EP4731208A2 - Processes for preparing crystalline soluble guanylate cyclase stimulators - Google Patents

Abstract

The invention relates to crystalline forms of and processes for preparing crystalline forms of a compound of Formula I or a pharmaceutically acceptable salt thereof, which are useful for the treatment of cardiovascular disease, endothelial dysfunction, diastolic dysfunction, atherosclerosis, hypertension, heart failure, pulmonary hypertension (WHO groups I, II, III, IV), angina pectoris, thrombosis, restenosis, myocardial infarction, stroke, cardiac insufficiency, fibrosis, pulmonary hypertonia, erectile dysfunction, asthma, chronic kidney disease, diabetes, cirrhosis of the liver, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome, acute lung injury, pulmonary fibrosis, cystic fibrosis, or interstitial lung disease.

Description

PROCESSES FOR PREPARING CRYSTALLINE SOLUBLE GUANYLATE CYCLASE STIMULATORS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/510,231, filed June 26, 2023. FIELD OF THE INVENTION [0002] The invention relates to crystalline forms of and processes for preparing crystalline soluble guanylate cyclase stimulator compounds useful for the treatment of treating diseases or disorders which are associated with a disturbed cyclic guanosine monophosphate (cGMP) balance. More specifically, the invention relates to novel crystalline forms of the soluble guanylate cyclase inhibitor (S)-3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H- indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid, and its use for the treatment of various disorders. The invention further relates to pharmaceutical compositions of crystalline forms of (S)-3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4- pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid. BACKGROUND OF THE INVENTION [0003] Cyclic GMP (cGMP) is an important intracellular messenger which triggers a multitude of different effects via the modulation of cGMP-dependent protein kinases, phosphodiesterases and ion channels. Examples are the relaxation of smooth muscles, the inhibition of thrombocyte activation and the inhibition of the proliferation of smooth-muscle cells and of leukocyte adhesion. cGMP is produced by particulate and soluble guanylate cyclases as a response to a number of extracellular and intracellular stimuli. In the case of the particulate guanylate cyclases, stimulation is essentially effected by peptidic messengers, such as the atrial natriuretic peptide or the cerebral natriuretic peptide. The soluble guanylate cyclases ("sGC"), which are cytosolic heterodimeric heme proteins, in contrast, are essentially regulated by a family of low-molecular- weight factors which are formed enzymatically. The most important stimulant is nitrogen monoxide ("NO") or a closely related species. The function of other factors such as carbon monoxide or the hydroxyl radical is still largely unclear. The binding of NO to the heme with formation of a penta-coordinate heme-nitrosyl complex is proposed as the mechanism of the activation by NO. The associated release of the histidine which is bound in the basal state to the iron converts the enzyme into the active conformation. [0004] Active soluble guanylate cyclases are each composed of an α and a β subunit. Several subunit subtypes have been described which differ from one another with respect to sequence, tissue-specific distribution and expression in different development stages. The subtypes α₁ and ^β ₁ ^{are mainly expressed in brain and lung, while β} ₂ ^{is found in particular in liver and kidney.} The subtype α₂ was shown to be present in human fetal brain. The subunits referred to as α₃ and ^β ₃ ^{were isolated from human brain and are homologous to α} ₁ ^{and β} ₁ ^{. More recent works indicate an α} _2i ^{subunit which contains an insert in the catalytic domain. All subunits show great} homologies in the region of the catalytic domain. The enzymes presumably contain one heme per ^{heterodimer, which is bound via β} ₁ ^{-Cys-78 and/or β} ₁ ^{-His-105 and is part of the regulatory} center. [0005] Under pathologic conditions, the formation of guanylate-cyclase-activating factors can be reduced, or their degradation may be promoted owing to the increased occurrence of free radicals. The resulting reduced activation of the sGC leads, via a weakening of the respective cGMP-mediated cellular response, for example to an increase of the blood pressure, to platelet activation or to increased cell proliferation and cell adhesion. As a consequence, formation of endothelial dysfunction, atherosclerosis, hypertension, stable or unstable angina pectoris, thrombosis, myocardial infarction, strokes or erectile dysfunction results. Pharmacological stimulation of sGC offers a possibility to normalize cGMP production and therefore may make possible the treatment and/or prevention of such disorders. [0006] For the pharmacological stimulation of the sGC, use has been made of compounds whose activity is based on an intermediate NO release, for example organic nitrates. The drawback of this treatment is the development of tolerance and a reduction of activity, and the higher dosage which is required because of this. [0007] International Patent Application WO 2017/112617 describes a class of soluble guanylate cyclate inhibitors. Among the compounds disclosed in WO ‘617 include (S)-3-(4-{4-Amino-2- [6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid: referred to as Compound 1). Methods of are in WO ‘617. [0008] Certain crystalline forms have advantages in the preparation of pharmaceutical compositions of Compound 1, such as ease of processing, crystallization and handling. In particular, they exhibit improved physicochemical properties, such as stability to stress, rendering them particularly suitable for the manufacture of various pharmaceutical dosage forms. In addition, certain forms provide advantages in dosing. [0009] Methods for preparing (S)-3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)- 1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid, are disclosed in PROCESSES FOR PREPARING SOLUBLE GUANYLATE CYCLASE STIMULATORS, US Application No.63/510,222, which is hereby incorporated by reference. SUMMARY OF THE INVENTION [0010] The invention is directed to crystalline forms of Compound 1, also represented as the compound of Formula I.: or pharmaceutically acceptable salts thereof. for preparation of crystalline forms of Compound 1, or pharmaceutically acceptable salts thereof. 25721 [0012] Embodiments, sub-embodiments and features of the invention are either further described herein or will be apparent from the ensuing description, examples and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS [0013] FIGURE 1 is a graph of a Powder X-Ray Diffraction (PXRD) pattern of crystalline Form I of Compound 1, generated using the equipment and methods described herein. The graph plots the intensity of the peaks as defined by counts per second versus the diffraction angle 2 theta (2θ) in degrees. [0014] FIGURE 2 is a Differential Scanning Calorimetry (DSC) curve of crystalline Form I of Compound 1, generated using the equipment and methods described herein. The graph plots the total heat flow (Q) in Watt per gram (W/g) as function of temperature in degree Celsius (°C). [0015] FIGURE 3 is a graph of a Powder X-Ray Diffraction (PXRD) pattern of crystalline Form II of Compound 1, generated using the equipment and methods described herein. The graph plots the intensity of the peaks as defined by counts per second versus the diffraction angle 2 theta (2θ) in degrees. [0016] FIGURE 4 is a Differential Scanning Calorimetry (DSC) curve of crystalline Form II of Compound 1, generated using the equipment and methods described herein. The graph plots the total heat flow (Q) in Watt per gram (W/g) as function of temperature in degree Celsius (°C). [0017] FIGURE 5 is a graph of a Powder X-Ray Diffraction (PXRD) pattern of crystalline Form III of Compound 1, generated using the equipment and methods described herein. The graph plots the intensity of the peaks as defined by counts per second versus the diffraction angle 2 theta (2θ) in degrees. [0018] FIGURE 6 is a Differential Scanning Calorimetry (DSC) curve of crystalline Form III of Compound 1, generated using the equipment and methods described herein. The graph plots the total heat flow (Q) in Watt per gram (W/g) as function of temperature in degree Celsius (°C). DETAILED DESCRIPTION OF THE INVENTION Definitions [0019] The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. [0020] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. In some embodiments, pharmaceutically acceptable salts are ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion- exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidinyl, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidinyl, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. [0021] The term “patient” refers to a mammalian patient, including a human, canine, feline, bovine, or porcine patient, preferably a human patient, receiving or about to receive medical treatment. [0022] The term "treat" or "treatment" means to administer an agent, such as a composition containing any of the compounds described herein, internally or externally to a subject or patient having one or more disease symptoms, or being suspected of having a disease, for which the agent has therapeutic activity. Typically, the agent is administered in an amount effective to alleviate one or more disease symptoms in the treated subject or population, whether by inducing the regression of or inhibiting, delaying or slowing the progression of such symptom(s) by any clinically measurable degree. The amount of an agent that is effective to alleviate any particular disease symptom may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the drug to elicit a desired response in the subject. Whether a disease symptom has been alleviated can be assessed by any clinical measurement typically used by physicians or other skilled healthcare providers to assess the severity or progression status of that symptom. The term further includes a postponement of development of the symptoms associated with a disorder and/or a reduction in the severity of the symptoms of such disorder. The terms further include ameliorating existing uncontrolled or unwanted symptoms, preventing additional symptoms, and ameliorating or preventing the underlying causes of such symptoms. Thus, the terms denote that a beneficial result has been conferred on a mammalian subject with a disorder, disease or symptom, or with the potential to develop such a disorder, disease or symptom. Crystalline Forms of Compound 1 [0023] Described herein are crystalline forms of Compound 1, also represented as the compound of Formula I: given, the term "crystalline Compound 1” refers to all crystalline forms of Compound 1 described herein. [0025] One embodiment of the crystalline forms described herein is Compound 1 (Form 1). Form I is further described below. [0026] Another embodiment of the crystalline forms described herein is Compound 1 (Form II). Form II is further described below. [0027] Another embodiment of the crystalline forms described herein is Compound 1 (Form III). Form III is further described below. [0028] A further embodiment of the invention provides a particular drug substance that comprises at least one of the crystalline forms described herein. By “drug substance” is meant the active pharmaceutical ingredient. The amount of crystalline form in the drug substance can be quantified by the use of physical methods such as X-ray powder diffraction, solid-state fluorine- 19 magic-angle spinning (MAS) nuclear magnetic resonance spectroscopy, solid-state carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance spectroscopy, solid state Fourier-transform infrared spectroscopy, and Raman spectroscopy. [0029] In a class of this embodiment, a crystalline form of the compound of Formula I is present in about 5% to about 100% by weight of the drug substance. In a second class of this embodiment, a crystalline form of the compound of Formula I is present in about 10% to about 100% by weight of the drug substance. In a third class of this embodiment, a crystalline form of the compound of Formula I is present in about 25% to about 100% by weight of the drug substance. In a fourth class of this embodiment, a crystalline form of the compound of Formula I is present in about 50% to about 100% by weight of the drug substance. In a fifth class of this embodiment, a crystalline form of the compound of Formula I is present in about 75% to about 100% by weight of the drug substance. In a sixth class of this embodiment, substantially all of the drug substance is a crystalline form of the compound of Formula I, i.e., the drug substance is substantially phase pure crystalline. [0030] In another class of this embodiment, at least 5% by weight of the drug substance is a crystalline form of the compound of Formula I. In a yet another class of this embodiment, at least 10% by weight of the drug substance is a crystalline form of the compound of Formula I. In a still another class of this embodiment, at least 15% by weight of the drug substance is a crystalline form of the compound of Formula I. In another class of this embodiment, at least 20% by weight of the drug substance is a crystalline form of the compound of Formula I. In yet another class of this embodiment, at least 25% by weight of the drug substance is a crystalline form of the compound of Formula I. In still another class of this embodiment, at least 30% by weight of the drug substance is a crystalline form of the compound of Formula I. In another class of this embodiment, at least 35% by weight of the drug substance is a crystalline form of the compound of Formula I. In a yet another class of this embodiment, at least 40% by weight of the drug substance is a crystalline form of the compound of Formula I. In a still another class of this embodiment, at least 45% by weight of the drug substance is a crystalline form of the compound of Formula I. In another class of this embodiment, at least 50% by weight of the drug substance is a crystalline form of the compound of Formula I. In yet another class of this embodiment, at least 55% by weight of the drug substance is a crystalline form of the compound of Formula I. In still another class of this embodiment, at least 60% by weight of the drug substance is a crystalline form of the compound of Formula I. In another class of this embodiment, at least 65% by weight of the drug substance is a crystalline form of the compound of Formula I. In a yet another class of this embodiment, at least 70% by weight of the drug substance is a crystalline form of the compound of Formula I. In a still another class of this embodiment, at least 75% by weight of the drug substance is a crystalline form of the compound of Formula I. In another class of this embodiment, at least 80% by weight of the drug substance is a crystalline form of the compound of Formula I. In yet another class of this embodiment, at least 85% by weight of the drug substance is a crystalline form of the compound of Formula I. In still another class of this embodiment, at least 90% by weight of the drug substance is a crystalline form of the compound 25721 of Formula I. In another class of this embodiment, at least 95% by weight of the drug substance is a crystalline form of the compound of Formula I. In a yet another class of this embodiment, at least 100% by weight of the drug substance is a crystalline form of the compound of Formula I. [0031] In a class of this embodiment, crystalline Form II of the compound of Formula I is present in about 5% to about 100% by weight of the drug substance. In a second class of this embodiment, crystalline Form II of the compound of Formula I is present in about 10% to about 100% by weight of the drug substance. In a third class of this embodiment, crystalline Form II of the compound of Formula I is present in about 25% to about 100% by weight of the drug substance. In a fourth class of this embodiment, crystalline Form II of the compound of Formula I is present in about 50% to about 100% by weight of the drug substance. In a fifth class of this embodiment, crystalline Form II of the compound of Formula I is present in about 75% to about 100% by weight of the drug substance. In a sixth class of this embodiment, substantially all of the drug substance is crystalline Form II of the compound of Formula I, i.e., the drug substance is substantially phase pure crystalline. [0032] In another class of this embodiment, at least 5% by weight of the drug substance is crystalline Form II of the compound of Formula I. In a yet another class of this embodiment, at least 10% by weight of the drug substance is crystalline Form II of the compound of Formula I. In a still another class of this embodiment, at least 15% by weight of the drug substance is crystalline Form II of the compound of Formula I. In another class of this embodiment, at least 20% by weight of the drug substance is crystalline Form II of the compound of Formula I. In yet another class of this embodiment, at least 25% by weight of the drug substance is crystalline Form II of the compound of Formula I. In still another class of this embodiment, at least 30% by weight of the drug substance is crystalline Form II of the compound of Formula I. In another class of this embodiment, at least 35% by weight of the drug substance is crystalline Form II of the compound of Formula I. In a yet another class of this embodiment, at least 40% by weight of the drug substance is crystalline Form II of the compound of Formula I. In a still another class of this embodiment, at least 45% by weight of the drug substance is crystalline Form II of the compound of Formula I. In another class of this embodiment, at least 50% by weight of the drug substance is crystalline Form II of the compound of Formula I. In yet another class of this embodiment, at least 55% by weight of the drug substance is crystalline Form II of the compound of Formula I. In still another class of this embodiment, at least 60% by weight of the drug substance is crystalline Form II of the compound of Formula I. In another class of this embodiment, at least 65% by weight of the drug substance is crystalline Form II of the compound of Formula I. In a yet another class of this embodiment, at least 70% by weight of the drug 25721 substance is crystalline Form II of the compound of Formula I. In a still another class of this embodiment, at least 75% by weight of the drug substance is crystalline Form II of the compound of Formula I. In another class of this embodiment, at least 80% by weight of the drug substance is crystalline Form II of the compound of Formula I. In yet another class of this embodiment, at least 85% by weight of the drug substance is crystalline Form II of the compound of Formula I. In still another class of this embodiment, at least 90% by weight of the drug substance is crystalline Form II of the compound of Formula I. In another class of this embodiment, at least 95% by weight of the drug substance is crystalline Form II of the compound of Formula I. In a yet another class of this embodiment, about 100% by weight of the drug substance is crystalline Form II of the compound of Formula I. In another class of this embodiment, 100% by weight of the drug substance is crystalline Form II of the compound of Formula I. [0033] In a class of this embodiment, crystalline Form III of the compound of Formula I is present in about 5% to about 100% by weight of the drug substance. In a second class of this embodiment, crystalline Form III of the compound of Formula I is present in about 10% to about 100% by weight of the drug substance. In a third class of this embodiment, crystalline Form III of the compound of Formula I is present in about 25% to about 100% by weight of the drug substance. In a fourth class of this embodiment, crystalline Form III of the compound of Formula I is present in about 50% to about 100% by weight of the drug substance. In a fifth class of this embodiment, crystalline Form III of the compound of Formula I is present in about 75% to about 100% by weight of the drug substance. In a sixth class of this embodiment, substantially all of the drug substance is crystalline Form III of the compound of Formula I, i.e., the drug substance is substantially phase pure crystalline. [0034] In another class of this embodiment, at least 5% by weight of the drug substance is crystalline Form III of the compound of Formula I. In a yet another class of this embodiment, at least 10% by weight of the drug substance is crystalline Form III of the compound of Formula I. In a still another class of this embodiment, at least 15% by weight of the drug substance is crystalline Form III of the compound of Formula I. In another class of this embodiment, at least 20% by weight of the drug substance is crystalline Form III of the compound of Formula I. In yet another class of this embodiment, at least 25% by weight of the drug substance is crystalline Form III of the compound of Formula I. In still another class of this embodiment, at least 30% by weight of the drug substance is crystalline Form III of the compound of Formula I. In another class of this embodiment, at least 35% by weight of the drug substance is crystalline Form III of the compound of Formula I. In a yet another class of this embodiment, at least 40% by weight of the drug substance is crystalline Form III of the compound of Formula I. In a still another class of 25721 this embodiment, at least 45% by weight of the drug substance is crystalline Form III of the compound of Formula I. In another class of this embodiment, at least 50% by weight of the drug substance is crystalline Form III of the compound of Formula I. In yet another class of this embodiment, at least 55% by weight of the drug substance is crystalline Form III of the compound of Formula I. In still another class of this embodiment, at least 60% by weight of the drug substance is crystalline Form III of the compound of Formula I. In another class of this embodiment, at least 65% by weight of the drug substance is crystalline Form III of the compound of Formula I. In a yet another class of this embodiment, at least 70% by weight of the drug substance is crystalline Form III of the compound of Formula I. In a still another class of this embodiment, at least 75% by weight of the drug substance is crystalline Form III of the compound of Formula I. In another class of this embodiment, at least 80% by weight of the drug substance is crystalline Form III of the compound of Formula I. In yet another class of this embodiment, at least 85% by weight of the drug substance is crystalline Form III of the compound of Formula I. In still another class of this embodiment, at least 90% by weight of the drug substance is crystalline Form III of the compound of Formula I. In another class of this embodiment, at least 95% by weight of the drug substance is crystalline Form III of the compound of Formula I. In a yet another class of this embodiment, about 100% by weight of the drug substance is crystalline Form III of the compound of Formula I. In another class of this embodiment, 100% by weight of the drug substance is crystalline Form III of the compound of Formula I. [0035] The crystalline compounds described, and their pharmaceutically acceptable salts can be useful, for example, for the treatment and prevention of disorders including cardiovascular disease, endothelial dysfunction, diastolic dysfunction, atherosclerosis, hypertension, heart failure, pulmonary hypertension (WHO groups I, II, III, IV), angina pectoris, thrombosis, restenosis, myocardial infarction, stroke, cardiac insufficiency, fibrosis, pulmonary hypertonia, erectile dysfunction, asthma, chronic kidney disease, diabetes, cirrhosis of the liver, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome, acute lung injury, pulmonary fibrosis, cystic fibrosis, or interstitial lung disease. [0036] The invention also provides pharmaceutical compositions comprising a crystalline form described herein, in association with one or more pharmaceutically acceptable carriers or excipients. The invention also provides pharmaceutical compositions comprising crystalline Form I described herein, in association with one or more pharmaceutically acceptable carriers or excipients. The invention also provides pharmaceutical compositions comprising crystalline Form II described herein, in association with one or more pharmaceutically acceptable carriers or 25721 excipients. The invention also provides pharmaceutical compositions comprising crystalline Form III described herein, in association with one or more pharmaceutically acceptable carriers or excipients. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the active pharmaceutical ingredient in admixture with one or more pharmaceutically acceptable excipients wherein the active pharmaceutical ingredient comprises a detectable amount of a crystalline (S)-3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)- 1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid. [0037] In a second embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the active pharmaceutical ingredient in an admixture with one or more pharmaceutically acceptable excipients wherein the active pharmaceutical ingredient comprises about 1% to about 100% by weight of crystalline (S)-3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4- pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid. In a class of this second embodiment, the active pharmaceutical ingredient in such compositions comprises about 5% to about 100% by weight of crystalline (S)- 3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid. In a second class of this embodiment, the active pharmaceutical ingredient in such compositions comprises about 10% to about 100% by weight of crystalline (S)-3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4- pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid. In a third class of this embodiment, the active pharmaceutical ingredient in such compositions comprises about 25% to about 100% by weight of crystalline (S)-3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo- 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid. In a fourth class of this embodiment, the active pharmaceutical ingredient in such compositions comprises about 50% to about 100% by weight of crystalline (S)-3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4- pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid. [0038] In a third embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the active pharmaceutical ingredient in an admixture one or more with pharmaceutically acceptable excipients wherein the active pharmaceutical ingredient comprises at least 1% by weight of crystalline (S)-3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4- pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid. In a class of this second embodiment, the active pharmaceutical 25721 ingredient in such compositions comprises at least 5% by weight of crystalline (S)-3-(4-{4- Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid. In a second class of this embodiment, the active pharmaceutical ingredient in such compositions comprises at least 10% by weight of crystalline (S)-3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5- methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid. In a third class of this embodiment, the active pharmaceutical ingredient in such compositions comprises at least 25% by weight of crystalline (S)-3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)- 1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid. In a fourth class of this embodiment, the active pharmaceutical ingredient in such compositions comprises at least 50% by weight of crystalline (S)-3-(4-{4- Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid. [0039] The compositions in accordance with the invention are suitably in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile solutions or suspensions, metered aerosol or liquid sprays, dry powders for inhalation, drops, ampoules, auto-injector devices or suppositories. The compositions are intended for oral, parenteral, intranasal, sublingual, or rectal administration, or for administration by inhalation or insufflation. Formulation of the compositions according to the invention can conveniently be affected by methods known from the art, for example, as described in Remington’s Pharmaceutical Sciences, 17th ed., 1995. [0040] The dosage regimen is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; and the renal and hepatic function of the patient. An ordinarily skilled physician, veterinarian, or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. [0041] Oral dosages of the invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, in some embodiments, some doses will range from between 0.01 to 10 mg/kg/day, and in other embodiments, some doses will range from between 0.1 to 5.0 mg/kg/day. For oral administration, the compositions are provided, in some embodiments, in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. For inhalation administration, the compositions are provided, in some embodiments, in the form of a dry powder containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 25721 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, and in some embodiments, from about 1 mg to about 200 mg of active ingredient. Intravenously, in some embodiments, doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. The crystalline forms of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Processes and Intermediates for Preparing the Compound of Formula I [0042] In one embodiment, the invention relates to a process for preparing a compound of Formula I according to the following scheme: . of Formula I a pharmaceutically acceptable salt thereof, 25721 acceptable salt thereof with a compound of Formula (III) acceptable salt thereof. the invention also relates to processes for preparing a compound of Formula (III) or a pharmaceutically acceptable salt thereof, comprising contacting a compound of Formula (IV) the ammonium salt is selected from the group consisting of ammonium trifluoromethanesulfonate, ammonium benzenesulfonate, ammonium diphenyl phosphate, ammonium camphor sufonate, ammonium bromide, ammonium iodide, ammonium chloride, ammonium perchlorate, ammonium triflamide, ammonium pentafluorophosphate. In certain embodiments, the ammonium salt is ammonium trifluoromethanesulfonate. [0046] In another embodiment, the invention also relates to processes for preparing a compound of Formula (IV) or a pharmaceutically acceptable salt thereof, comprising contacting a compound of Formula (V) H N CF₃ salt thereof, with a copper salt and a ligand. 25721 [0047] In particular embodiments, the copper salt is selected from the group consisting of copper (I) chloride, copper (I) iodide and copper (I) bromide. In certain embodiments, the copper salt is copper (I) chloride. [0048] In particular embodiments, the ligand is selected from the group consisting of quinolin- 8-ol, dimethylglycine, proline, picolinic acid, N¹,N¹,N²,N²-tetramethylethane-1,2-diamine, N¹,N²- dimethylethane-1,2-diamine, cyclohexane-1,2-diamine, 2,2'-bipyridine, 1,10-phenanthroline, (2E,4E)-N²,N⁴-dimethylpentane-2,4-diimine, picolinamide, N,N-diethyl-2-hydroxybenzamide, 2,2':6',2''-terpyridine, thiophene-2-carboxylic acid, and 1,3-di(pyridin-2-yl)propane-1,2-dione. In certain embodiments, the ligand is 1,10-phenanthroline. [0049] In another embodiment, the invention also relates to processes for preparing a compound of Formula (V) or a pharmaceutically salt thereof, comprising contacting a compound of Formula (VI) of K2CO3, K₃PO₄, K₂HPO₄, KOtBu, LiOtBu, NaOEt. In certain embodiments, the base is K₂CO₃. [0051] In another embodiment, the invention also relates to processes for preparing a compound of Formula (II) salt thereof, comprising contacting a compound of Formula (VIII) 25721 [0052] In particular embodiments, the hydroxide is selected from the group consisting of LiOH, NaOH, KOH, and NH₄OH. In certain embodiments, the hydroxide is LiOH. [0053] In another embodiment, the invention also relates to processes for preparing a compound of Formula (VIII) or a pharmaceutically acceptable salt thereof, comprising contacting a compound of Formula (IX) 2,2,4,4,5,5-hexamethyl-1,3,2-dioxaborolan-2-uide. the compound of Formula (IX) is treated with trimethylboroxine in the presence of a copper salt, a ligand, an alkoxide and an alcohol. A ligand refers to an organic molecule attached to a transition metal ion through coordination bonding used to modulate reactivity and/or selectivity of the desired chemical transformation. In certain embodiments, the copper salt is selected from the group consisting of copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) pentafluorophosphate tetraacetonitrile complex, copper (I) thiophene-2-carboxylate, copper (I) trifluoromethanesulfonate. In specific embodiments, the copper salt is copper (I) chloride. In some embodiments, the alkoxide is selected from the group consisting of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert- amylate, sodium tert-amylate, potassium tert-amylate. In particular embodiments, the alkoxide is potassium tert-amylate. In certain embodiments, the alcohol is selected from the group consisting of tert-butanol and tert-amyl alcohol. In specific embodiments, the alcohol is tert-amyl alcohol. [0055] In particular embodiments, the ligand is a Pymox or Quinox ligand of formulas A and B , wherein R¹, R², R³, and R^{4 6 7} or heteroaryl, and R , R , and R⁸ are independently alkyl, cycloalkyl, aryl or heteroaryl. In some embodiments, the ligand is selected from the group consisting of (4R,5S)-4,5-diphenyl-2-(quinolin-2-yl)-4,5- dihydrooxazole, (R)-4-(naphthalen-1-yl)-2-(quinolin-2-yl)-4,5-dihydrooxazole, (4R,5S)-2-(6- methoxyquinolin-2-yl)-4,5-diphenyl-4,5-dihydrooxazole, (4R,5S)-2-(6-methylpyridin-2-yl)-4,5- diphenyl-4,5-dihydrooxazole, (R)-2-(6-methylpyridin-2-yl)-4-(naphthalen-1-yl)-4,5- 25721 dihydrooxazole, and (R)-4-(2-(tert-butyl)phenyl)-2-(quinolin-2-yl)-4,5-dihydrooxazole. In certain embodiments. the ligand is (4R,5S)-4,5-diphenyl-2-(quinolin-2-yl)-4,5-dihydrooxazole or (4R,5S)-2-(6-methoxyquinolin-2-yl)-4,5-diphenyl-4,5-dihydrooxazole. [0056] In particular embodiments, the compound of Formula (IX) is treated with lithium 2,2,4,4,5,5-hexamethyl-1,3,2-dioxaborolan-2-uide in the presence of a copper salt and a ligand. In certain embodiments, the copper salt is selected from the group consisting of copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) pentafluorophosphate tetraacetonitrile complex, copper (I) thiophene-2-carboxylate, copper (I) trifluoromethanesulfonate. In specific embodiments, the copper salt is copper (I) chloride. In particular embodiments, the ligand is selected from the group consisting of (4R,5S)-4,5-diphenyl-2-(quinolin-2-yl)-4,5- dihydrooxazole, (R)-4-(naphthalen-1-yl)-2-(quinolin-2-yl)-4,5-dihydrooxazole, (4R,5S)-2-(6- methoxyquinolin-2-yl)-4,5-diphenyl-4,5-dihydrooxazole, (4R,5S)-2-(6-methylpyridin-2-yl)-4,5- diphenyl-4,5-dihydrooxazole, (R)-2-(6-methylpyridin-2-yl)-4-(naphthalen-1-yl)-4,5- dihydrooxazole, and (R)-4-(2-(tert-butyl)phenyl)-2-(quinolin-2-yl)-4,5-dihydrooxazole. In certain embodiments, the ligand is (4R,5S)-4,5-diphenyl-2-(quinolin-2-yl)-4,5-dihydrooxazole or (4R,5S)-2-(6-methoxyquinolin-2-yl)-4,5-diphenyl-4,5-dihydrooxazole. [0057] In another embodiment, the invention also relates to processes for preparing a compound of Formula (VIII’) salt thereof, comprising contacting a compound of Formula (IX) source. [0058] In particular embodiments, the organometallic methyl source is selected from the group consisting of methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide, dimethyl zinc, trimethyl aluminum. 25721 [0059] In another embodiment, the invention also relates to processes for preparing a compound of Formula (IX), or a pharmaceutically acceptable salt thereof, comprising contacting a compound of Formula (X) the invention also relates to processes for preparing a compound of Formula (X) or a pharmaceutically acceptable salt thereof, comprising contacting a compound of formula (XI) the compound of Formula (XI) is treated with malononitrile in the presence of an amine catalyst. In certain embodiments, the amine catalyst is 6- aminohexanoic acid. EXAMPLES [0062] The meanings of the abbreviations in Examples and Specification are shown below. Rb flask = round-bottomed flask Meldrum’s acid = 2,2-dimethyl-1,3-dioxane-4,6-dione °C means degrees Celsius FIG (or FIG. or Fig. or Fig or fig. or fig) means Figure (or figure) and refers to the corresponding figure 6 N HCl = 6 normal hydrochloric acid 1H NMR = proton nuclear magnetic resonance 13C NMR = carbon-13 nuclear magnetic resonance DMSO-d6 = per-deuterated dimethyl sulfoxide MHz = megahertz THF = tetrahydrofuran 25721 LiBr = lithium bromide Ot = tert-butoxide N2 = nitrogen EA = ethyl acetate MeOH = methanol H₃PO₄ = phosphoric acid V = volumes KF = Karl Fischer (i.e water content determined by Karl Fischer titration) TMSCl = trimethylsilyl chloride HOAc = acetic acid IY = isolated yield CDCl3 = deuterated chloroform (R,S)-(4,5-diphenyl)-6-MeO-Quinox = (4R,5S)-2-(6-methoxyquinolin-2-yl)-4,5-diphen l-4,5-dihydrooxazole CuCl = copper (I) chloride Me = methyl LiOH = lithium hydroxide 2-MeTHF = 2-methyltetrahydrofuran MeOH-d4 = deuterated methanol P(OEt)3 = triethyl phosphite Rpm = revolutions per minute Nm = nanometers LED = light emitting diode W = watt SCCM = standard cubic centimeters per minute PSIG = pounds per square inch gauge MSA = methanesulfonic acid NMP = N-methyl-2-pyrrolidone NaHCO3 = sodium hydrogen carbonate or sodium bicarbonate EOR = end of reaction MTBE = methyl tert-butyl ether IPA = isopropyl alcohol or isopropanol mL/min = milliliters per minute MeCN = acetonitrile Wt% = weight percent HOTf = trifluoromethanesulfonic acid HMDS = hexamethyldisilazane KOH = potassium hydroxide NaCl = sodium chloride NH3 = ammonia 19F NMR = fluorine 19 nuclear magnetic resonance K2CO3 = potassium carbonate EXAMPLE 1 [0063] Bisnitrile acid amine salt (II) (8.0 g, 17.18 mmol, 1 eq) was partitioned between MTBE (32 mL) and 2 N aq. HCl (20 mL, 2.33 eq). The aqueous layer was discarded and the organic phase was washed with H2O (2 x 8 mL) and then the solvent was switched into 2-propanol (final volume = 60 mL) in vacuo. Amidine MSA salt (II) (8.25 g, 18.90 mmol, 1.1 eq) was then charged, followed by K2CO3 (3.56 g, 25.77 mmol, 1.5 eq). The reaction mixture was stirred for 36-48 h at 75 – 80 °C. The mixture was then diluted with H₂O (20 mL) and cooled to 20 °C. The pH of the mixture was adjusted to 6.0 – 6.1 using 2 N HCl (13.7 mL, 1.6 eq). The resulting homogeneous mixture was seeded with crystalline (III) and aged at 20 °C for 4 h, at which point the slurry was warmed to 35 °C and 0.6 N HCl (16 mL, 0.56 eq) was charged over 4 h. Upon completion of the addition, the mixture was slowly cooled to 20 °C over 4 h and then aged at 20 °C for 12 h. The solids were filtered and then washed with 45:55 IPA:H2O (2 x 25 mL), and dried in a vacuum oven at 55 °C for 24 h. The product (III) was obtained (8.37 g, 13.74 mmol, 80 % yield) as a white solid. EXAMPLE 2 O OEt HOTf (2 equiv) HN H₂O (2 equiv) NH₂ 1. work up w/ HN 1 N KOH NH₂ HMDS (5 equ ; N iv) , mol), and hexamethyldisilazane (4.55 kg, 28.2 mol). The mixture was cooled to 0-5 ^oC and the vessel was placed under slight positive pressure with no N₂ sweeping. A solution of H₂O (203.21 g, 11.27 mol) in sulfolane (6.39 L) was added while keeping at < 10 ^oC in order to minimize NH₃ gas escaping. The resulting mixture was cooled to -10 ^oC, then TfOH (1.692 kg, 11.27 mol) was slowly added at < 22 ^oC. The vessel was sealed and the mixture was heated at 120-130 °C for 24 h. The upper vessel was kept warm so that solid ammonium triflate did not deposit there. [0065] After cooling the mixture to rt, the batch (biphasic) was further cooled to 0-10 ^oC. 2.4 equiv 1N KOH (13.53 L, 14.207 kg, 13.53 mol) was slowly added at < 25 ^oC. After agitating for 30 min, and letting settle at rt, the bottom aqueous layer was removed (pH~14). The organic layer was washed with 18% brine (10.5 L). The aqueous layer was removed (pH ~12). To the organic phase was added ¼ (101 mL, 149 g) of 1.1 equiv methanesulfonic acid (402 mL, 595 g, 6.20 mol), then seeded with 0.2 wt% amidine MSA type A (8.5 g). The rest of MSA (447 g, 302 mL) was then slowly added over 1 h. During MSA addition, the temperature was controlled at < 25 ^oC. The resulting slurry, after aging at 22 ^oC for 15 h, was filtered, then displacement washed with 2 x 3 vol 2-MeTHF (2 x 6.4 L), and vacuum dried under N₂ at < 30 °C for 24 h. The product (III) was obtained (4.62 kg, 10.58 mol, 93 % yield) as an off-white to light beige solid. EXAMPLE 3-4 25721 mmol, 25 wt% in MeCN), (7.60 g, 22.26 mmol), potassium carbonate solution (6.19 g, 6.78 mmol, 15 wt% in water) were mixed together. The mixture was stirred for 20 h before potassium carbonate solution (3.68 g, 12.14 mmol, 46 wt% in water) was charged. The aqueous layer was discarded and the organic layer (V) was charged with acetonitrile (26.0 ml), potassium carbonate (5.59 g, 40.5 mmol), 1,10-phenanthroline (0.073 g, 0.405 mmol), and copper(I) chloride (0.020 g, 0.202 mmol). Air was purged with N2 three times and the mixture was stirred for 22 h at 70 °C. The mixture was then cooled down to 35 °C for 2 hours and water (25 mL) was charged. The aqueous layer was discarded and the organic layer was charged with acetonitrile (1.5 mL). The stream was cooled down to 7 °C, seeded with crystalline (IV) and aged for 4 h, at which point water (40 mL) was charged over 6 h. The mixture was aged for additional 2 h, then the solids were filtered and washed with 1.5:1 Water:MeCN (2 x 20 mL), and dried in a vacuum oven at 30 °C for 24 h. The product (IV) was obtained (6.66 g, 19.97 mmol, 89 % yield) as a white solid. EXAMPLE 5 [0067] The organic phase containing 1,4-additon Me-ester (VIII) (408 g, 4.55 wt%) was cooled to 0 °C.1 M LiOH (170 mL, 3 eq) was then added slowly, maintaining the internal temperature below 5 °C. The resulting biphasic mixture was stirred at 0 °C for 3 hours.3 M HCl (33 mL, 1.75 eq) was then charged slowly to tune the pH between 9.0 and 9.5. While cold, the biphasic mixture was allowed to settle, and the organic phase discarded. The aqueous phase was then transferred to a separate flask along with 2-MeTHF (180 mL, 7.2 V).3 M HCl (1.5 eq) was then 25721 charged to a final aqueous pH of 2. The aqueous phase was discarded, and the organic phase (II) washed with 13% brine (35 mL). EXAMPLE 6 . mg, was at room temperature for 3 hours. A separate round bottom flask was purged 3x with N₂/vacuum cycles. Toluene (275 mL, 11 V), Trimethylboroxine (50 wt% in THF, 66.5 mL, 3 eq) and tert-amyl alcohol (17.5 mL, 2 eq) were added to the flask. Potassium tert-pentoxide (25 wt% in toluene, 89 mL, 2 eq) was then added slowly over the course of 30 minutes. The resulting heterogeneous mixture was stirred at room temperature for 1 hour. Bisnitrile SM (IX) (25.0 g) was added to the boroxine mixture. The Cu-Quinox catalyst mixture was then transferred to the reaction vessel. The reaction mixture was heated to 75 °C and stirred under N₂ for 40 hours. The reaction mixture was cooled to 40 °C.3 M HCl (175 mL, 7 V) was added, and the biphasic mixture stirred at 40 °C for 3 hours. The aqueous phase was then discarded. The organic phase (VIII) was washed with 13% brine (125 mL, 5 V) and the aqueous phase discarded. EXAMPLE 7 [0069] Me-THF (15.1 L) and the mixture was cooled to -60 °C. Methylmagnesium bromide (3 M in THF, 1.2 eq, 5.41 mol, 1.8 kg) was charged dropwise over 2 h. The mixture was stirred at -60 °C for 1 h, at which point AcOH (3.5 eq, 15.82 mol, 0.95 kg) in 2-Me-THF (0.9 L) was added over 1 h at -60 °C. The mixture was warmed to 5 °C and water (9.0 L) was added over 1 h. The aqueous phase was discarded. The organic phase containing (VIII) (9.6 wt%, 4.59 mol, 1.507 kg, 95.6 % yield) was further processed according to the procedure from Example 5. Processes for Preparing Crystalline Forms of Compound 1 Crystallization of Form 1 (Example A) [0070] A 0.4 g sample of amorphous compound of Formula (I) was suspended in 3 mL of 3:1 v/v n-heptane:THF and heated to 70 °C with stirring for 3 days. The suspension was centrifuged, and the excess solvent was decanted to retain the wet solids. The recovered solids were dried under vacuum at 60 °C for 1h and then 11 days at 40 °C. XRPD and DSC analysis confirmed presence of Form 1. (Example B) [0071] A 1.0 g sample of amorphous compound of Formula (I) made by the process described in Example 1 was slurried in xylenes (2.4 mL) and heated to 100 °C. Seed of crystalline Form 1 (obtained according to the process of example A) was added to the suspension and a thick slurry rapidly formed.3 mL of additional xylenes was added to facilitate stirring. The suspension was stirred for one day at 100 °C and then the temperature was reduced to ambient. The suspension was stirred for one additional day and then was filtered onto a tared fritted funnel. The solids were dried under vacuum at 80 °C and characterized by XPRD and DCS. See Figures 1 and 2 respectively. The results of the XPRD analysis are displayed in Table 1. Table 1. d-spacing Pos [°2θ] [Å] 8 7 3 7 1 0 9 9 5 6 8 5 Crystallization of Form 2 (Example A] [0072] 17.3 g of Compound 1 was dissolved in IPAc (5.2 mL IPAc/g Compound 1) and heated to 75 °C. Heptane (2.1 mL/g of Compound 1) was added over 1 hour followed by Form 2 seed (1 wt%). The temperature of the system was subsequently decreased to 55 °C and aged for 12 hours prior to charging an additional heptane (2.1 mL/g of Compound 1) over 3 hours. After aging for 4 hours at 55 °C, the system was cooled to room temperature and the solids are filtered, washed with IPAc/heptane (1:1.5 v/v), and dried under vacuum to isolate 14.7 g (85% yield) of Form 2 solids. The solids were characterized by XPRD and DCS. See Figures 3 and 4 respectively. The results of the XPRD analysis are displayed in Table 2. Table 2. Pos. d-spacing [°2θ] [Å] Crystallization of Form 3 (Example A: unseeded crystallization) [0073] A 420 g sample of Compound 1 (Form 2) was suspended in IPAc (1.0 L) at 20 °C and charged to a 10 L vessel followed by 1L of IPAc rinsate. The combined batch was aged at room temperature overnight to fully dissolve all solids. [0074] Heptane (24L) was added to a 30 L vessel and warmed to 60 °C. The IPAc solution of Compound 1 was added to the heptane via reverse addition. The batch was agitated for an additional 1.5h and then the reactor jacket temperature was set to 20 °C followed by an overnight age. The batch was filtered through a medium frit sintered glass Buchner funnel and the cake washed with heptane (4 L/kg product). The solids were dried in a vacuum oven under full vacuum at 20 °C for 3 days and then at 40 °C until fully dried. The final isolated yield of Form 3 was 94.8%. The solids were characterized by XPRD and DCS. See Figures 5 and 6 respectively. The results of the XPRD analysis are displayed in Table 3. 25721 Table 3. Pos. d-spacing [°2θ] [Å] p d crystallization) [0075] A suspension of Form 2 (51.8 mg) and Form 3 (51.4 mg) was prepared in o-xylenes (0.5 mL) and heated to 120 °C for 90 minutes with stirring. The solids were sampled and analyzed by XRPD. The analysis confirmed full turnover to Form 3 had occurred.

Claims

25721 WHAT IS CLAIMED 1. A crystalline form of the compound of Formula (I). 2. The crystalline form of Claim 1 characterized by having at least three peaks in its powder X-ray diffraction pattern selected from the group consisting of 9.8 + 0.22θ, 11.2 + 0.22θ, 12.4 + 0.22θ, 13.3 + 0.22θ, 14.2 + 0.22θ, 18.1 + 0.22θ, 18.9 + 0.22θ, 19.8 + 0.22θ, 22.5 + 0.22θ, 24.3 + 0.22θ, 25.6 + 0.22θ, and 26.6 + 0.22θ. 3. The crystalline form of Claim 2 characterized by having three peaks in its powder X-ray diffraction pattern at peak positions of 18.1 + 0.22θ, 18.9 + 0.22θ, and 19.8 + 0.22θ. 4. The crystalline form of Claims 1 further characterized by the differential scanning calorimetric (DSC) curve of FIG.2. 5. The crystalline form of Claim 1 characterized by having at least three peaks in its powder X-ray diffraction pattern selected from the group consisting of 6.8 + 0.22θ, 8.3 + 0.22θ, 9.9 + 0.22θ, 12.1 + 0.22θ, 13.7 + 0.22θ, 15.4 + 0.22θ, 16.1 + 0.22θ, 18.4 + 0.22θ, 19.7 + 0.22θ, 21.9 + 0.22θ, 22.4 + 0.22θ, 22.9 + 0.22θ, and 23.6 + 0.22θ. 6. The crystalline form of Claim 5 characterized by having three peaks in its powder X-ray diffraction pattern at peak positions of 6.8 + 0.22θ, 8.3 + 0.22θ, and 18.4 + 0.22θ. 7. The crystalline form of Claims 1 further characterized by the differential scanning calorimetric (DSC) curve of FIG.4. 8. The crystalline form of Claim 1 characterized by having at least three peaks in its powder X-ray diffraction pattern selected from the group consisting of 9.3 + 0.22θ, 14.3 + 0.22θ, 14.7 + 0.22θ, 16.3 + 0.22θ, 16.9 + 0.22θ, 17.3 + 0.22θ, 18.3 + 0.22θ, 19.2 + 0.22θ, 19.7 + 0.22θ, 20.2 + 0.22θ, 20.7 + 0.22θ, 21.9 + 0.22θ, 23.7 + 0.22θ, and 25.0 + 0.22θ. 9. The crystalline form of Claim 8 characterized by having four peaks in its powder X-ray diffraction pattern at peak positions of 9.3 + 0.22θ, 16.3 + 0.22θ, 19.2 + 0.22θ, and 21.9 + 0.2 2θ. 25721 10. The crystalline form of Claims 1 further characterized by the differential scanning calorimetric (DSC) curve of FIG.6. 11. A pharmaceutical composition comprising a drug substance that comprises the crystalline form of the compound of Formula (I) of claim 1 and a pharmaceutically acceptable carrier. 12. The pharmaceutical composition of Claim 11, wherein at least 5% by weight of the crystalline form of the compound of Formula (I) is present in the drug substance. 13. A pharmaceutical composition of Claim 12, wherein at least 50% by weight of the crystalline form of the compound of Formula (I) is present in the drug substance.