder diffraction n as shown in FIG. ll.

In certain embodiments, the ion relates to Form B of Compound (I): CI \ N o / "AOH OH O which has an X-ray powder diffraction pattern as shown in .

In certain embodiments, Form A, Form B and Form C of Compound (I) exist in the following zwitterionic form: Also provided herein are pharmaceutical compositions comprising a singlecomponent crystal form, a multiple-component crystal form, a single-component amorphous form and/or a multiple-component amorphous form of Compound (I) and a pharmaceutically acceptable t, excipient or carrier. In certain ments, the invention relates to pharmaceutical itions comprising one or more of the solid forms described herein, such as Form A, Form B or Form C of Compound (I).

Further embodiments herein provide methods of making, ing and/or characterizing the solid forms of the invention. [0028A] Without limiting the foregoing, the present invention particularly relates to the embodiments below: 1. Crystalline Compound (I): Cl N O OH O which has an X-ray powder diffraction pattern comprising peaks at 18.1, 20.3, 22.9, 24.0, and 26.3 ±0.2° 2θ; and wherein the crystalline compound (I) comprises less than 5% by weight of any other crystalline Compound (I); wherein the crystalline compound (I) comprises less than 5% by weight of ous Compound (I); (followed by 7A) wherein the crystalline compound (I) comprises less than 100 ppm of a compound of Formula (II), (II), as ined by GC/MS; and wherein the crystalline Compound (I) is at least 99.5% pure as measured by HPLC. 2. The lline nd (I) of embodiment 1, wherein the crystalline compound (I) comprises less than 50 ppm of a compound of Formula (II). 3. The crystalline compound (I) of embodiment 1, wherein the crystalline compound (I) comprises less than 10 ppm of a compound of Formula (II). 4. The lline compound (I) of embodiment 1, wherein the crystalline compound is at least 99.6% pure as ed by HPLC.

. The crystalline compound (I) of embodiment 1, wherein the crystalline compound is at least 99.7% pure as measured by HPLC. 6. The crystalline compound (I) of embodiment 1, wherein the crystalline compound is at least 99.8% pure as measured by HPLC. 7. The lline compound (I) of embodiment 1, wherein the crystalline compound comprises less than 50 ppm of a compound of Formula (II), (followed by 7B) (II), as determined by GC/MS; and wherein the lline compound is at least 99.6% pure as measured by HPLC. 8. A pharmaceutical composition comprising the lline compound (I) of any one of ments 1-7. 9. An oral dosage form comprising the crystalline compound (I) of any one of embodiments 1-7.

. The use of a crystalline compound of any one of embodiments 1-7, a pharmaceutical composition according to embodiment 8, or an oral dosage form according to embodiment 9, in the manufacture of a medicament for the treatment of anemia. 11. The use according to embodiment 10, wherein the anemia is secondary to or associated with chronic kidney disease. 12. A method for preparing a crystalline Compound (I) of embodiment 1: Cl N O OH O a) ing a solution of a Compound (I) in an organic solvent that is acetone; (followed by 7C) b) bringing the solution to super-saturation to cause formation of crystals; c) isolating the crystals. 13. The method of embodiment 12, wherein the crystalline compound (I) comprises less than 50 ppm of a compound of Formula (II). 14. The method of embodiment 12, wherein the crystalline compound (I) comprises less than 10 ppm of a compound of Formula (II).

. The method of any one of ments 12-14, further comprising filtering the solution through a charcoal filter. 16. The method of any one of embodiments 12-15, wherein bringing the solution to super-saturation comprises on of an anti-solvent that is water, allowing the solution to cool, and reducing the volume of the solution by evaporation, solvent exchange, or any combination thereof. 17. The method of any one of embodiments 12-16, further comprising washing the crystals. 18. The method of embodiment 17, n the g comprises washing with acetone or water, or any ation thereof. 19. The method of embodiment 18, wherein the washing comprises g with a combination of acetone and water.

. The method of any one of embodiments 12-19, wherein isolating the crystals comprises ing the crystals. 21. The method of any one of embodiments 12-20, further comprising drying the crystals under reduced pressure, optionally at an elevated temperature. 22. The method of embodiment 22, wherein the drying is performed at a ature of about 50 °C. (followed by 7D) BRIEF DESCRIPTION OF THE FIGURES shows an X-ray powder diffraction (XRPD) is of Compound (I), Form A. shows a polarized light microscopy (PLM) analysis of Compound (I), Form A. shows a thermal gravimetric/differential thermal analysis (TG/DTA or TGA) is of Compound (I), Form A. shows a differential scanning calorimetry (DSC) analysis of Compound (I), Form A. shows a dynamic vapor sorption (DVS) isotherm plot of Compound (I), Form A. shows the pre and post DVS XRPD analysis of Compound (I), Form A. shows the particle size analysis of nd (I), Form A. shows the 1H NMR spectrum of Compound (I), Form A. shows the IR spectrum of Compound (I), Form A. shows the HPLC analysis of Compound (I), Form A. (followed by 8) shows an X-ray powder diffraction (XRPD) analysis of Compound (I), Form B. shows an X-ray powder ction (XRPD) analysis of Compound (I), Form C.

. DETAILED DESCRIPTION OF THE INVENTION .1 Definitions As used herein, the term a" is art-recognized and is defined by hemoglobin threshold as follows: Hemoglobin Threshold (g/dL) Age or Gender Group Children (0.50—4.99 yrs.) Children 1 1.99 yrs.) Children (12.00-14.99 yrs.) egnant Women (215.00 yrs) Pregnant Women Men (215.00 yrs) Anemia may be chronic (e.g., anemia ary to chronic kidney disease, anemia secondary to chronic heart failure, idiopathic anemia of aging, anemia of chronic disease, such as inflammatory bowel disease or rheumatoid arthritis, myelodysplastic syndrome, bone marrow fibrosis, and other ic or dysplastic anemias), subacute (e.g., chemotherapy induced anemia, such as chemotherapy for treating cancer, heptatitis C, or other chronic disease that reduces bone marrow tion), acute (e.g., blood loss from injury or surgery), nutrition related (e.g., iron deficiency or Vitamin B12 deficiency), or hemaglobinpathies (e.g., sickle cell disease, thalassemia, etc.).

As used herein, the term "Compound (1)" means the compound {[5-(3- phenyl)hydroxypyridinecarbonyl]amino}acetic acid Compound (I) has the following structure : CI |\N ZI COZH In certain embodiments, the compound may be {[5-(3-chlorophenyl)hydroxypyridine carbonyl]amino}acetic acid, while in certain alternative embodiments, the compound may be a pharmaceutically acceptable salt of {[5-(3-chlorophenyl)hydroxypyridine carbonyl]amino}acetic acid. In certain alternative embodiments, the compound may be a solvate of -chlorophenyl)—3-hydroxypyridinecarbonyl]amino}acetic acid. In certain alternative embodiments, the compound may be a hydrate of -chlorophenyl)hydroxypyridine carbonyl]amino}acetic acid. In certain preferred embodiments, the compound can be in its parent form (z'.e., not a salt, solvate, or hydrate). As used herein, Compound (1) includes any zwitterionic species as well as any ceutically acceptable salts.

As used herein, the terms "prevent", "preventing" and "prevention" are art- ized, and when used in relation to a condition, such as a local recurrence, a disease or any other medical condition, such as those described herein, is well understood in the art, and includes stration of a compound, such as Compound (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof, which reduces the frequency of, or delays the onset of, symptoms of a l condition in a subject relative to a subject which does not receive the composition.

As used herein, the terms "treat", "treating" and "treatment" refer to the reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a disease condition, such as those described herein, in manner to e or stabilize a subj ect's condition.

The terms "treat" and "treatment" also refer to the eradication or amelioration of the disease or symptoms associated with the disease. In certain ments, such terms refer to minimizing the spread or worsening of the disease resulting from the administration of nd (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof to a t with such a disease.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts for Compound (I) include, but are not limited to, lithium, calcium, magnesium, zinc, bismuth, ammonium (including alkyl substituted ammonium), meglumine and choline. Suitable xic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, c, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, romic, hydrochloric, isethionic, lactic, maleic, malic, ic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, lic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Other es of salts are well known in the art. See, e.g., Remington’s ceutical Sciences, 22nd ed., Pharmaceutical Press, (2012).

As used herein, the term "hydrate" means 5-(3-chlorophenyl)hydroxypyridine- 2-carbonyl]amino}acetic acid or a pharmaceutically able salt thereof, that r includes a stoichiometric or non-stoichiometric amount of water bound by valent intermolecular forces.

As used herein, the term "solvate" means 5-(3-chlorophenyl)hydroxypyridine- 2-carbonyl]amino}acetic acid or a pharmaceutically acceptable salt thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent, other than water, bound by non- covalent intermolecular forces.

As used herein, the term "HIF prolyl ylase" is art-recognized and may be abbreViated as "PHD". HIF prolyl hydroxylase is also known as "prolyl hydroxylase domain- containing protein" which may be abbreViated as "PHD". In this regard, there are three ent PHD isoforms, PHDl, PHD2, and PHD3, also referred to as EGLN2, EGLNl, and EGLN3, or HPH3, HPH2, and HPHl, respectively.

The terms "solid form," "solid forms" and related terms, when used herein to refer to Compound (I), refer to a physical form comprising Compound (I) which is not predominantly in a liquid or a gaseous state. Crystal forms and amorphous forms are examples of solid forms. In one embodiment, the solid form is Form A. In another ment, the solid form is Form B. In another embodiment, the solid form is Form C.

The term "crystalline" and related terms used herein, when used to describe a substance, component, product, or form, means that the substance, component or product is substantially crystalline as ined by X-ray diffraction. See, e.g, Remington’s Pharmaceutical Sciences, 22nd ed., Pharmaceutical Press, (2012).; The United States Pharmacopoeia, 30th ed., (2011).

The term "crystal form," alline form" and d terms herein refer to a crystalline solid form comprising a chemical compound, and may refer to a particular single- ent or multiple-component crystal form, including, but not limited to, a polymorph, a e, a hydrate or other molecular complex, a salt, a solvate of a salt, a hydrate of a salt, or other molecular complex of a salt, or a rph thereof.

The terms "polymorphs,3, CCpolymorphic forms" and related terms herein refer to two or more crystal forms that comprise the same molecule, molecules or ions. Different polymorphs may have different physical properties such as, for example, melting temperatures, heats of fusion, solubilities, dissolution rates and/or ional spectra as a result of the arrangement or conformation of the molecules or ions in the crystal lattice. The differences in physical properties exhibited by polymorphs affect pharmaceutical ters such as storage stability, compressibility and density (important in formulation and product manufacturing), and ution rate (an important factor in bioavailability). Differences in stability can result from changes in chemical reactiVity (e.g, differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical changes (e.g., s e on e as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g, tablets of one polymorph are more susceptible to breakdown at high humidity). As a result of solubility/dissolution differences, in the extreme case, some polymorphic transitions may result in lack of potency or, at the other extreme, ty. In addition, the physical properties of the crystal may be important in processing; for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of ties (e.g. and size distribution might be , particle shape different n polymorphs).

Techniques for characterizing crystal forms and amorphous forms include, but are not limited to, thermal graVimetric analysis (TGA), melting point, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single-crystal X-ray diffractometry, vibrational spectroscopy, e.g., ed (IR) and Raman spectroscopy, solid-state and solution nuclear magnetic nce (NMR) spectroscopy, optical microscopy (e.g., polaraized light microscopy), hot stage l microscopy, ng electron microscopy (SEM), electron crystallography, dynamic vapor sorption (DVS), and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies and ution studies.

The term "amorphous,3, CCamorphous form," and related terms used herein mean that the substance, component or product in on is not substantially crystalline as determined by X-ray diffraction. In certain embodiments, a sample comprising an amorphous form of a substance may be substantially free of other ous forms and/or crystal forms.

As used herein, and unless ise ed, the terms "about" and "approximately," when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by those of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. cally, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percent within 15%, more specifically within 10%, more specifically within 5%, of the specified dose, amount, or weight percent.

As used , and unless otherwise specified, the terms "about" and "approximately," when used in connection with a numeric value or range of values which is provided to characterize a particular solid form, e.g., a specific temperature or temperature range, such as, for example, that bing a melting, dehydration, desolvation or glass tion temperature; a mass change, such as, for example, a mass change as a function of temperature or humidity; a solvent or water content, in terms of, for example, mass or a percentage; or a peak position, such as, for example, in analysis by IR or Raman spectroscopy or XRPD; indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the particular solid form. Specifically, the terms "about" and "approximately," when used in this context, indicate that the numeric value or range of values may vary, in particular embodiments, within 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values. With respect to XRPD, values given are ::0.2 degrees 2 theta.

As used herein, an "effective amount" refers to that amount of Compound (I) or a pharmaceutically acceptable salt, solvate or e f sufficient to provide a therapeutic benefit in the ent of the disease or to delay or minimize symptoms ated with the disease, such as any disease or condition described herein.

The terms "subject" and "patient," unless otherwise specified, are defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In specific embodiments, the subject or patient is a human. In certain embodiments, the t has a disease or condition as described herein. .2 Solid Forms Certain embodiments herein provide single-component and multiple-component (e.g., salts, solvates, hydrates) solid forms comprising Compound (I), which has the chemical structure shown below: CI \ N I H / chozH OH 0 Compound (I) may be synthesized or obtained according to any method apparent to those of skill in the art based upon the teachings herein, including the methods described in detail in the examples below. Compound (I) may also be prepared according to the methods described in US. Pat. No. 7,811,595, filed June 26, 2007 (See inter alia Schemes I and II and accompanying synthetic procedures in columns 15-17, and 25) and US. Publication 2012- 0309977 (US. Pat. Appl. No. 13/488,554), filed in June 5, 2012 (See inter alia paragraphs — [267]), the entireties of each of which is incorporated by reference herein. Solid forms of Compound (I) may then be ed from the Compound (I) made by such methods.

Certain embodiments herein provide single-component solid forms of the free acid of Compound (I) having utility for the treatment or prevention of anemia (e.g. anemia ary to or associated with chronic kidney disease, anemia secondary to c heart disease, idiopathic anemia of aging, anemia of c disease, ysplastic syndrome, bone marrow fibrosis, other aplastic or dysplastic anemias, chemotherapy induced anemia (including chemotherapy for treating cancer, hepatitis C, or other chronic drug therapy that reduces bone marrow tion), anemia resulting from blood loss, anemia ing from iron deficiency, anemia resulting from vitamin B12 ncy, sickle cell disease, or thalassemia). Accordingly, provided herein are methods for the treatment of anemia, sing administering to a patient having anemia an effective amount of a solid form of Compound (I).

The single-component solid forms of Compound (I) can be prepared by any method apparent to those skilled in the art based upon the teachings herein. The single- component solid forms of Compound (I) can also be prepared according to the techniques described herein, ing the methods described in detail in the examples below. .2.1 Form A of Compound (I) Certain ments herein provide the Form A crystal form of Compound (I).

In certain embodiments, Form A of Compound (I) can be obtained from a Compound (I) as prepared in a procedure according to e.g., US. Pat. No. 7,811,595, filed June 26, 2007 (See inter alia Schemes I and II and anying synthetic procedures in columns 15-17, and 25) and US. Publication 2012-0309977 (US. Pat. Appl. No. 13/488,554), filed in June 5, 2012 (See inter alia paragraphs [0254] — [267]) followed by subjecting the resulting Compound (I) to a crystallization procedure as described herein below.

A representative XRPD pattern of Form A of Compound (I) is ed in In n embodiments, Form A of nd (I) is characterized by XRPD peaks located at one or more ofthe following approximate positions: 9.8, 11.0, 13.3, 14.6, 14.8, 15.0, 16.3, 16.4, 16.9, 18.1, 18.6, 19.7, 20.3, 22.0, 22.9, 23.3, 24.0, 24.2, 25.2, 25.7, 25.9, 26.3, 26.8, 27.6, 28.3, 28.9, 29.6, 29.8, 30.3, 31.3, 32.2, 32.9, 34.1, 34.9, 35.2, 35.7, 36.2, 36.7, 37.2, 37.4, 37.7, 38.3, 38.6, and 38.9 degrees 20. In particular embodiments, Form A of Compound (I) is characterized by XRPD peaks located at one, two, three, four, five or six, seven, eight, nine, ten, eleven, twelve, or thirteen of the following approximate positions: 15.0, 18.1, 18.6, 19.7, 20.3, 22.9, 24.0, 24.2, 25.2, 26.3, 26.8, 35.2, and 37.4 degrees 20. In certain embodiments, Form A of Compound (I) has an XRPD pattern comprising peaks at approximately 18.1, 20.3, 22.9, 24.0, 26.3, 26.8, and 35.2 degrees 020. In certain embodiments, Form A of Compound (I) has an XRPD pattern r comprising peaks at approximately 18.1, 20.3, 22.9, 24.0, and 26.3 degrees Representative thermal teristics of Form A of nd (I) are shown in and A representative TGA/DTA gram, ted in exhibits ible weight loss from t, then significant weight loss above ca. 220 °C which is consistent with decomposition. The DTA shows a single sharp endotherm with an onset of 171.5 A representative DSC thermogram, presented in exhibits shows a single sharp endotherm with an onset at about 172.4°C and a peak at about 175.8°C. In certain embodiments, the thermal event at about 175.8 CC is a g event. In certain embodiments, Form A melts at about 175.8 c’C. In certain embodiments, Form A is unsolvated. In certain embodiments, Form A is anhydrous.

Form A of Compound (I) exhibits desirable characteristics for the synthesis, processing and manufacture of drug product containing Compound (I). For example, in certain embodiments, Form A of Compound (I) has an advantageous ity profile, which is an important characteristic for processing and manufacturing.

In certain embodiments, Form A of Compound (I) is non-hygroscopic, e.g., water sorption at 90% relative ty (RH) is less than about 0.5%. For example, in certain embodiments, when subjected to moisture sorption analysis, Form A ts a mass gain of less than about 0.4%, less than about 0.3%, less than about 0.2%, when increased from about 0% to about 90% RH. In certain embodiments, Form A exhibits a mass gain of about 0.13% when increased from about 0% to about 90% RH. In certain embodiments, ing moisure sorption analysis, the XRPD pattern of the Form A material is substantially unchanged. A representative dynamic vapor sorption (DVS) isotherm plot of Compound (1), Form A is presented in In certain embodiments, the moisture sorption analysis may be determined using a g profile from 20—90-20% relative humidity (RH) in 10% increments, maintaining the sample at each step until a stable weight had been achieved (99.5% step completion) or 1000 minutes have elapsed. After completion of the sorption cycle, the sample may be dried using the same procedure, but all the way down to about 0% RH and finally taken back to the starting point of % RH.

In certain embodiments, Form A of Compound (1) comprises small particles with the majority of the particles being less than 100 um. In certain embodiment, Form A of Compound (1) comprises particles with an average size of less than 100 um. A representative particle size analysis is ted in In certain embodiments, Form A of Compound (I) is substantially pure. In certain ments Form A of Compound (I) is at least about 99.6% pure, at least about 99.7% pure, at least about 99.8% pure, or at least about 99.9% pure. In certain embodiments, the purity may be determined e.g., by HPLC.

In certain embodiments Form A of Compound (I) is substantially free of a compound of Formula (11): as determined by GC/MS In certain embodiments, the crystalline compound comprises less than about 100 ppm, less than about 75 ppm, less than about 50 ppm, less than about 25 ppm, less than about 10 ppm, less than about 5 ppm, less than about 3 ppm, less than about 2 ppm, or less than about 1 ppm of a compound of Formula (II) as determined by GC/MS. In certain ments, Form A of Compound (I) comprises an amount of Formula (II) that is less than a detectable amount by GC/MS.

In n embodiments, Form A of Compound (1) comprises less than about 15%, less than about 10% or less than about 5% by weight of amorphous Compound (I).

In certain embodiments, Form A of nd (1) comprises less than 15%, less than 10%, or less than 5% by weight of any other crystalline Compound (I). .2.2 Form B of Compound (I) Certain embodiments herein provide the Form B l form of Compound (I).

In certain embodiments, Form B of Compound (I) can be ed from a Compound (I) as prepared in a procedure according to e.g., US. Pat. No. 7,811,595, filed June 26, 2007 (See inter alia Schemes I and II and accompanying synthetic procedures in columns 15-17, and 25) and US. Publication 2012-0309977 (US. Pat. Appl. No. 13/488,554), filed in June 5, 2012 (See inter alia aphs [0254] — [267]) followed by subjecting the resulting Compound (I) to a crystallization procedure as bed herein below.

A representative XRPD pattern of Form B of nd (I) is provided in . In certain ments, Form B of Compound (I) is characterized by XRPD peaks d at one or more ofthe following approximate positions: 8.6, 15.3, 18.6, 21.3, 22.7, 23.8, 28.1 and .0 degrees 20. In particular embodiments, Form B of Compound (I) is characterized by XRPD peaks located at one, two, three or four of the following approximate positions: 8.6, 15.3, 22.7 and 28.1 degrees 20.

In certain embodiments, Form B of Compound (I) is substantially pure. In certain embodiments Form B of Compound (I) is at least about 99.6% pure, at least about 99.7% pure, at least about 99.8% pure, or at least about 99.9% pure. In certain embodiments, the purity may be ined e.g., by HPLC.

In certain embodiments Form B of Compound (I) is substantially free of a compound of Formula (11): as determined by GC/MS In certain embodiments, the crystalline compound comprises less than about 100 ppm, less than about 75 ppm, less than about 50 ppm, less than about 25 ppm, less than about 10 ppm, less than about 5 ppm, less than about 3 ppm, less than about 2 ppm, or less than about 1 ppm of a compound of Formula (II) as determined by GC/MS. In certain embodiments, Form B of Compound (I) comprises an amount of Formula (II) that is less than a detectable amount by GC/MS.

In certain embodiments, Form B of Compound (1) comprises less than about 15%, less than about 10% or less than about 5% by weight of amorphous Compound (I).

In certain ments, Form B of Compound (1) comprises less than 15%, less than 10%, or less than 5% by weight of any other crystalline Compound (I). .2.3 Form C of Compound (I) Certain ments herein provide the Form C crystal form of Compound (I).

In certain embodiments, Form C of Compound (I) can be ed from a Compound (I) as prepared in a ure according to e.g., US. Pat. No. 7,811,595, filed June 26, 2007 (See inter alia Schemes I and II and accompanying synthetic procedures in s 15-17, and 25) and US. Publication 2012-0309977 (US. Pat. Appl. No. 13/488,554), filed in June 5, 2012 (See inter alia paragraphs [0254] — [267]) followed by subjecting the resulting nd (I) to a crystallization procedure as described herein below.

A representative XRPD pattern of Form C of Compound (I) is ed in . In certain embodiments, Form C of Compound (I) is characterized by XRPD peaks located at one or more 0fthe following approximate positions: 7.2, 9.2, 11.1, 13.7, 14.3, 16.7, 17.4, 18.4, 19.1, 19.9, 20.1, 21.6, 22.3, 22.4, 22.4, 23.1, 24.8, 25.3, 26.3, 26.6, 27.6, 27.9, 28.3, 28.9, 29.5, .3, 31.4, 31.5, 32.5, 33.7, 33.8, 36.0, 37.0, 37.5, 39.1 and 39.5 degrees 20. In particular embodiments, Form C of Compound (I) is characterized by XRPD peaks located at one, two, three, four, five or six, seven or eight of the following approximate positions: 7.2, 17.4, 22.3, 22.4., 22.4, 28.9, 33.7 and 33.8 degrees 20. In n embodiments, Form C of Compound (I) has an XRPD pattern comprising peaks at approximately 17.4, 22.3 and 22.4 degrees C’20. In certain embodiments, Form C of Compound (I) has an XRPD pattern further sing an additional peak at approximately 22.4 degrees c’20. In certain embodiments, Form C of Compound (I) has an XRPD pattern further comprising peaks at approximately 7.2, 28.9, 33.7 and 33.8 degrees 020.

In certain embodiments, Form C of Compound (I) is substantially pure. In certain embodiments Form C of Compound (I) is at least about 99.6% pure, at least about 99.7% pure, at least about 99.8% pure, or at least about 99.9% pure. In certain ments, the purity may be determined e.g., by HPLC.

In certain embodiments Form C of Compound (I) is substantially fiee of a compound of Formula (II): as determined by GC/MS In certain embodiments, the crystalline compound comprises less than about 100 ppm, less than about 75 ppm, less than about 50 ppm, less than about 25 ppm, less than about 10 ppm, less than about 5 ppm, less than about 3 ppm, less than about 2 ppm, or less than about 1 ppm of a compound of Formula (II) as determined by GC/MS. In certain embodiments, Form C of nd (I) ses an amount of Formula (II) that is less than a detectable amount by GC/MS.

In certain embodiments, Form C of Compound (I) comprises less than about 15%, less than about 10% or less than about 5% by weight of amorphous Compound (I).

In certain embodiments, Form C of Compound (I) comprises less than 15%, less than 10%, or less than 5% by weight of any other crystalline Compound (I). .3 Methods of Making Certain embodiments herein provide a crystalline Compound (I), such as Form A.

In certain embodiments, Form A of Compound (I) may be ed from Compound (I) as prepared according to e.g., US. 7,811,595 and/or US. Patent Application No. 13/488,554 and then subjecting the resulting Compound (I) CI \ N o / NdkOHH OH O to a ure comprising a) preparing a solution of Compound (I) in an organic solvent; b) bringing the solution to super-saturation to cause formation of crystals; and c) isolating the crystals; wherein the crystalline nd (I), such as Form A of Compound (I) is substantially free of any other crystalline compound of Formula (I), such as where the cystalline Compound (I), such as Form A of Compound (I) comprises less than about 15%, less than about 10%, less than about %, or less than 1% by weight of any other crystalline Compound (1).; or wherein the crystalline Compound (I), such as Form A of nd (I) is substantially free of a compound of Formula (II): (11); as ined by GC/MS, such as where the crystalline Compound (I), such as Form A of Compound (I) comprises less than about 100 ppm, less than about 75 ppm, less than about 50 ppm, less than about 25 ppm, less than about 10 ppm, less than about 5 ppm, less than about 3 ppm, less than about 2 ppm, or less than about 1 ppm of a compound of Formula (II) as determined by GC/MS; or wherein the crystalline Compound (I), such as Form A of Compound (I) is ntially free of amorphous Compound (I), such as where the crystalline compound (I) comprises less than about %, less than about 10%, less than about 5%, or less than 1% by weight of amorphous nd (I).

In certain such embodiments, the crystalline Compound (I) is at least 99.5% pure as measured by HPLC.

In n such embodiments, the organic solvent is selected fiom acetone, methyl yl ketone, n-heptane, tetrahydrofuran, methyl tethydrofuran (e.g., 2-methyl tetrahydrofuran) and water, or any combination thereof. In certain such embodiments, the organic solvent is acetone.

In certain such embodiments, the process further comprises filtering the solution through a charcoal filter. In certain embodiments, such filtering may be performed after preparing the solution of Compound (I) in an organic solvent. In certain ments, such filtering may be performed prior to bringing the solution to super-saturation.

In certain embodiments, bringing the solution to super-saturation comprises addition of an anti-solvent, allowing the solution to cool, reducing the volume of the solution, solvent exchange, or any combination thereof. In certain such ments where bringing the solution to super-saturdation comprises reducing the volume of the on, the volume reduction is performed by evaporation. In certain such embodiments where bringing the solution to super-saturation comprises the addition of anti-solvent, the anti-solvent is water or heptane propanol. In certain such embodiments, bringing the solution to saturation comprises ng the on to cool and addition of anti-solvent. In certain alternative such embodiments, ng the solution to super-saturation comprises solvent exchange and ng the solution to cool.

In certain embodiments where bringing the solution to super-saturation comprises solvent exchange, the solvent exchange comprises a distillative solvent exchange under reduced pressure. In certain such embodiments, acetone is exchanged for methyl isobutyl .

In certain embodiments where bringing the solution to super-saturation comprises allowing the solution to cool, the solution is allowed to cool to between about 19 oC and about 0C, or even to between about 0 oC and about 5 0C.

In certain embodiments, the method further comprises seeding the solution with a crystalline Compound (I), such as Form A of Compound (I).

In n embodiments, the method further comprises washing the crystals. In certain such embodiments, the washing ses washing the crystals with a liquid selected from acetone, methyl isobutyl ketone, n-heptane, and water, or any combination thereof. In certain such embodiments, the washing comprises washing with a combination of acetone and water. In certain alternative such embodiments, the washing comprises washing with methyl isobutyl ketone.

In n embodiments, isolating the crystals comprises filtering the crystals. In certain embodiments, the method further comprises drying the ed ls under reduced pressure, optionally at an elevated temperature. In certain such embodiments, the drying is med at a temperature of about 50 0C.

In certain embodiments, the invention relates to a crystalline nd (I), such as Form A of Compound (I), which is produced by a process comprising: (3| "~Iu C) / NQK(DH OH O a) preparing a solution of Compound (I) in an organic solvent; b) bringing the solution to super-saturation to cause formation of crystals; and c) isolating the crystals; with optional drying of the crystals. the crystalline Compound (I), such as Form A of Compound (I) is substantially free of any other crystalline nd (I); or wherein the crystalline Compound (I), such as Form A of Compound (I) is substantially free of a compound of a (II): as determined by GC/MS; or wherein the crystalline Compound (I), such as Form A of Compound (I) is substantially free of amorphous nd (I).

In certain such embodiments, the crystalline Compound (I) is at least 99.5% pure as measured by HPLC.

In certain such embodiments, the organic solvent is selected fiom acetone, methyl isobutyl ketone, n-heptane, and water, or any combination thereof. In certain such embodiments, the organic solvent is e.

In certain such embodiments, the process further comprises filtering the on through a charcoal filter. In certain embodiments, such filtering may be performed after preparing the solution of Compound (I) in an c solvent. In certain embodiments, such filtering may be performed prior to ng the solution to super-saturation.

In certain embodiments, bringing the solution to saturation comprises addition of an anti-solvent, allowing the solution to cool, reducing the volume of the solution, t exchange, or any ation f. In certain such embodiments where bringing the solution to super-saturation ses reducing the volume of the solution, the volume reduction is performed by evaporation. In certain such embodiments where bringing the solution to super- saturation comprises the addition of anti-solvent, the anti-solvent is water. In certain such embodiments, bringing the solution to super-saturation ses ng the solution to cool and addition of anti-solvent. In certain alternative such embodiments, bringing the on to saturation comprises solvent exchange and allowing the solution to cool.

In certain embodiments where bringing the solution to super-saturation comprises solvent exchange, the solvent exchange comprises a distillative solvent exchange under reduced pressure. In certain such embodiments, acetone is exchanged for methyl isobutyl ketone.

In certain embodiments where ng the solution to super-saturation comprises allowing the solution to cool, the solution is allowed to cool to n about 19 oC and about 0C, or even to between about 0 oC and about 5 0C.

In certain embodiments, the process further comprises seeding the solution with a crystalling Compound (I), such as Form A of Compound (I).

In certain embodiments, the process further comprises washing the crystals. In n such embodiments, the washing comprises washing the crystals with a liquid selected from acetone, methyl isobutyl ketone, n-heptane, and water, or any combination thereof. In certain such embodiments, the washing comprises washing with a combination of acetone and water. In certain alternative such embodiments, the washing comprises washing with methyl isobutyl ketone.

In certain ments, isolating the crystals comprises filtering the crystals. In certain embodiments, the process further comprises drying the isolated crystals under reduced pressure, optionally at an elevated temperature. In certain such ments, the drying is med at a temperature of about 50 0C.

In certain ments, Form B of Compound (I) may be obtained from Compound (I) as prepared ing to e.g., US. 7,811,595 and/or US. Patent Application No. 13/488,554 and then subjecting the resulting Compound (I) l ::;11 k}\\v//jl\\(3+4 OH O to a procedure sing a) preparing a on of Compound (I) in acetonitrile; and b) evaporating the solvent.

In certain embodiments, the crystalline Compound (I), such as Form B of Compound (I) is substantially free of any other crystalline compound of Formula (I), such as where the cystalline Compound (I), such as Form B of Compound (1) comprises less than about %, less than about 10%, less than about 5%, or less than 1% by weight of any other crystalline Compound (1).; or wherein the crystalline Compound (I), such as Form B of Compound (I) is substantially free of a compound of Formula (11): (11); as determined by GC/MS, such as where the lline Compound (I), such as Form B of Compound (1) comprises less than about 100 ppm, less than about 75 ppm, less than about 50 ppm, less than about 25 ppm, less than about 10 ppm, less than about 5 ppm, less than about 3 ppm, less than about 2 ppm, or less than about 1 ppm of a compound of Formula (II) as determined by GC/MS; or wherein the crystalline Compound (I), such as Form B of Compound (I) is substantially free of amorphous Compound (I), such as where the crystalline nd (1) ses less than about %, less than about 10%, less than about 5%, or less than 1% by weight of amorphous Compound (I).

WO 73779 In certain such embodiments, the crystalline Compound (I), such as Form B of Compound (I) is at least 99.5% pure as measured by HPLC.

In certain embodiments, Form C of Compound (I) may be obtained from nd (I) as prepared according to e.g., US. 595 and/or US. Patent Application No. 13/488,554 and then subjecting the resulting Compound (I) I :::]u F] \\"/ii\\ OH O to a procedure comprising a) preparing a solution of Compound (I) in 2-methyltetrahydrofuran; b) adding n-heptane; c) heating the suspension (e.g., to about 40-50 0C); d) cooling the suspension (e.g., to about 0-10 0C); and c) isolating the crystals.

In certain embodiments, the crystalline Compound (I), such as Form C of Compound (I) is substantially free of any other crystalline compound of Formula (I), such as Where the cystalline Compound (I), such as Form C of Compound (I) comprises less than about %, less than about 10%, less than about 5%, or less than 1% by weight of any other crystalline nd (I).; or wherein the crystalline nd (I), such as Form C of Compound (I) is substantially free of a compound of Formula (II): (11); as determined by GC/MS, such as where the crystalline Compound (I), such as Form C of Compound (I) comprises less than about 100 ppm, less than about 75 ppm, less than about 50 ppm, less than about 25 ppm, less than about 10 ppm, less than about 5 ppm, less than about 3 ppm, less than about 2 ppm, or less than about 1 ppm of a compound of Formula (II) as ined by GC/MS; or wherein the crystalline Compound (I), such as Form C of nd (I) is substantially free of amorphous Compound (I), such as where the crystalline compound (I) comprises less than about %, less than about 10%, less than about 5%, or less than 1% by weight of amorphous Compound (I).

In certain such embodiments, the lline Compound (I), such as Form C of Compound (I) is at least 99.5% pure as measured by HPLC.

In certain embodiments, the addition of n-heptane is carried over not less than 30 minutes (e.g., about 30 to about 60 minutes). In certain embodiments, the addition of n-heptane is carried out at about 40-50 0C. In certain embodiments, the suspension is heated to about 40-50 0C with stirring for at least about 1 hour (e.g., about 1 to about 2 hours). In certain ments, the suspension cooled to about 0-10 0C is stirred for at least about 1 hour (e.g., about 1 to about 2 hours). In certain embodiments, isolating the crystals comprises filtering the crystals. In certain embodiments, the filtered crystals are washed with cold n-heptane / 2-methyltetrahydrofuran (e.g., 6:1) and dried. In n such embodiments, the drying is performed at a temperature of not more than about 50 0C (e.g., about 50 0C) under vacuum. .4 Methods of Use In certain embodiments, the invention relates to s for treating or ting a disease or disorder ameliorated by modulation of HIF prolyl hydroxylase (e.g. , PHDl, PHD2, and/or PHD3) comprising administering to a t having a e ameliorated by modulation of HIF prolyl hydroxylase an ive amount of a solid form of Compound (I), such as Form A, Form B or Form C of Compound (I) or any other solid form described herein.

In certain embodiments, the invention encompasses s of treating or preventing a e or disorder ameliorated by inhibiting HIF prolyl hydroxylase (e.g. , PHDl, PHD2, and/or PHD3), comprising administering to a patient having a disease or disorder ameliorated by inhibiting HIF prolyl hydroxylase an effective amount of a solid form of Compound (I). In certain such embodiments, the invention relates to methods of treating or preventing a disease or disorder ameliorated by inhibiting PHDl, comprising administering to a t having a disease or disorder ameliorated by inhibiting PHDl an effective amount of a solid form of Compound (I). In certain such embodiments, the ion relates to methods of treating or preventing a disease or disorder ameliorated by ting PHD2, sing administering to a patient having a disease or disorder rated by inhibiting PHD2 an effective amount of a solid form of Compound (I). In n such ments, the ion relates to methods of treating or preventing a disease or disorder ameliorated by inhibiting PHD3, comprising administering to a patient having a disease or disorder ameliorated by inhibiting PHD3 an effective amount of a solid form of Compound (I).

] In certain embodiments, the invention encompasses methods of treating or preventing a disease or disorder ameliorated by stabilizing HIFu (e.g., HIF-lu, HIP-20L, and/or HIF-3 0L), comprising administering to a patient having a disease or disorder ameliorated by izing HIFu an effective amount of a solid form of Compound (I). In certain such embodiments, the invention relates to ng or ting a disease or disorder ameliorated by stabilizing HIF-lu, comprising administering to a patient having a disease or disorder ameliorated by stabilizing HIF-lu an effective amount of a solid form of Compound (I). In certain such embodiments, the invention relates to treating or preventing a disease or disorder ameliorated by stabilizing HIP-20L, comprising administering to a patient having a disease or disorder ameliorated by inhibiting HIP-20L an effective amount of a solid form of Compound (I).

In certain such embodiments, the invention relates to treating or preventing a disease or disorder ameliorated by stabilizing HIP-30L, sing administering to a patient having a disease or disorder rated by stabilizing HIP-30L an effective amount of a solid form of Compound (I).

In certain embodiments, the invention relates to methods of treating or preventing a disease or ion related to diminished endogenous production of erythropoietin (EPO), comprising administering to a patient having a disease or disorder related to diminished endogenous production of EPO an effective amount of a solid form of Compound (I).

In certain embodiments, the invention s to methods of treating or preventing anemia (e.g., anemia secondary to or associated with chronic kidney disease, anemia secondary to chronic heart disease, idiopathic anemia of aging, anemia of chronic disease, myelodysplastic me, bone marrow f1brosis, other aplastic or dysplastic anemias, chemotherapy induced anemia (including chemotherapy for treating cancer, hepatitis C, or other chronic drug therapy that reduces bone marrow production), anemia resulting from blood loss, anemia resulting from iron deficiency, anemia resulting from vitamin B12 deficiency, sickle cell disease, or thalassemia), comprising administering to a patient having anemia an effective amount of a solid form of Compound (I). In certain embodiments, the invention relates to methods of treating anemia, such as anemia secondary to chronic kidney disease, comprising administering to a patient having anemia an effective amount of a solid form of Compound (I).

In certain embodiments, the invention relates to treating or preventing anemia ary to chronic kidney disease (CKD), sing administering to a patient having anemia secondary to CKD an effective amount of a solid form of Compound (I). In certain embodiments, the CKD is stage 1, 2, 3, 4, or 5 chronic kidney disease. In certain such embodiments, the CKD is stage 3, 4, or 5 chronic kidney disease. In certain embodiments, the CKD is stage 1 chronic kidney disease. In n embodiments, the CKD is stage 2 c kidney e. In certain embodiments, the CKD is stage 3 chronic kidney disease. In certain embodiments, the CKD is stage 4 c kidney disease. In n embodiments, the CKD is stage 5 chronic kidney disease. In certain embodiments, the chronic kidney disease is pre- dialysis chronic kidney disease. In certain embodiments, the patient is a dialysis patient and these patients may be referred to as having end stage renal disease (ESRD). In certain such embodiments, the anemia, such as anemia secondary to CKD or ESRD may be refractory to treatment with an erythropoiesis stimulating agent, including a rhEPO product, such as, epoetin alfa, epoetin beta, darbepoetin, or peginesatide. In certain embodiments, the patient has been previously treated for , While in certain alternative embodiments, the patient has not previously been treated for .

In certain embodiments, the invention relates to methods of treating or preventing an angiogenesis-related e or disorder, comprising administering to a patient having angiogenesis-related disease or disorder an effective amount of a solid form of Compound (I). In n embodiments, the ion relates to methods of regulating angiogenesis, comprising administering to a t an effective amount of a solid form of Compound (I).

In certain ments, the invention relates to methods of treating or ting disease or disorder affected by the level ofVEGF or GAPDH, comprising administering to a patient having a disease or disorder affected by the level ofVEGF or GADPH an effective amount of a solid form of Compound (I).

] In certain embodiments, the invention relates to methods of promoting wound healing, comprising administering to a patient having a wound an effective amount of a solid form of Compound (I).

] In certain embodiments, the invention relates to methods of enhancing the revascularization of damaged tissue or increasing vasculature, comprising administering to a t having d tissue an effective amount of a solid form of Compound (I). In certain embodiments, the invention relates to methods of vascularizing ischemic tissue, comprising administering to a patient having ischemic tissue an effective amount of a solid form of nd (I).

In certain embodiments, the invention relates to methods of promoting the growth of skin graft replacements, comprising administering to a patient having a skin graft an effective amount of a solid form of Compound (I).

In certain embodiments, the invention relates to methods of promoting tissue repair in the context of guided tissue regeneration (GTR), comprising administering to a t an effective amount of a solid form of Compound (I).

In certain embodiments, the invention relates to methods for treating a disease or condition related to diminished endogenous production of erythropoietin (EPO), comprising administering to a patient having a disease or ion related to diminished endogenous production of EPO a sufficient number of successive doses of a solid form of Compound (I) so as to raise the level of hemoglobin relative to a baseline hemoglobin level in a patient without cantly increasing the level of serum EPO relative to the baseline level of serum EPO.

In certain embodiments, the invention relates to methods for treating a disease or condition d to diminished endogenous production of erythropoietin (EPO), comprising administering to a patient having a disease or condition related to diminished endogenous production of EPO a ent number of sive doses of a solid form of Compound (I) so as to raise the level of hemoglobin relative to a baseline hemoglobin level in a patient without significantly increasing the level of serum EPO relative to the baseline level of serum EPO,.

In certain embodiments, the invention relates to methods for treating a e or ion d to diminished endogenous production of erythropoietin (EPO), comprising administering to a t having a disease or condition related to diminished endogenous production of EPO a sufficient number of successive doses of a solid form of Compound (I) so as to raise the total iron binding capacity (TIBC) relative to a baseline TIBC in a patient, Without significantly increasing the serum iron level relative to a ne serum iron level.

In certain ments, the invention s to methods for treating or preventing anemia in a subject, wherein the method comprises administering to the subject a pharmaceutically ive amount of solid form of nd (I) While: a) ing or maintaining the diurnal pattern ofEPO serum levels; and/or b) maintaining pre-treatment levels of total iron (i.e., Without increasing significantly the total iron levels); and/or c) not significantly decreasing hepcidin levels.

In certain embodiments, the invention relates to methods of treating a e or ion selected from non-severe anemia secondary to chronic kidney e, non-severe anemia secondary to congestive heart failure, and idiopathic anemia of aging, comprising administering to a t having non-severe anemia secondary to chronic kidney disease, non- severe anemia secondary to congestive heart failure, or idiopathic anemia of aging a sufficient number of successive doses of a solid form of Compound (I) so as to raise the serum obin levels ve to a baseline serum hemoglobin level in a patient, Without significantly decreasing hepcidin expression relative to a ne hepcidin expression level.

In certain embodiments, the invention relates to methods of treating or preventing a disease or disorder selected from diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, sarcoid, is, xanthoma elasticum, Paget's disease, vein occlusion, artery occlusion, carotid ctive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosis, retinopathy of prematurity, Eales' disease, Behcet's disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, trauma post-laser complications, diseases associated with rubeosis, and proliferative retinopathy, Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, Osler-Weber-Rendu disease, or hereditary hemorrhagic telangiectasia, solid or blood borne tumors, acquired immune deficiency syndrome, skeletal muscle and myocardial ischemia, stroke, coronary artery e, peripheral vascular disease, and coronary artery disease, comprising administering to a patient having such a disease or disorder an ive amount of a solid form of Compound (I).

In n embodiments, a solid form of Compound (I) may be administered according to a dosing regimen, such as that disclosed in US. Application No. 61/834,808, filed in June 13, 2013. .5 Combination y In certain ments, the invention relates to methods for ng , such as anemia secondary to chronic kidney disease, sing administering {[5-(3-chlorophenyl)- 3-hydroxypyridinecarbonyl]amino}acetic acid in combination with another medicament. Such combination y may be achieved by way of the simultaneous, sequential, or separate dosing of the individual components of the treatment. Additionally, when administered as a component of such combination therapy, the {[5-(3-chlorophenyl)—3-hydroxypyridine carbonyl]amino}acetic acid and the other medicament may be synergistic, such that the daily dose of either or both of the components may be reduced as compared to the dose of either component that would normally be given as a monotherapy. Alternatively, when administered as a component of such combination therapy, the {[5-(3-chlorophenyl)hydroxypyridine carbonyl]amino}acetic acid and the other medicament may be additive, such that the daily dose of each of the components is similar or the same as the dose of either component that would normally be given as a monotherapy.

In certain embodiments, the invention relates to methods for ng anemia, such as anemia secondary to chronic kidney disease, comprising administering a compound which is {[5-(3-chlorophenyl)hydroxypyridinecarbonyl]amino}acetic acid to a patient having , wherein the Compound (I) is optionally stered in combination with an iron supplement, such as ferrous sulfate, ferrous gluconate, or ferrous fumarate. In certain such embodiments, the iron supplement is administered at least one hour, at least two hours, at least three hours, at least four hours, or even at least six hours ing administration of the compound. In n embodiments, the iron supplement is administered in an amount such that ferritin is maintained at a level of between about 50 ng/mL and about 300 ng/mL. In certain embodiments, the iron supplement is administered orally at a daily dose of at least about 50 mg of elemental iron. In certain embodiments, the iron supplement is administered orally at a dose of about 50 mg of elemental iron. In certain embodiments, the iron supplement is administered enously. In certain embodiments, the iron supplement is administered continuously and/or indefinitely, such as for more than 42 consecutive days. In certain alternative embodiments, the iron supplement is administered on an as needed basis such that in is maintained at a level of between about 50 ng/mL and about 300 ng/mL. In certain such embodiments, the daily dose of the Compound (I) is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a solid form of Compound (I). In n such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily.

In certain embodiments, the invention relates to methods for treating anemia, such as anemia ary to chronic kidney disease, comprising administering a compound which is {[5-(3-chlorophenyl)hydroxypyridinecarbonyl]amino}acetic acid to a patient having anemia, n the Compound (I) is optionally administered in combination with an erythropoiesis stimulating agent (ESA), such as an erythropoietin mimetic. In certain such embodiments, the ESA is an rhEPO product, including, but not limited to, epoetin alfa, epoetin beta, darbepoetin, or peginesatide. In n such embodiments, the ESA is administered as a rescue therapy. In certain alternative embodiments, the ESA is administered continuously and/or indefinitely, such as for more than 42 consecutive days. In certain such ments, the daily dose is of the nd (I) is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a solid form of Compound (I). In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered orally, once daily, twice daily, or three times daily, preferably once daily. . 6 Pharmaceutical Compositions Pharmaceutical compositions may be used in the preparation of individual, single unit dosage forms. ceutical itions and dosage forms ed herein comprise a compound as provided , or a pharmaceutically acceptable salt, solvate, or hydrate thereof (e.g., the parent compound). Pharmaceutical compositions and dosage forms can further comprise one or more excipients.

In certain embodiments, pharmaceutical compositions and dosage forms comprise one or more excipients. le excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient. For example, oral dosage forms such WO 73779 as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water.

Lactose-free compositions can comprise excipients that are well known in the art and are listed, for example, in the US. Pharmacopeia (USP) 25 NF20 (2002). In l, lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically ible and pharmaceutically acceptable amounts. In one embodiment, lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.

Also provided are anhydrous pharmaceutical itions and dosage forms since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of ting erm storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug ity: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In , water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are ly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.

An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, ous compositions are, in one embodiment, ed using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms that comprise one or more nds that reduce the rate by which an active ingredient will decompose. Such nds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to ts. . 6.1 Oral Dosage Forms Pharmaceutical compositions that are suitable for oral administration can be provided as discrete dosage forms, such as, but not limited to, tablets (e. g., chewable tablets), caplets, capsules, suspensions and liquids (e.g., flavored syrups). Such dosage forms contain ermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington’s The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005).

Oral dosage forms provided herein are prepared by combining the active ingredients in an intimate admixture with at least one excipient according to conventional ceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation d for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, s, oils, alcohols, flavoring agents, preservatives, and coloring . Examples of excipients suitable for use in solid oral dosage forms (e.g., s, tablets, capsules, and caplets) include, but are not limited to, starches, , micro-crystalline cellulose, diluents, granulating , lubricants, binders, and egrating agents.

In one ment, oral dosage forms are tablets or capsules, in which case solid excipients are employed. In another embodiment, tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, ceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid rs, or both, and then shaping the product into the desired presentation if necessary.

For e, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ients in a free- flowing form such as powder or granules, optionally mixed with an excipient.

Examples of excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, egrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, n, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its tives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e. g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are not d to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-S 81, AVICEL-PH-105 able from FMC Corporation, American e Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture ents or additives include AVICEL-PH-103TM and Starch 1500 LM. Other suitable forms of microcrystalline cellulose include, but are not limited to, silicif1ed microcrystalline cellulose, such as the materials sold as PROSOLV 50, PROSOLV 90, PROSOLV HD90, PROSOLV 90 LM, and mixtures thereof.

] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms ed herein include, but are not limited to, talc, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, , pre-gelatinized starch, and mixtures thereof. The binder or filler in pharmaceutical compositions is, in one embodiment, present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form. The binder or filler in pharmaceutical compositions is, in another ment, t in from about 20 to about 30 weight percent of the pharmaceutical composition or dosage form. The binder or filler in pharmaceutical compositions is, in another embodiment, present in about 24 weight percent of the ceutical composition or dosage form.

In certain embodiments, fillers may e, but are not limited to block copolymers of ethylene oxide and propylene oxide. Such block copolymers may be sold as POLOXAMER or PLURONIC, and include, but are not d to POLOXAMER 188 NF, POLOXAMER 237 NF, POLOXAMER 338 NF, POLOXAMER 437 NF, and mixtures thereof.

In certain embodiments, POLOXAMER or PLURONIC, including, but not limited to POLOXAMER 188 NF, POLOXAMER 237 NF, POLOXAMER 338 NF, POLOXAMER 437 NF, and mixtures thereof, are surfactants.

In certain embodiments, fillers may e, but are not limited to isomalt, lactose, lactitol, mannitol, sorbitol xylitol, erythritol, and mixtures thereof.

Disintegrants may be used in the compositions to provide s that disintegrate when d to an aqueous environment. s that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to entally alter the release of the active ingredients may be used to form solid oral dosage forms. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. In one ment, pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, or from about 5 to about 9 weight percent of disintegrant, or from about 1 to about 5 weight percent of disintegrant, or from about 1 to about 7 weight percent of disintegrant, or about 7 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, gar, c acid, calcium ate, microcrystalline cellulose, croscarmellose sodium, povidone, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca , other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof Glidants and/or lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium stearyl fumarate, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, seed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof Additional glidants include, for example, a syloid silica gel (AEROSILZOO, manufactured by W.R. Grace Co. of ore, MD), a coagulated aerosol of tic silica (marketed by a Co. of Plano, TX), CAB-O-SIL (a pyrogenic colloidal silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, glidants and/or lubricants may be used in an amount of less than about 1 WO 73779 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.

In certain ments, an oral dosage form comprises the compound, fied microcrystalline cellulose, sodium starch glycolate, a block copolymer of ethylene oxide and propylene oxide, sodium l filmarate and colloidal silicon dioxide. In certain ments, an oral dosage form comprises the nd (I) in an amount of about 5% to about 75% by weight, silicified microcrystalline cellulose in an amount of about 15% to about 85%, sodium starch glycolate in an amount of about 2% to about 10%, block copolymer of ethylene oxide and propylene oxide in an amount of about 2% to about 10%, sodium stearyl fumarate in an amount of 0.2% to about 2%, and colloidal silicon dioxide in an amount of about 0.2% to about 2% by weight of the oral dosage form.

In certain embodiments, an oral dosage form comprises the compound, microcrystalline cellulose, t, sodium starch glycolate, sodium lauryl sulfate, povidone, dal silicon dioxide, and magnesium stearate. In certain embodiments, an oral dosage form comprises the Compound (I) in an amount of about 40% to about 50%, microcrystalline cellulose in an amount of about 40% to about 50%, isomalt in an amount of 0% to about 5%, sodium starch glycolate in an amount of about 5% to about 10%, sodium lauryl sulfate in an amount of 0.2% to about 2%, povidone in an amount of about 2% to about 10%, colloidal silicon dioxide in an amount of 0.1% to about 1%, and magnesium stearate in an amount of about 0.1% to about 1% by weight of the oral dosage form.

In certain embodiments, the invention relates to unit dosage forms that comprise between about 100 mg and about 1,200 mg, about 200 mg and about 1,000 mg, about 400 mg and about 800 mg, or about 450 mg and about 600 mg of Compound (I).

] In certain embodiments, the invention relates to unit dosage forms that comprise about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,050 mg, 1,100 mg, 1,150, or even about 1,200 mg of a solid form of Compound (I). In certain such embodiments, the unit dosage form is a capsule comprising about 40 mg, about 120 mg, about 185 mg, about 200 mg, about 200, about 250 mg, or even about 300 mg of a solid form of Compound (I). In certain such embodiments, the unit dosage form is a tablet comprising about 150 mg of a solid form of Compound (I). In certain such embodiments, the unit dosage form is a tablet comprising about 315 mg of a solid form of Compound (I).

Liquid dosage forms for oral administration include pharmaceutically acceptable ons, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may n inert diluents ly used in the art, such as, for example, water or other solvents, solubilizing agents, and emulsifiers such as ethyl l, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene , l ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof.

] Besides inert diluents, the oral itions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

Suspensions, in addition to the active inhibitor(s) may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. 6. Examples The following examples are presented by way of ration, not limitation. The ing abbreviations are used in descriptions and examples: ACN: Acetonitrile Am: Amorphous AS: ID for anti-solvent llization experiment DCM: romethane DIPEA: N,N—Diisopropylethylamine DMA: Dimethylacetamide DMF: N,N—Dimethylformide DMSO: Dimethylsulfoxide DSC: Differential ng Calorimetry DTA: Differential Thermal Analysis DVS: Dynamic Vapor Sorption EtOH: Ethanol FBRM: Focussed Beam Reflectance Measurement HPLC: High performance liquid chromatography IPA: 2-Propanol LCMS: Liquid Chromatography with Mass Spectroscopy VIEK: Methyl Ethyl Ketone VIeOH: Methanol VliBK: Methyl isoButyl Ketone mp: Melting point VIS: Mass spectrometry VITBE: tert-Butyl methyl ether VITBE: methyl tert-butyl ether \IMP: N—Methyl-2—pyrrolidone \IMP: N—methylpyrrolidinone \IMR: Nuclear ic resonance RH: Relative Humidity RT: Room Temperature S: Solvent SDTA: Single Differential Thermal Analysis SM: Starting material TA: Thermal is TCP: ID for thermocycling and reflux experiment TGA: ThermograVimetric is THF: Tetrahydrofuran TLC: Thin layer chromatography XRPD: X-Ray Powder Diffraction ] The following non-limiting examples show methods for generating Compound (I) with high purity by removing Compound (11), (II).

ChemDraw Ultra (Cambridgesoft, Cambridge, MA) was used to generate names for chemical structures. 6.1 Form A of Compound [I] Precursor of Form A of Compound (I) (10.01 g, 0.033mol) was charged into a 500ml round bottom flask equipped with mechanical or, temperature probe and nitrogen line. 50ml THF was charged into the 500ml round bottom flask and the resulting e was agitated at room temperature until all solids dissolved. 50g deionized water was d into the 500ml round bottom flask and the mixture was cooled down to 0-5°C.

A sodium hydroxide solution was prepared by mixing 6.65g of 50% by weight aqueous sodium hydroxide solution with 50g water. The prepared sodium hydroxide on was charged into the 500ml round bottom flask slowly while the temperature of the mixture was maintained between 0 and 5°C. The pH of the mixture was 13 after addition of the prepared sodium hydroxide solution. The mixture was warmed up to 19-25 0C and agitated for 1 to 2 hours (the mixture may be agitated longer). ] 37% by weight concentrated aqueous HCl solution was added slowly into the reaction mixture until the pH of the reaction mixure reached 5, while the temperature of the reaction mixture was maintained below 25°C. About 8.5g 37% by weight concentrated aqueous HCl on was used.

The mixture was then concentrated to about 60ml (55 to 65ml is recommended).

Additional 50g deionized water was added and the mixture was agitated for about 2 hours.

] Solids were collected from the mixture by filtration and washed with 20g deionized water. The solid material was air dried until transferrable. The weight of the dried solid was l3.4g. The HPLC analysis indicated that the purity of the solid was 99.46% (area%). 6.1.1 Hot water trituration of Form A of Compound (I) The solid material obtained in section 6.1 was d into to a 500ml round bottom flask ed with mechanical agitator, ature probe and nitrogen line. 70g deionized water was charged into the 500ml round bottom flask and the ing mixture was agitated at 70-80°C for 16 hours. After the mixture was cooled down to room temperature, solids were collected from the mixture by filtration and washed by 20g deionized water. The solid material was air dried until transferrable. 6.1.2 Charcoal treatment and recrystallization of Form A of Compound (I) The solid material obtained in section 6.1 was charged into to a 500ml round bottom flask equipped with mechanical agitator, temperature probe and nitrogen line. l30g acetone was charged into the 500ml round bottom flask and the resulting mixture was agitated at room temperature until all solids dissolved (ca. 30 minutes). If the solids did not dissolve completely, more e was added. The resulting solution was treated with activated carbon.

The activated carbon was then removed by filtration and the resulting acetone on was trated to about 73ml (70 to 75 ml is recommended). The concentrated acetone solution was heated to reflux. While keeping the solution below 50 0C, 65g water was added slowly.

Precipitation of a light d solid was observed. The mixture was cooled down to 22 0C (between 19 to 25 0C) over ca. 2 hours and agitated at 22 0C for ca. 2 to 3 hours. Solids were collected from the mixture by filtration and washed with a mixture of l 1 .5g acetone and 15g deionized water. The solid material was air dried for at least 6 hours. The weight of the dried solid material was 9.2g. The HPLC analysis indicated the purity of the solid was 99.71% (area%). 6.2 Solid Form A of Compound (1) 6.2.1 Characterization of Form A of Compound (I) XRPD analysis as depicted in shows Form A to be predominantly crystalline with sharp, distinct peaks up to 40° 20 on a ably flat baseline. The raised background from ca. 8° to 16° 20 is a known artifact due to the sample . A list of X-Ray Diffraction Peaks for Form A of Compound (I) is provided below in Table 1.

Table 1. X-Ray Diffraction Peaks for Form A of Compound (1) Relative Two-theta angle (0) Intensity (%) 9.8 3.2 11.0 1.9 —13.3 1.1 —14.6 2.5 —14.8 5.5 .0 12.7 16.3 5.7 —16.4 2.5 —16.9 9.1 —18.1 14.5 18.6 11.0 19.7 9.9 .3 46.2 22.0 3.2 —22.9 53.7 —24.0 31.4 24.2 11.4 .2 11.3 .7 3.5 .9 8.4 —26.3 100.0 —26.8 12.8 —27.6 28.3 1.5 28.9 1.0 —29.6 —29.8 1.4 —30.3 0.5 31.3 1.2 32.2 1.2 Relative Two theta angle (0- ) Intensity (%) 32.9 2'4 PLM analysis as depicted in shows some birefringence under polarised light; however the ls are very small with no clearly defined morphology.

TGA analysis as depicted in shows negligible weight loss from ambient temperature, and then significant weight loss above ca. 220°C which is consistent with decomposition. DTA analysis as depicted in shows a single sharp endotherm with an onset of l7l.5°C.

DSC analysis as depicted in shows a single sharp endotherm with an onset at l72.4°C and a peak at l75.8°C.

DVS analysis as depicted in shows that water sorption at 90% RH is 0.13% indicating that the material is non-hygroscopic. XRPD analysis ing DVS as depicted in shows no change in form.

The FBRM data as depicted in shows the material to t of small les with the majority being less than 100 um as illustrated in the non-weighted distribution.

] The solution NMR spectrum as depicted in is consistent with the structure of nd (I). The IR absorption spectrum is provided in HPLC analysis as depicted in indicates that the sample purity as shown in Table 2.

Table 2. HPLC purity of Form A of Compound (I) Peak Number Retention Time minutes Area % 11588 10000 6.2.2 Solubility ments ] Approximately 20 mg of Form A of Compound (I) was placed in each of 48 vials and 5 volume aliquots of the appropriate solvent systems were added to the appropriate vial.

Between each addition, the mixture was checked for dissolution and if no dissolution was apparent, the mixture was warmed to ca. 50°C and checked again. This procedure was continued until dissolution was ed or until 100 volumes of solvent had been added. The approximate solubilities are shown in Table 3. [00 1 8 1] Table 3. Solvent List for solubility experiement Solvent Solubility (mg/mL) RT Solubility (mg/mL) (ca. (ca. 22°C) 50°C) Acetone 100 >100 Acetone/Water (3%) <200 200 Acetone/Water (20%) <200 200 Acetonitrile < l 3 l 3 Anisole <40 40 Benzonitrile <10 <10 Benzyl alcohol <68 nol (l-BuOH) <20 Chloroform < l 0 Cyclohexane <10 Cyclohexanone <200 Cumene <10 Dichloromethane (DCM) < l 0 Diethyl ether <10 Diisopropyl ether (DIPE) <10 Dimethylacetamide (DMA) >200 Dimethylformamide (DMF) >200 yl sulfoxide >200 l,4-Dioxane >200 Ethanol (EtOH) 34 xyethanol <200 200 Ethyl acetate (EtOAc) <41 EtOAc/Cyclohexane (1 :2) <10 EtOAc/Toluene (1 :2) <14 Ethylene glycol <10 Heptane <10 Isobutyl acetate (iBuOAc) <20 Isopropyl acetate (iPrOAc) <26 Methanol (MeOH) <5 1 MeOH/Water (1 %) <40 MeOH/Water (20%) <10 MeOH/Water (50%) <10 2-Methoxyethanol >200 Methyl e (MeOAc) <68 3 -Methylbutanol <10 Methyl ethyl ketone (MEK) < 1 00 Methyl isobutyl ketone <34 2-Methyl tetrahydrofuran >200 2-MeTHF Nitromethane <10 N—n1ethylpyrrolidone >200 1 ,2-Propanediol <20 20 anol (1 -PrOH) <20 20 2-Propanol (IPA) <13 methyl tert-butyl ether 14 Tetrahydrofuran (THF) >200 Toluene <10 Trifluoroethanol (TFE) < 1 0 Water < 1 0 6.2.3 Analysis Methods XRPD is was conducted on a Siemens D5000, scanning the samples between 3 and 50 C’20. Approximately, 5 mg or less (material dependant) of sample was gently compressed on a glass disc inserted into an XRPD sample holder. The sample was then loaded into a Siemens D5000 diffractometer running in reflection mode and analysed, using the following experimental conditions in Table 4. A calibration check was med on the Siemens D5000 XRPD on a monthly basis using the Alumina Powder Standard Reference Material 676a.

Table 4. X-ray Powder ction (XRPD) emental conditions Raw Data Origin Siemens-binary V2 (.RAW) Start Position [020] 3.0000 End Position [020] 40.000 Ste Size [020] 0.0200 Scan Ste Time [s] Scan Type Continuous Offset [020] 0.0000 Divergence Slit Type Fixed Diver_ence Slit Size [0] 2.0000 S ecimen Lenth [mm] various Receivin_ Slit Size [mm] 0.2000 Measurement Temoerature [0C] 20.00 Anode Material Cu K-Alohal [A] 1.54060 K-Alpha2 [A] 3 K-Beta [A] 1.39225 K-A2/K-A1 Ratio 0.50000 l Generator Settin_s 40 mA, 40 kV Diffractometer T oe d5000 Diffractometer Number 0 Goniometer Radius [mm] 217.50 |HIncident Beam Monochromator o Diffracted Beam Monochromator Gra ohite S oinnin; No It should be understood that the numerical values of the peaks of an X-ray powder diffraction pattern may vary slightly from one machine to another or from one sample to r, and so the values quoted are not to be construed as absolute, but with an allowable variability, such as ::0.2 degrees 2 theta (see e.g., Remington’s Pharmaceutical Sciences, 22nd ed., Pharmaceutical Press, (2012); The United States copoeia, 30th ed., (2011)).

Polarised Light Microscopy (PLM) was conducted on an Olympus BX50 polarising microscope, equipped with a Motic camera and image capture software (Motic Images Plus 2.0). All images were recorded using the 20x ive, unless otherwise stated.

] Thermal Gravimetric/Differential Thermal Analysis (TG/DTA) were performed on a simultaneous thermogravimetric/differential thermal analyser. Approximately 5 mg or less (material dependant) was accurately weighed into an open aluminium pan and loaded into the analyser and held at room temperature. The sample was then heated at a rate of 10°C/min from °C to 300°C during which time the change in sample weight was recorded along with any ential thermal events (DTA). Nitrogen was used as the purge gas, at a flow rate of 100 cm3/min. The TGA furnace was cleaned by bum-out on a monthly basis prior to a temperature check using an Indium reference standard. A weight check was also med on a monthly basis. DSC data can vary with scan rate and sample pan configuration.

Differential Scanning Calorimetry (DSC) was performed on a Seiko DSC6200 equipped with a cooler. Approximately 5mg or less (material dependant) was tely weighed into an aluminium DSC pan and sealed rmetically with a pierced aluminium lid.

The sample pan was then loaded into the Seiko 0 cooled and held at 25°C. Once a stable heat-flow response was obtained, the sample and reference were heated to ca. 220°C at scan rate of 10°C/min and the resulting heat flow response monitored. A monthly temperature check was performed using an Indium reference standard.

Dynamic Vapour Sorption (DVS) was performed on a DVS-l dynamic vapour sorption balance by Surface Measurement Systems. Approximately 10-20 mg of sample was loaded into a wire mesh vapour sorption balance pan of the balance. The sample was subjected to a ramping profile from 20—90% relative humidity (RH) in 10 % increments, maintaining the sample at each step until a stable weight had been achieved (99.5 % step tion) or 1000 minutes had elapsed. After completion of the sorption cycle, the sample was dried using the same procedure, but all the way down to 0% RH and y taken back to the starting point of % RH. The weight change during the sorption/desorption cycles were plotted, allowing for the hygroscopic nature of the sample to be determined. Following the DVS analysis, the solid was lysed by XRPD in order to determine whether there had been any change in physical form.

Focussed Beam Reflectance Measurement (FBRM) was carried out using a Mettler Toledo D600 probe for le size analysis. The probe was placed into a suspension of the material in ca. 200ml acetonitrile and chord length distributions with various count statistics were monitored over a few minutes, while the sample was being stirred. A quarterly performance verification was carried out on the FBRM using a PVC nce standard and a fixed beaker stand. FBRM data can vary depending on solubility in the solvent system used.

Infrared Spectroscopy (IR) was carried out on a Bruker ALPHA P ometer.

Sample material was placed onto the centre of a plate on the spectrometer and the spectra were obtained directly from the material (i.e. no KBr disc) using the following parameters in Table 5.

An internal performance quality check on the IR spectrometer was performed on a monthly basis.

Table 5. Infrared Spectroscopy (IR) emental ions Resolution 4 cm"1 Background Scan Time 16 scans Samle Scan Time 16 scans Data Collection 4000 to 400 cm'1 Result S oectrum Transmittance Software OPUS version 6 1H Nuclear Magnetic nce (1H NMR) experiements were performed on a Bruker AV400 (1H frequency: 400 MHz). 1H NVIR experiments of each sample were performed in DMSO-d6 and samples were prepared to ca. lmg/mL concentration.

High Performance Liquid Chromatography (HPLC) was performed according to the conditions in Table 6 and gradient program in Table 7.

Table 6. High Performance Liquid Chromatography (HPLC) experiemental conditions Sample Preparation 0.6 mg/mL prepared in water/ acetonitrile; l/l; v/v Instrument Agilent 1100 Column Waters ry Shield RP18 150 x 4.6mm; Sum Column ature 30 OC 9» 263 nm Injection Volume 5 ul Flow Rate 1 ml/min Mobile Phase A Water/ acetonitrile / TFA; 950/50/ 1; v/v/v Mobile Phase B Acetonitrile / water / TFA; 950/50/ 1; v/v/v Run Time 40 minutes Integration Time 30 minutes Wash Vial Water/ acetonitrile; 1/ 1; v/v Table 7. High mance Liquid Chromatography (HPLC) experiemental gradient program 01 100 0 w0 6.3 Solid Form B of Compound (I) Solid Form B of Compound (I) was prepared by weighing approximately 600 mg of Compound (1) into a 100 mL Duran flask and dissolving in approximately 40 mL of acetonitrile. The solution was then filtered into a clean 100 mL glass beaker and placed in a dessicator under vacuum until all solvent had been removed. XRPD analysis as depicted in shows Form B to be predominantly lline with sharp, distinct peaks up to 40° 20 on a ably flat baseline. The raised background from ca. 8° to 16° 20 is a known artifact due to the sample holder.

TGA analysis of Form B showed a small weight loss of 1.2% between 100 0C and 130 0C, then significant weight loss above ca. 220 0C. DTA showed an event(s) n 120 0C and 135 0C (which corresponds to the weight loss by TGA), however it was indistinct. There was a main, sharp endotherm having an onset of 171.5 0C and a peak at 175.7 0C.

DSC analysis showed a small exotherm with an onset at 109.2 0C and a peak at 113.7 °C, followed by a main, sharp endotherm with an onset at 173.4 0C and a peak at 176.2 0C.

DVS analysis showed that water sorption at 90% RH was 0.33% indicating that the al is non-hygroscopic. XRPD is following DVS showed no change in form.

Form B exhibits good qualities such as crystallinity and high melting point, along with being anhydrous and groscopic. However, Form B is able and can t to Form A in slurries at high temperature. 6.4 Solid Form C of Compound (I) An approximately 22% (g/ml) solution of Compound (I) in 2- methyltetrahydrofuran was adjusted to approximately 7% (g/mL) solution of Compound (I) in 2- methyltetrahydrofuran by adding n-heptane in not less than 30 minutes. at 40-50°C. The suspension was stirred at 40-50°C for not less than 1 hour, followed by slow cooling to 0-10°C.

The sion was stirred out for not less than 1 hour at 0-10°C and filtered. The wet cake was washed with cold ane / 2-methyltetrahydrofuran (6:1) and dried at not more than 50°C under vacuum, yielding Form C as white crystals. XRPD analysis as depicted in shows Form C to be predominantly crystalline with sharp, distinct peaks up to 40° 20 on a reasonably flat baseline. 6.5 Pharmaceutical itions 6.5.1 40 mgl 200 mgI and 300 mg Cagsule Formulations Capsule formulations can be prepared as follows: Casule, 40 m Caosule, 200 m Caosule 300m Form A of 300 mg Compound (1) (parent) ProSolv® HD 90 124.8 m Explotab® 28.5 mg 24.0 mg 24.0 mg sodium starch _l colate, NF Poloxamer 188 28.5 mg 24.0 mg 24.0 mg PRUV® 5.7 mg 4.8 mg 4.8 mg Cab-O-Sil M-5P 2.85 m_ 2.40 m_ 2.40 m_ 570 m 480.0 m 480.0 m 6.5.2 120 m 185 m 250 m and 315 Ca sule Formulations Capsule formulations can be ed as follows: Material Capsule, 120 Capsule, 185 Capsule 250 Capsule, m_ m_ mg 315 m: Foronf 120.00 mg 185.00 mg 250.00 mg 315.00 mg Compound (I) oarent ProSolV® HD 304.80 mg 239.80 mg 173.60 mg 107.40 mg Explotab® sodium starch glycolate, NF Poloxamer 188 NF PRUV® 4 80 m- 4 80 m 4 80 m 4 80 m Sil M- 2.40 mg 2.40 mg 3.60 mg 4.80 mg 480.00 m 480.00 m 480.00 m 480.00 m 6.5.3 150 mg Tablet ation ] A tablet formulation can be prepared as follows: Intra-granular Components Povidone, USP/NF Kollidon®25 8.92 (8.925) Purified Water or Water for Injection, USP1 As ed Extra-granular Components Explotab® sodium starch glycolate, NF Explotab® 14.28 Colloidal Silicon Dioxide, NF Cab-O-Sil 0.89 Magnesium Stearate, NF quual® 5712 0.71 (0.714) Total 357.0 Abbreviations: NF = National Formulary, USP = United States Pharmacopeia 1 Removed dur1ng process1ng. . 6. 5.4 315 mg Tablet Formulation A 315 mg tablet formulation can be prepared as follows using a wet granulation process: Material Exci n ient Grade Quanti m_ Intra-_ranular Com n onents Form A of Com.ound I oarent 315.0 Microc stalline cellulose, USP/NF AVicel® PH105 317.9 Isomalt, USP/NF Galen 10801 20.00 EXolotab® sodium starch _l colate, NF ab® 22.50 Sodium lauryl sulfate, NF 7.500 Povidone, USP/NF Kollidon® 25 33.75 Purified water for In'ection, USP As reuired Extra-_ranular Com n onents Manesium Stearate, NF H ual® 5712 1.5 6.5.5 Alternative 315 mg Tablet Formulation A 315 mg tablet formulation may be prepared as follows using a wet ation pI'OCGSSC Excinient Grade Intra-_ranular Com n onents Form A of Compound (1) (parent) 315.0 Microc stalline cellulose, USP/NF AVicel® PH105 317.9 ab® sodium starch glycolate, NF Explotab® 22.50 Sodium lau l e, NF 7.500 Povidone, USP/NF on® 25 33.75 Purified water for In'ection, USP As reuired Extra-_ranular Com n onents Explotab® sodium starch glycolate, NF Explotab® 30.00 Colloidal Silicon Dioxide, NF Cab-O-Sil 1.875 Magnesium Stearate, NF quual® 5712 1.5 Total 730.0 6.5.6 100 mg Tablet Formulation A 100 mg tablet formulation may be prepared as follows using a wet granulation pI'OCGSSC Abbreviations: NF = al Formulary, USP = United States Pharmacopeia l Removed durmg processmg. . 6.5. 7 250 mg Tablet Formulation A 250 mg tablet formulation may be prepared as follows using a wet granulation pI'OCGSSC Abbreviations: NF = National Formulary, USP = United States copeia l Removed durmg processmg. .

Claims (22)

WHAT WE CLAIM IS:

1. Crystalline Compound (I): Cl N O OH O which has an X-ray powder diffraction n comprising peaks at 18.1, 20.3, 22.9, 24.0, and 26.3 ±0.2° 2θ; and wherein the lline compound (I) comprises less than 5% by weight of any other crystalline Compound (I); wherein the crystalline nd (I) comprises less than 5% by weight of amorphous Compound (I); wherein the crystalline compound (I) comprises less than 100 ppm of a compound of Formula (II), (II), as ined by GC/MS; and wherein the crystalline Compound (I) is at least 99.5% pure as measured by HPLC.

2. The crystalline compound (I) of claim 1, wherein the crystalline compound (I) comprises less than 50 ppm of a compound of Formula (II).

3. The crystalline compound (I) of claim 1, wherein the crystalline compound (I) comprises less than 10 ppm of a compound of Formula (II).

4. The crystalline compound (I) of claim 1, wherein the crystalline compound is at least 99.6% pure as measured by HPLC.

5. The crystalline compound (I) of claim 1, wherein the lline compound is at least 99.7% pure as measured by HPLC.

6. The crystalline compound (I) of claim 1, wherein the crystalline nd is at least 99.8% pure as measured by HPLC.

7. The crystalline compound (I) of claim 1, wherein the crystalline compound comprises less than 50 ppm of a compound of Formula (II), (II), as determined by GC/MS; and wherein the crystalline compound is at least 99.6% pure as measured by HPLC.

8. A pharmaceutical composition sing the crystalline compound (I) of any one of claims 1-7.

9. An oral dosage form sing the crystalline compound (I) of any one of claims 1-7.

10. The use of a crystalline compound of any one of claims 1-7, a pharmaceutical composition according to claim 8, or an oral dosage form according to claim 9, in the manufacture of a medicament for the treatment of anemia.

11. The use according to claim 10, wherein the anemia is secondary to or associated with c kidney disease.

12. A method for preparing a crystalline Compound (I) of claim 1: Cl N O OH O comprising: a) ing a solution of a Compound (I) in an organic solvent that is acetone; b) bringing the solution to super-saturation to cause formation of crystals; c) ing the crystals.

13. The method of claim 12, wherein the crystalline compound (I) comprises less than 50 ppm of a compound of Formula (II).

14. The method of claim 12, wherein the crystalline compound (I) comprises less than 10 ppm of a compound of Formula (II).

15. The method of any one of claims 12-14, further comprising ing the solution through a charcoal .

16. The method of any one of claims 12-15, wherein bringing the solution to super-saturation comprises addition of an anti-solvent that is water, ng the solution to cool, and reducing the volume of the solution by evaporation, solvent exchange, or any ation thereof.

17. The method of any one of claims 12-16, further comprising washing the crystals.

18. The method of claim 17, wherein the washing comprises washing with acetone or water, or any combination thereof.

19. The method of claim 18, wherein the washing comprises washing with a combination of acetone and water.

20. The method of any one of claim 12-19, wherein isolating the crystals comprises filtering the crystals.

21. The method of any one of claim 12-20, r comprising drying the crystals under reduced pressure, optionally at an elevated temperature.

22. The method of claim 21, wherein the drying is performed at a temperature of about 50 °C. £28; ov 53 £98 mm $823 29 on mméémmé .EmnE mm 3va F .8 om fl : .9“. 32.:gmomomumweméum; Aoomvmimqiqoiqm 9 ooom coon O O ooom coo N) _ (swnoo) msueuul SUBSTITUTE SHEET (RULE 26) /////////// 105.0 100.0 16.0 95.0 E 12.0 5\° E 10.0 85.0 9 8.00 80.0 2.00 70.0 50.0 100.0 150.0 200.0 250.0 Temp Cel SUBSTITUTE SHEET (RULE 26) Ulw/Mw osaa odNN me>e©é odom 68.2— 3Eoo.w| 8— 33% 35%: odN— .GE T cchI coed: oooél ooodl acqml oooNI coed: Mm 080 SUBSTITUTE SHEET (RULE 26) 01.3 32% 068%.: xmg aea ”5% E: oo— Sow 8 298 E BE E E5502 888 on .O_u_