WO2009158450A1 - Crystalline forms of ((((4-((5-(cyclopropylcarbamoyl)-2-methylphenyl)amino)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)carbonyl)(propyl)carbamoyl)oxy)methyl (4-(phosphonooxy)phenyl)acetate, preparation and use thereof - Google Patents

Abstract

The present invention generally relates to crystalline forms of ((((4-((5- (cyclopropylcart>amoyl)-2-methylphenyl)amino)-5-methylpyrrolo[2, 1 -J][ I,2,4]triazin- 6-yl)carbonyl)(propyl)carbamoyl)oxy)methyl (4-(phosphonooxy)phenyl)acetate. The present invention also generally relates to a pharmaceutical composition comprising said crystalline form, as well of methods of obtaining and using the crystalline form for the treatment of inflammatory-associated diseases.

Description

CRYSTALLINE FORMS OF ((((4-((5-(CYCLOPROPYLCARBAMOYL)^- METHYLPHENYL)AMINO)-5-METHYLPYRROLO[2,l-/] [l,2,4]TRIAZIN-6-

YL)CARBONYL)(PROPYL)CARBAMOYL)OXY)METHYL (4- (PHOSPHONOOXY)PHENYL)ACETATE, PREPARATION AND USE THEREOF

[0001] This application claims priority from U.S. Provisional Application No. 61/075372, filed June 25, 2008, incorporated in its entirety herein by reference.

FIELD OF THE INVENTION [0002] The present invention generally relates to crystalline forms of ((((4-((5-

(cyclopropylcarbamoyl)-2-methylphenyl)amino)-5-methylpyrrolo[2,l-/|[l,2,4]triazin- 6-yl)carbonyl)(propyl)carbamoyl)oxy)methyl (4-(phosphonooxy)phenyl)acetate. The present invention also generally relates to a pharmaceutical composition comprising said crystalline form, as well of methods of obtaining and using the crystalline form for the treatment of inflammatory-associated diseases.

BACKGROUND OF THE INVENTION

[0003] A large number of cytokines participate in the inflammatory response, including IL-I, IL-6, IL-8 and TNF-α. Overproduction of cytokines such as IL-I and TNF-α are implicated in a wide variety of diseases, including inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, and congestive heart failure, among others [Henry et al, Drugs FuL, 24: 1345-1354 (1999); Salituro et al, Curr. Med. Chem., 6:807-823 (1999)]. Evidence in human patients indicates that protein antagonists of cytokines are effective in treating chronic inflammatory diseases, such as, for example, monoclonal antibody to TNF-α (Enbrel) [Rankin et al., Br. J. Rheumatol, 34:334-342 (1995)], and soluble TNF-α receptor-Fc fusion protein (Etanercept) [Moreland et al., Ann. Intern. Med., 130:478-486 (1999)]. [0004] The biosynthesis of TNF-α occurs in many cell types in response to an external stimulus, such as, for example, a mitogen, an infectious organism, or trauma. Important mediators of TNF-α production are the mitogen-activated protein (MAP) kinases, and in particular, p38 kinase. These kinases are activated in response to various stress stimuli, including but not limited to proinflammatory cytokines, endotoxin, ultraviolet light, and osmotic shock. Activation of p38 requires dual phosphorylation by upstream MAP kinase kinases (MKK3 and MKK6) on threonine and tyrosine within a Thr-Gly-Tyr motif characteristic of p38 isozymes. [0005] There are four known isoforms of p38, i.e., p38α, p38β, p38γ, and p38δ. The α and β isoforms are expressed in inflammatory cells and are key mediators of TNF-α production. Inhibiting the p38α and β enzymes in cells results in reduced levels of TNF-α expression. Also, administering p38α and β inhibitors in animal models of inflammatory disease has proven that such inhibitors are effective in treating those diseases. Accordingly, the p38 enzymes serve an important role in inflammatory processes mediated by IL-I and TNF-α. Compounds that reportedly inhibit p38 kinase and cytokines such as IL-I and TNF-α for use in treating inflammatory diseases are disclosed in U.S. Patent Nos. 6,277,989 and 6,130,235 to Scios, Inc; U.S. Patent Nos. 6,147,080 and 5,945,418 to Vertex Pharmaceuticals Inc; U.S. Patent Nos. 6,251,914, 5,977,103 and 5,658,903 to Smith-Kline Beecham Corp.; U.S. Patent Nos. 5,932,576 and 6,087,496 to G.D. Searle & Co.; WO 00/56738 and WO 01/27089 to Astra Zeneca; WO 01/34605 to Johnson & Johnson; WO 00/12497 (quinazoline derivatives as p38 kinase inhibitors); WO 00/56738 (pyridine and pyrimidine derivatives for the same purpose); WO 00/12497 (discusses the relationship between p38 kinase inhibitors); and WO 00/12074 (piperazine and piperidine compounds useful as p38 inhibitors).

[0006] Other compounds that inhibit p38 kinase are pyrrolotriazine aniline compounds. Information on these compounds is disclosed in U.S. Patent Nos. 6,670,357; 6,867,300; 7,034,151; 7,160,883; 7,211,666; 7,253,167; and U.S. Application Publication Nos. 2003/0232831 (published Dec. 18, 2003);

2004/0229877 (published Nov. 18, 2004); 2005/0043306 (published Feb. 24, 2005; 2006/0003967 (published Jan. 5, 2006); 2006/0030708 (published Feb. 9, 2006); 2006/0041124 (published Feb. 23, 2006); 2006/0229449 (published Oct. 12, 2006); 2006/0235020 (published Oct. 19, 2006); and 2007/0213300 (published Sept. 13, 2007).

[0007] In particular, U.S. Patent Application Publication No. 2007/02133OOA discloses the compound ((((4-((5-(cyclopropylcarbamoyl)-2-methylphenyl)amino)-5- methylpyrrolo[2, 1 -f\ [ 1 ,2,4]triazin-6-yl)carbonyl)(propyl)carbamoyl)oxy)methyl (4- (phosphonooxy)phenyl)acetate having the structure of formula I:

or pharmaceutically acceptable salts thereof, which are advantageous as inhibitors of p38 kinase and may be used for treating p38 kinase-associated conditions, including rheumatoid arthritis. The compound of formula I is also referred to herein as "Compound 1". Processes for preparing Compound 1 and methods of treatment employing Compound 1 are also disclosed in U.S. Patent Publication No. 2007/0213300A. This patent is assigned to the present assignee and is incorporated herein by reference in its entirety.

[0008] In some cases it is desirable to find more optimal forms of such compounds. Properties of more desirable forms of pyrrolotriazine aniline compounds include improved solubility, stability, bioavailability, and/or storage stability. Particle size, particle shape and reproducibility of form may also be important considerations.

SUMMARY OF THE INVENTION

[0009] This invention comprises selected forms of a compound of Formula I (also referred to herein as "Compound 1") especially a first crystalline form whose IUPAC name is ((((4-((5-(cyclopropylcarbamoyl)-2-methylphenyl)amino)-5- methylpyrrolo[2, 1 -J] [ 1 ,2,4]triazin-6-yl)carbonyl)(propyl)carbamoyl)oxy)methyl (4- (phosphonooxy)phenyl)acetate:

Compound 1 .

[0010] In particular, Compound 1 has very limited solubility in common organic solvents and it has been am important challenge to crystallize suitable forms of the compound of Formula I. This invention comprises such crystalline forms such as the group consisting of Forms IA2-1; MIBK2-1; MA2.5-1; TRA-I; SA-3; SB-3; SC-3;

TFE-4; TFA-12; IBU2-5; HPA2-6; SA-7; SA-8; SA-9; BY2-10; VA2-10; CP2-10; and SA-11. Also described herein are processes for preparing various forms.

[0011] A first crystalline form of Compound 1 is IA2-1. [0012] A second crystalline form of Compound 1 is MIBK2-1.

[0013] A third crystalline form of Compound 1 is MA2.5-1.

[0014] A fourth crystalline form of Compound 1 is TRA-I.

[0015] A fifth crystalline form of Compound 1 is SA-3.

[0016] A sixth crystalline form of Compound 1 is SB-3. [0017] A seventh crystalline form of Compound 1 is SC-3.

[0018] An eighth crystalline form of Compound 1 is TFE-4.

[0019] A ninth crystalline form of Compound 1 is TFA-4.

[0020] A tenth crystalline form of Compound 1 is TFA-12.

[0021] An eleventh crystalline form of Compound 1 is IBU2-5. [0022] A twelfth crystalline form of Compound 1 is HPA2-6.

[0023] A thirteenth crystalline form of Compound 1 is SA-7.

[0024] A fourteenth crystalline form of Compound 1 is SA-8. [0025] A fifteenth crystalline form of Compound 1 is SA-9. [0026] A sixteenth crystalline form of Compound 1 is SA-11. [0027] A seventeenth crystalline form of Compound 1 is BY2-10. [0028] An eighteenth crystalline form of Compound 1 is VA2-10. [0029] A nineteenth crystalline form of Compound 1 is CP2-10.

[0030] Further described herein are one or more pharmaceutical compositions comprising at least one crystalline form of Compound 1 and at least one pharmaceutically acceptable carrier and/or diluent. It is also contemplated that other embodiments of the invention will comprise at least one crystalline form of a compound of Compound 1, at least one pharmaceutically acceptable carrier and/or diluent, and, optionally, a second active ingredient particularly, for example, a second p38-kinase active agent.

BRIEF DESCRIPTION OF THE DRAWINGS [0031] Figure 1. Shows simulated and observed PXRD curves of Form IA2-1.

[0032] Figure 2. Shows simulated and observed PXRD curves of Form MIBK2-

1.

[0033] Figure 3. Shows a simulated PXRD of curve of Form MA2.5-1.

[0034] Figure 4. Shows a simulated PXRD curve of Form TRA- 1. [0035] Figure 5. Shows a simulated and observed PXRD curves of Form SA-3.

[0036] Figure 6. Shows a simulated PXRD curve of Form SB-3.

[0037] Figure 7. Shows s a simulated PXRD curve of Form SC-3.

[0038] Figure 8. Shows simulated and observed PXRD curves of Form TFE-4.

[0039] Figure 9.. Shows a simulated PXRD curve of Form TFA-4. [0040] Figure 10. Shows simulated and observed PXRD curve of Form IBU2-5.

[0041] Figure 11. Shows a simulated PXRD curve of Form HPA2-6

[0042] Figure 12. Shows simulated and observed PXRD curve of Form SA-7.

[0043] Figure 13. Shows simulated and observed PXRD curve of Form SA-8.

[0044] Figure 14. Shows a simulated PXRD curve of Form SA-9. [0045] Figure 15. Shows a simulated PXRD curve of Form BY2-10.

[0046] Figure 16. Shows simulated and observed PXRD curves of Form VA2-10.

[0047] Figure 17. Shows simulated and observed PXRD curves of Form CP2-10. [0048] Figure 18. Shows simulated and observed PXRD curves of Form SA-11. [0049] Figure 19. Shows a simulated PXRD curve of Form TFA- 12.

DETAILED DESCRIPTION OF THE INVENTION [0050] The features and advantages of the invention may be more readily understood by those of ordinary skill in the art upon reading the following detailed description. It is to be appreciated that certain features of the invention that are, for clarity reasons, described above and below in the context of separate embodiments, may also be combined to form a single embodiment. Conversely, various features of the invention that are, for brevity reasons, described in the context of a single embodiment, may also be combined so as to form sub-combinations thereof. [0051] The names used herein to characterize a specific crystalline form, e.g., IA2-1, MIBK2-1, etc., are identifiers that are to be interpreted in accordance with the characterization information presented herein. [0052] The definitions set forth herein take precedence over definitions set forth in any patent, patent application, and/or patent application publication incorporated herein by reference. All numbers expressing quantities of ingredients, weight percentages, temperatures, and so forth whether or not they are preceded by the word "about" are to be understood as only target approximations so that slight variations above and below the stated number may be used to achieve substantially the same results as the stated number. Accordingly, unless indicated to the contrary, numerical parameters whether or not they are preceded by the word "about" are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0053] All measurements are subject to experimental error and are within the spirit of the invention. [0054] As used herein, "polymorphs" refer to crystalline forms having the same chemical structure but different spatial arrangements of the molecules and/or ions forming the crystals. [0055] As used herein, "amorphous" refers to a solid form of a molecule and/or ion that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern with sharp maxima.

[0056] As used herein, the term "substantially pure" means the crystalline form of Compound 1 referred to which contains at least about 90 wt.%, based on the weight of such crystalline form. The term "at least about 90 wt.%," while not intending to limit the applicability of the doctrine of equivalents to the scope of the claims, includes, but is not limited to, for example, about 90, 90, about 91, 91, about 92, 92, about 93, 93, about 94, 94, about 95, 95, about 96, 96, about 97, 97, about 98, 98, about 99, 99, and about 100 wt. %, based on the weight of the crystalline form referred to. The remainder of the crystalline form of Compound 1 may comprise other Form(s) of Compound 1 and/or reaction impurities and/or processing impurities that arise, for example, when the crystalline form is prepared. For example, a crystalline form of Compound 1 may be deemed substantially pure if the crystalline form contains at least 90 wt. %, based on the weight of such crystalline form as measured by means that are at this time known and generally accepted in the art, and less than about 10 wt. %, based on the weight of such crystalline form, of material comprising other form(s) of Compound 1 and/or reaction impurities and/or processing impurities. The presence of reaction impurities and/or processing impurities may be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, and/or infrared spectroscopy. [0057] As used herein, the parameter "molecules/asymmetric unit" refers to the number of molecules of Compound 1 in the asymmetric unit. [0058] As used herein, the unit cell parameter "molecules/unit cell" refers to the number of molecules of Compound 1 in the unit cell.

[0059] When dissolved, the crystalline form of Compound 1 loses its crystalline structure, and is therefore referred to as a solution of Compound 1. At least one crystalline form of Compound 1 disclosed herein may be used to prepare at least one liquid formulation in which at least one crystalline form of Compound 1 is dissolved and/or suspended.

[0060] By "therapeutically effective amount" is meant an amount that when administered either alone, or in combination with an additional therapeutic agent is effective to prevent, suppress, and/or ameliorate a disease and/or condition and/or the progression of a disease and/or condition.

[0061] Other definitions include the following:

[0062] For ease of reference, the following abbreviations are employed herein, including the methods of preparation and Examples that follow: a, b and c = unit cell lengths in Angstroms α, β, and γ = unit cell angles in degrees(°)

Ac = acetic acid aq. = aqueous DSC = differential scanning calorimetry

Et = ethyl

EtOAc = ethyl acetate

EtOCHO = ethyl formate

EtOH = ethanol g = gram(s) h = hour(s)

HPLC = high performance liquid chromatography iBuOH = isobutanol iPr or Iso-P or iso-p = isopropyl L or 1 = liter

LC/MS = high performance liquid chromatography/mass spectrometry

Me = methyl

MeOAc = methyl acetate

MeOH = methanol Meq = milliequivalent mg = milligram(s)

MIBK = methylisobutylketone min = minute(s) mL = milliliter mmol = millimole(s) mol = moles mp = melting point MS or ms = mass spectrometry

MTBE = methyl tert-butyl ether

NaH = sodium hydride

NaOH = sodium hydroxide BuOAc = butyl acetate nBuOAc = n-butyl acetate

PG = propylene glycol nPrOAc = n-propyl acetate

NMR = nuclear magnetic resonance Ph = phenyl

Pr = propyl

PXRD = powder x-ray diffraction

R factor = crystallographic agreement factor which is a measure of the agreement between the crystallographic model and the experimental X-ray diffraction data rh = relative humidity ret. t. = HPLC retention time (minutes)

RP HPLC = reverse phase HPLC

RT or rt = room temperature sat or sat'd = saturated t-Bu = a tertiary butyl group

TFA = trifluoroacetic acid

TFE = 2,2,2 trifluoroethanol

TGA = thermogravimetric analysis

THF = tetrahydrofuran TLC = thin layer chromatography μg = microgram(s) μL or μl = microliter(s) μm = micromole(s)

V/Z = Unit cell volume/number of Compound 1 in the unit cell Z = molecules of Compound 1 in unit cell

Z'= Zprime = molecules of Compound 1 in the asymmetric unit [0063] Disclosed herein are crystalline forms of Compound 1 including Forms IA2-1; MIBK2-1; MA2.5-1; TRA-I; SA-3; SB-3; SC-3; TFE-4; TFA-12; IBU2-5; HPA2-6; SA-7; SA-8; SA-9; BY2-10; VA2-10; CP2-10; and SA-I l.

FORM EMBODIMENTS

Form IA2-1

[0064] A first crystalline form of Compound 1 comprises a diisopropylacetate solvate of Compound 1 referred to herein as "Form IA2-1" or "IA2-lForm". The IA2-1 Form is the diisopropylacetate solvate form of Compound 1. [0065] In one embodiment of Form IA2-1, the form is characterized by unit cell parameters approximately equal to the following as listed in Table 1, displayed in Example 1 (infra), wherein the unit cell parameters of Form IA2-1 are measured at - 50⁰C. [0066] In a second embodiment of Form IA2-1, the IA2-1 Form is characterized by a simulated powder x-ray diffraction (PXRD) pattern substantially in accordance with the simulated and/or observed PXRD pattern shown in Figure 1. [0067] In a third embodiment of Form IA2-1, the IA2-1 Form is characterized by a PXRD pattern (CuKa λ= 1.5418 A at a temperature of about 25°C) comprising four or more, preferably five or more, 2 theta ("2Θ") values selected from: 6.4, 8.0, 8.3, 10.6, 15.6, 18.3, 18.7, 20.5, 22.7, 23.3, 25.7 (degrees 2Θ ±0.1) wherein the PXRD pattern of Form IA2-1 is measured at a temperature of about 25°C. [0068] In a fourth embodiment of Form IA2-1, the IA2-1 Form is characterized by fractional atomic coordinates substantially as listed in Table 2, displayed in Example 1, infra.

Form MIBK2-1

[0069] A second crystalline form of Compound 1 comprises a solvated form of Compound 1 referred to herein as "Form MIBK2-1" or "MIBK2-1 Form". The MIBK2-1 Form is the dimethylisobutylketone solvate form of Compound 1. [0070] In one embodiment of Form MIBK2-1, the form is characterized by unit cell parameters approximately equal to the data listed in Table 3 (displayed in Example 32, infra), wherein the unit cell parameters of Form MIBK2-1 are measured at room temperature (about -50⁰C)

[0071] In a second embodiment of Form MIBK2-1, the MIBK2-1 Form is characterized by a PXRD pattern substantially in accordance with the simulated and/or observed PXRD pattern shown in Figure 2.

[0072] In a third embodiment of Form MIBK2-1, the MIBK2-1 Form is characterized by a PXRD pattern (CuKa λ= 1.5418 A at a temperature of about 25°C) comprising four or more, preferably five or more, 2 theta ("2Θ") values selected from: 6.4, 8.2, 9.5, 10.5, 12.8, 13.2, 15.70 and 25.6 (degrees 2Θ ±0.1) wherein the PXRD pattern of Form MIBK2-1 is measured at a temperature of about 25°C.

[0073] In a fourth embodiment of Form MIBK2-1, the MIBK2-1 Form is characterized by fractional atomic coordinates substantially as listed in Table 4 (in Example 2, infra).

Form MA2.5-1

[0074] A third crystalline form of Compound 1 comprises a methyl acetate form of Compound 1 referred to herein as "Form MA2.5-1" or "MA2.5-1 Form". The MA2.5-1 Form is the 2.5 methyl acetate solvate form of Compound 1. [0075] In one embodiment of Form MA2.5-1, the form is characterized by unit cell parameters approximately equal to data listed in Table 5 (displayed in Example 3, infra) wherein the unit cell parameters of Form MA2.5-1 are measured at about - 100⁰C.

[0076] In a second embodiment of Form MA2.5-1, the Form MA2.5-1 Form is characterized by fractional atomic coordinates substantially as listed in Table 6 (displayed in Example 3, infra). Occupancies are 1 unless otherwise indicated.

[0077] In a third embodiment of Form MA2.5, the MA2.5 Form is characterized by a PXRD pattern substantially in accordance with the simulated and/or observed PXRD pattern shown in Figure 3.

Form TRA-I [0078] A fourth crystalline form of Compound 1 comprises a triacetin solvate of Compound 1 referred to herein as "Form TRA-I" or "TRA-I Form". The TRA-I Form is the monotriacetin solvate form of Compound 1.

[0079] In one embodiment of Form TRA-I, the form is characterized by unit cell parameters approximately equal to data listed in Table 7 (displayed in Example 4 infra) wherein the unit cell parameters of Form TRA-I are measured at about -60⁰C. [0080] In a second embodiment of Form TRA-I, the TRA-I Form is characterized by a PXRD pattern substantially in accordance with the simulated and/or observed PXRD pattern shown in Figure 4. [0081] In a third embodiment of Form TRA-I, the TRA-I Form is characterized by fractional atomic coordinates substantially as listed in Table 8 (displayed in Example 4, infra). Occupancies are 1 unless otherwise indicated.

Form SA-3 [0082] A fifth crystalline form of Compound 1 comprises a formic acid/ethyl formate form of Compound 1 referred to herein as "Form SA-3" or "SA-3 Form".

The SA-3 Form is a monoformic acid/monoethyl formate solvate form of Compound

1.

[0083] In one embodiment of Form SA-3, the form is characterized by unit cell parameters approximately equal to data listed in Table 9 (displayed in Example 5 infra) wherein the unit cell parameters of Form SA-3 are measured at about -50⁰C.

[0084] In a second embodiment of Form SA-3, the SA-3 Form is characterized by a PXRD pattern substantially in accordance with the simulated and/or observed

PXRD pattern shown in Figure 5. [0085] In a third embodiment of Form SA-3, the SA-3 Form is characterized by a

PXRD pattern (CuKa λ=1.5418A at a temperature of about 25°C) comprising four or more, preferably five or more, 2 theta ("2Θ") values selected from: 6.7, 7.2, 8.2±0.2,

10.5, 13.5, 16.5, 19.6, 21.6, 22.5, 23.7 and 25.8, (degrees 2Θ ±0.1) wherein the PXRD pattern of Form SA-3 is measured at a temperature of about 25°C. [0086] In a fourth embodiment of Form SA-3, the SA-3 Form is characterized by fractional atomic coordinates substantially as listed in Table 10 (displayed in Example

5, infra). Form SB-3

[0087] A sixth crystalline form of Compound 1 comprises a solvated form of Compound 1 referred to herein as "Form SB-3" or "SB-3 Form". The SB-3 Form is the diformic acid/monohydrate solvate form of Compound 1.

[0088] In one embodiment of Form SB-3, the form is characterized by unit cell parameters approximately equal to data listed in Table 11 (displayed in Example 6 infra) wherein the unit cell parameters of Form SB-3 are measured at about -70⁰C. [0089] In a second embodiment of Form SB-3, the SB-3 Form is characterized by a PXRD pattern substantially in accordance with the simulated and/or observed PXRD pattern shown in Figure 6.

[0090] In a fourth embodiment of Form SB-3, the SB-3 Form is characterized by fractional atomic coordinates substantially as listed in Table 12 (displayed in Example 6, infra). Occupancies are 1 unless otherwise indicated

Form SC-3

[0091] A seventh crystalline form of Compound 1 comprises a mixed acetic acid and acetonitrile solvate form of Compound 1 referred to herein as "Form SC-3" or "SC-3 Form". The SC-3 Form is the mono acetic acid monoacetonitrile solvate form of Compound 1.

[0092] In one embodiment of Form SC-3, the form is characterized by unit cell parameters approximately equal to data listed in Table 13 (displayed in Example 7 infra) wherein the unit cell parameters of Form SC-3 are measured at about -60⁰C. [0093] In a second embodiment of Form SC-3, the SC-3 Form is characterized by a PXRD pattern substantially in accordance with the simulated and/or observed PXRD pattern shown in Figure 7.

[0094] In a third embodiment of Form SC-3, the SC-3 Form is characterized by a PXRD pattern (CuKa λ= 1.5418 A at a temperature of about 25°C) comprising four or more, preferably five or more, 2 theta ("2Θ") values selected from: 6.63, 7.1, 10.8, 13.1, 16, 18.7, 20.0, 24.2 and 26.3 (degrees 2Θ ±0.1), wherein the PXRD pattern of Form SC-3 is measured at a temperature of about 25°C. [0095] In a fourth embodiment of Form SC-3, the SC-3 Form is characterized by fractional atomic coordinates substantially as listed in Table 14 (displayed in Example 7, infra). Occupancies are 1 unless otherwise indicated.

Form TFE-4

[0096] An eighth crystalline form of Compound 1 comprises monotrifluoroethanol solvate form of Compound 1 referred to herein as "Form TFE- 4" or "TFE-4 Form". The TFE-4 Form is the monotrifluoroethanol solvate form of Compound 1. [0097] In one embodiment of Form TFE-4, the form is characterized by unit cell parameters approximately equal to data listed in Table 15 (displayed in Example 8 infra) wherein the unit cell parameters of Form SC-3 are measured at about -50⁰C. [0098] In a second embodiment of Form TFE-4, the TFE-4 Form is characterized by a PXRD pattern substantially in accordance with the simulated and/or observed PXRD pattern shown in Figure 8.

[0099] In a third embodiment of Form TFE-4, the TFE-4 Form is characterized by a PXRD pattern (CuKa λ= 1.5418 A at a temperature of about 25°C) comprising four or more, preferably five or more, 2 theta ("2Θ") values selected from: 7.27, 9.0, 9.9, 11.3, 12.9, 15.4, 16.9, 21.6, 23.8, 24.8 and 26.0 (degrees 2Θ ±0.1), wherein the PXRD pattern of Form TFE-4 is measured at a temperature of about 25 ⁰C.

[00100] In a fourth embodiment of Form TFE-4, the TFE-4 Form is characterized by fractional atomic coordinates substantially as listed in Table 16 (displayed in Example 8 infra). Occupancies are 1 unless otherwise indicated.

TFA-4

[00101] A ninth crystalline form of Compound 1 comprises a monotrifluoroacetic acid solvate form of Compound 1 referred to herein as "Form TFA-4" or "TFA-4 Form". The TFA-4 Form is the monotrifluoroacetic acid solvate form of Compound 1. [00102] In one embodiment of Form TFA-4, the form is characterized by unit cell parameters approximately equal to data listed in Table 17 wherein the unit cell parameters of Form TFA-4 are measured at about 25 ⁰C. [00103] In a second embodiment of Form TFA-4, the TFA-4 Form is characterized by a simulated powder x-ray diffraction (PXRD) pattern substantially in accordance with the pattern shown in Figure 9.

[00104] In a fourth embodiment of Form TFA-4, the TFA-4 Form is characterized by fractional atomic coordinates substantially as listed in Table 18 (displayed in Example 9, infra). Occupancies are 1 unless otherwise indicated.

Form IBU2-5

[00105] A tenth crystalline form of Compound 1 comprises isobutyl alcohol solvate form of Compound 1 referred to herein as "Form IBU2-5" or "IBU2-5 Form". [00106] In one embodiment of Form IBU2-5, the form is characterized by unit cell parameters approximately equal to data listed in Table 19 (displayed in Example 10, infra) wherein the unit cell parameters of Form IBU2-5 are measured at about -30⁰C. [00107] In a second embodiment of Form IBU2-5, the IBU2-5 Form is characterized by a PXRD pattern substantially in accordance with the simulated and/or observed PXRD pattern shown in Figure 10.

[00108] In a third embodiment of Form IBU2-5, the IBU2-5 Form is characterized by a PXRD pattern (CuKa λ= 1.5418 A at a temperature of about 25°C) comprising four or more, preferably five or more, 2 theta ("2Θ") values selected from: 5.7, 7.8, 9.9, 10.7, 17.8, 18.9, 19.9 and 20.9 (degrees 2Θ ±0.1), wherein the observed PXRD pattern of Form IBU2-5is measured at a temperature of about 25°C. [00109] In a fourth embodiment of Form IBU2-5, the IBU2-5 Form is characterized by fractional atomic coordinates substantially as listed in Table 20 (displayed in Example 10, infra). Occupancies are 1 unless otherwise indicated.

Form HPA2-6

[00110] An eleventh crystalline form of Compound 1 comprises a proprionic acid solvate form of Compound 1 referred to herein as "Form HPA2-6" or "HPA2-6 Form". The HPA2-6 Form is the di-proprionic acid solvate form of Compound 1. [00111] In one embodiment of Form HPA2-6, the form is characterized by unit cell parameters approximately equal to data listed in Table 21 (displayed in Example 11, infra) wherein the unit cell parameters of Form HPA2-6 are measured at about -70⁰C. [00112] In a second embodiment of Form HPA2-6, the HPA2-6 Form is characterized by a simulated powder x-ray diffraction (PXRD) pattern substantially in accordance with the pattern shown in Figure 11.

[00113] In a third embodiment of Form HPA2-6, the HPA2-6 Form is characterized by fractional atomic coordinates substantially as listed in Table 22 (displayed in Example 11, infra). Occupancies are 1 unless otherwise indicated.

Form SA-7

[00114] A twelfth crystalline form of Compound 1 comprises a mixed solvate of formic acid and proprionic acid in a form of Compound 1 referred to herein as "Form

SA-7" or "SA-7 Form". The SA-7 Form is the 3 formic acid and 1 proprionic acid form of Compound 1.

[00115] In one embodiment of Form SA-7, the form is characterized by unit cell parameters approximately equal to data listed in Table 23 (displayed in Example 12, infra) wherein the unit cell parameters of Form SA-7 are measured at about -50 ⁰C.

[00116] In a second embodiment of Form SA-7, the SA-7 Form is characterized by a PXRD pattern substantially in accordance with the simulated and/or observed

PXRD pattern shown in Figure 12.

[00117] In a third embodiment of Form SA-7, the SA-7 Form is characterized by a PXRD pattern (CuKa λ = 1.5418 A at a temperature of about 25°C) comprising four or more, preferably five or more, 2 theta ("2Θ") values selected from: 6.1, 7.2, 7.9,

10.5, 11.1, 12.1, 15.9, 19.0, 21.0, 23.7 and 29.9 (degrees 2Θ ±0.1), wherein the PXRD pattern of Form SA-7 is measured at a temperature of about 25°C.

[00118] In a fourth embodiment of Form SA-7, the SA-7 Form is characterized by fractional atomic coordinates substantially as listed in Table 24 (displayed in Example

12, infra). Occupancies are 1 unless otherwise indicated.

Form SA-8

[00119] A thirteenth crystalline form of Compound 1 comprises a mixed solvate benzoic acid and butyl acetate form of Compound 1 referred to herein as "Form SA- 8" or "SA-8 Form". The SA-8 Form is the benzoic acid and butyl acetate solvate form of Compound 1. [00120] In one embodiment of Form SA-8, the form is characterized by unit cell parameters approximately equal to data listed in Table 25 (displayed in Example 13, infra) wherein the unit cell parameters of Form SA-8 are measured at about -50 ⁰C. [00121] In a second embodiment of Form SA-8, the SA-8 Form is characterized by a PXRD pattern substantially in accordance with the simulated and/or observed PXRD pattern shown in Figure 13.

[00122] In a third embodiment of Form SA-8, the SA-8 Form is characterized by a PXRD pattern (CuKa λ = 1.5418 A at a temperature of about 25°C) comprising four or more, preferably five or more, 2 theta ("2Θ") values selected from: 5.6, 8.8, 11.2, 12.5, 14.1, 15.6±0.2, 21.7 and 23.5 (degrees 2Θ ±0.1), wherein the observed PXRD pattern of Form SA-8 is measured at a temperature of about 25°C. [00123] In a fourth embodiment of Form SA-8, the SA-8 Form is characterized by fractional atomic coordinates substantially as listed in Table 26 (displayed in Example

13, infra). Occupancies are 1 unless otherwise indicated.

Form SA-9

[00124] A fourteenth crystalline form of Compound 1 comprises a formic acid and butyl acetate form of Compound 1 referred to herein as "Form SA-9" or "SA-9 Form". The SA-9 Form is the 3 formic acid and BuOAc solvate form of Compound 1.

[00125] In one embodiment of Form SA-9, the form is characterized by unit cell parameters approximately equal to data listed in Table 27 (displayed in Example 14, infra) wherein the unit cell parameters of Form SA-9 are measured at about -100 ⁰C. [00126] In a second embodiment of Form SA-9, the SA-9 Form is characterized by a simulated powder x-ray diffraction (PXRD) pattern substantially in accordance with the pattern shown in Figure 14.

[00127] In a third embodiment of Form SA-9, the SA-9 Form is characterized by fractional atomic coordinates substantially as listed in Table 28 (displayed in Example

14, infra). Occupancies are 1 unless otherwise indicated.

Form BY2-10 [00128] A fifteenth crystalline form of Compound 1 comprises a butyric acid form of Compound 1 referred to herein as "Form BY2-10" or "BY2-10 Form". The BY2- 10 Form is the di -butyric acid solvate form of Compound 1.

[00129] In one embodiment of Form BY2-10, the form is characterized by unit cell parameters approximately equal to data listed in Table 29 (displayed in Example 15, infra) wherein the unit cell parameters of Form BY2-10 are measured at about -50⁰C. [00130] In a second embodiment of Form BY2-10, the BY2-10 Form is characterized by a powder x-ray diffraction (PXRD) pattern substantially in accordance with the pattern shown in Figure 15. [00131] In a third embodiment of Form BY2-10, the BY2-10 Form is characterized by fractional atomic coordinates substantially as listed in Table 30 (displayed in Example 15, infra). Occupancies are 1 unless otherwise indicated.

Form VA2-10 [00132] A sixteenth crystalline form of Compound 1 comprises a valeric acid form of Compound 1 referred to herein as "Form VA2-10" or "VA2-10 Form". The VA2- 10 Form is the di-valeric acid solvate form of Compound 1.

[00133] In one embodiment of Form VA2-10, the form is characterized by unit cell parameters approximately equal to data listed in Table 31 (displayed in Example 16, infra) wherein the unit cell parameters of Form VA2-10 were measured at about - 70⁰C.

[00134] In a second embodiment of Form VA2-10, the VA2-10 Form is characterized by a PXRD pattern substantially in accordance with the simulated and/or observed PXRD pattern shown in Figure 17. [00135] In a third embodiment of Form VA2-10, the VA2-10 Form is characterized by a PXRD pattern (CuKa λ = .5418 A at a temperature of about 25°C) comprising four or more, preferably five or more, 2 theta ("2Θ") values selected from: 5.6, 9.7, 11.9, 15.9, 16.8, 20.6 and 23.7 (degrees 2Θ ±0.1), wherein the PXRD pattern of Form VA2-10 is measured at a temperature of about 25°C. [00136] In a fourth embodiment of Form VA2- 10, the VA2- 10 Form is characterized by fractional atomic coordinates substantially as listed in Table 32 (displayed in Example 16, infra). Occupancies are 1 unless otherwise indicated. Form CP2-10

[00137] An seventeenth crystalline form of Compound 1 comprises a di-caproic acid solvate form of Compound 1 referred to herein as "Form CP2-10" or "CP2-10 Form". The CP2-10 Form is the di-caproic acid solvate form of Compound 1.

[00138] In one embodiment of Form CP2-10, the form is characterized by unit cell parameters approximately equal to data listed in Table 33 (displayed in Example 17, infra) wherein the unit cell parameters of Form CP2-10 were measured at about -50 ⁰C. [00139] In a second embodiment of Form CP2- 10, the CP2- 10 Form is characterized by a PXRD pattern substantially in accordance with the simulated and/or observed PXRD pattern shown in Figure 17.

[00140] In a third embodiment of Form CP2- 10, the CP2- 10 Form is characterized by a PXRD pattern (CuKa λ= 1.5418 A at a temperature of about 25°C) comprising four or more, preferably five or more, 2 theta ("2Θ") values selected from: 5.3±0.2, 11.6+0.2, 15.9±0.2, 16.5±0.2, 19.1±0.2, 21. l±0.2 and 28.6+0.2, wherein the PXRD pattern of Form CP2-10 is measured at a temperature of about 25°C. [00141] In a fourth embodiment of Form CP2-10, the CP2-10 Form is characterized by fractional atomic coordinates substantially as listed in Table 34 (displayed in Example 17, infra). Occupancies are 1 unless otherwise indicated.

Form SA-Il

[00142] An eighteenth crystalline form of Compound 1 comprises a solvated form of Compound 1 referred to herein as "Form SA-11" or "SA-11 Form". The SA-11 Form is the monotrifluoroacetic acid and 1/3 BuOAc solvate form of Compound 1. [00143] In one embodiment of Form SA-11, the form is characterized by unit cell parameters approximately equal to data listed in Table 35 (displayed in Example 18, infra) wherein the unit cell parameters of Form SA-11 are measured at about -50 ⁰C. [00144] In a second embodiment of Form SA-11, the SA-11 Form is characterized by a PXRD pattern substantially in accordance with the simulated and/or observed PXRD pattern shown in Figure 18. [00145] In a third embodiment of Form SA-11, the SA-11 Form is characterized by a PXRD pattern (CuKa λ= 1.5418 A at a temperature of about 25°C) comprising four or more, preferably five or more, 2 theta ("2Θ") values selected from: 6.3, 8.1, 10.6, 11.3, 12.6, 13.7, 16.0, 18.4, 20.5, 21.3 and 23.5 (degrees 2Θ ±0.1), wherein the PXRD pattern of Form SA-11 is measured at a temperature of about 25°C.

[00146] In a fourth embodiment of Form SA-11, the SA-11 Form is characterized by fractional atomic coordinates substantially as listed in Table 36, (displayed in Example 18, infra). Occupancies are 1 unless otherwise indicated.

Form TFA-12

[00147] A nineteenth crystalline form of Compound 1 comprises a monotrifluoroacetic acid solvate form of Compound 1 referred to herein as "Form TFA-12" or "TFA-12 Form". The TFA-12 Form is the monotrifluoroacetic acid solvate form of Compound 1. [00148] In one embodiment of Form TFA-12, the form is characterized by unit cell parameters approximately equal to data listed in Table 37 (displayed in Example 19, infra) wherein the unit cell parameters of Form TFA-12 are measured at about -70⁰C. [00149] In a second embodiment of Form TFA-12, the TFA-12 Form is characterized by a powder x-ray diffraction (PXRD) pattern substantially in accordance with the pattern shown in Figure 19.

[00150] In a third embodiment of Form TFA-12, the TFA-12 Form is characterized by a PXRD pattern (CuKa λ= 1.5418 A at a temperature of about 25°C) comprising four or more, preferably five or more, 2 theta ("2Θ") values selected from: 7.3, 9.1, 11.3, 12.5, 16.5, 18.1, 21.4, 23.9, 25.1 and 28.0 (degrees 2Θ ±0.1), wherein the PXRD pattern of Form TFA-12 is measured at a temperature of about 25°C.

[00151] In a fourth embodiment of Form TFA-12, the TFA-12 Form is characterized by fractional atomic coordinates substantially as listed in Table 38 (displayed in Example 19, infra). Occupancies are 1 unless otherwise indicated.

GENERAL EMBODIMENTS OF THE INVENTION

[00152] For each of the Forms described above, various purities and compositions can be obtained. [00153] For each of the Forms described above an embodiment may be obtained which is substantially pure.

[00154] For each of the Forms described above another embodiment may be obtained which contains at least about 90 wt.%, preferably at least about 95 wt.%, and more preferably at least about 99 wt.%, based on weight of the particular crystalline form.

[00155] For each of the Forms described above yet another embodiment may be found which is a substantially pure crystalline form with a substantially pure phase homogeneity of less than about 10%, preferably less than about 5%, and more preferably less than about 2% of the total peak area of the experimentally measured PXRD pattern arising from peaks that are absent from the simulated PXRD pattern. Most preferably, such a substantially pure crystalline form has substantially pure phase homogeneity with less than about 1% of the total peak area of the experimentally measured PXRD pattern arising from peaks that are absent from the simulated PXRD pattern.

[00156] For each of the Forms described above yet another embodiment may be found which consists essentially of the particular form. The particular crystalline form of such an embodiment may comprise at least about 90 wt. %, preferably at least about 95 wt. %, and more preferably at least about 99 wt. %, based on the weight of the particular crystalline form.

[00157] For each of the Forms described above yet another embodiment may be found which comprises a particular form and at least one pharmaceutically- acceptable carrier and/or diluent. [00158] For each of the Forms described above yet another embodiment may be found which comprises a substantially pure crystalline form; and at least one pharmaceutically-acceptable carrier and/or diluent.

[00159] For each of the Forms described above yet another embodiment may be found in which a particular form is combined with at least one pharmaceutically acceptable carrier and/or diluent to provide at least one pharmaceutical composition. [00160] In still another embodiment is provided a method for treating a inflammatory disorder comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, wherein Compound 1 is provided in a crystalline form comprising a form selected from the group consisting of Form IA2- 1; MIBK2-1; MA2.5-1; TRA-I; SA-3; SB-3; SC-3; TFE-4; TFA-4; TFA-12; IBU2-5; HPA2-6; SA-7; SA-8; SA-9; BY2-10; VA2-10; CP2-10; and SA-I l. [00161] In one embodiment, the patient is a human. [00162] In another embodiment, the inflammatory-associated disorder or disease is selected from the group consisting of asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, diabetes, inflammatory bowel disease, Alzheimer's disease, osteoporosis, psoriasis, graft vs. host rejection, multiple sclerosis, atherosclerosis, multiple myeloma, pain, myocardial ischemia and arthritis, including rheumatoid arthritis, psoriatic arthritis, traumatic arthritis, rubella arthritis, gouty arthritis and osteoarthritis. [00163] In another embodiment, the disorder or disease is selected from the group consisting of rheumatoid arthritis, psoriasis, asthma, COPD, ARDS, inflammatory bowel disease, multiple myeloma, pain, atherosclerosis, osteoporosis, myocardial ischemia and ischemia, particularly psoriasis, atherosclerosis and rheumatoid arthritis; and more particularly, rheumatoid arthritis.

[00164] In an even further embodiment, the method of treating an inflammatory disorder or disease comprises administering a crystalline form of at least one of Form IA2-1; MIBK2-1; MA2.5-1; TRA-I; SA-3; SB-3; SC-3; TFE-4; TFA-4; TFA-12; IBU2-5; HPA2-6; SA-7; SA-8; SA-9; BY2-10; VA2-10; CP2-10; SA-I l; and/or TFA-12.

[00165] After the isolation of Compound 1 crystals from solution, the crystalline material is dried to remove excess solvent and/or water. The drying time can be reduced by heating at reduced pressure to speed the removal of excess solvent and/or water from the crystalline material.

[00166] Administration of a Compound 1 as a solvated crystalline form, includes the concomitant delivery of the solvent to the patient. Since certain solvents are unacceptable for administration to patients, solvated crystalline forms comprising unacceptable solvents cannot be employed for pharmaceutical drug delivery of Compound 1, although these crystalline forms can be usefully in processes to isolate and/or purify Compound 1. Solvated crystalline forms comprising other solvents, such as ethanol or acetic acid, may be acceptable for certain routes of administration (e.g., oral administration) but these solvated crystalline forms of Compound 1 typically require more extensive testing to obtain regulatory approval than neat or hydrated forms.

[00167] A further requirement for the selection of a physical form for pharmaceutical development is suitable chemical and physical stability, such as stability of the form during processing to the desired dosage form and/or stability during storage.

UTILITY [00168] The compounds of the invention are prodrugs that release selective inhibitors of p38 kinase activity, and in particular, isoforms p38α and p38β. Accordingly, compounds of Formula I have utility in treating conditions associated with p38 kinase activity. Such conditions include diseases in which cytokine levels are modulated as a consequence of intracellular signaling via p38, and in particular, diseases that are associated with an overproduction of cytokines IL-I, IL-4, IL-8, and TNF-α. As used herein, the terms "treating" or "treatment" encompass either or both responsive and prophylaxis measures, e.g., measures designed to inhibit or delay the onset of the disease or disorder, achieve a full or partial reduction of the symptoms or disease state, and/or to alleviate, ameliorate, lessen, or cure the disease or disorder and/or its symptoms. When reference is made herein to inhibition of "p38α/β kinase," this means that either p38α and/or p38β kinase are inhibited. Thus, reference to an IC50 value for inhibiting p38α/β kinase means that the compound has such effectiveness for inhibiting at least one of, or both of, p38α and p38β kinases. [00169] In view of their utility as prodrugs that release inhibitors of p38α/β kinase activity, the compounds of Formula I are useful in treating p38 associated conditions including, but not limited to, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, angiogenic disorders, infectious diseases, neurodegenerative diseases, and viral diseases. [00170] More particularly, the specific conditions or diseases that may be treated with the inventive compounds include, without limitation, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease, inflammatory reaction induced by endotoxin, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic β-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, ankylosing spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, allograft rejections, fever and myalgias due to infection, cachexia secondary to infection, myeloid formation, scar tissue formation, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis and multiple myeloma-related bone disorder, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson's disease, cerebral ischemias or neurodegenerative disease caused by traumatic injury; angiogenic disorders including solid tumors, ocular neovasculization, and infantile haemangiomas; viral diseases including acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy, and herpes; stroke, myocardial ischemia, ischemia in stroke heart attacks, organ hyposia, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, and conditions associated with prostaglandin endoperoxidase syndase-2.

[00171] In addition, p38 inhibitors of this invention inhibit the expression of inducible pro-inflammatory proteins such as prostaglandin endoperoxide synthase-2 (PGHS-2), also referred to as cyclooxygenase-2 (COX-2). Accordingly, additional p38-associated conditions include edema, analgesia, fever and pain, such as neuromuscular pain, headache, pain caused by cancer, dental pain and arthritis pain. The inventive compounds also may be used to treat veterinary viral infections, such as lentivirus infections, including, but not limited to equine infectious anemia virus; or retro virus infections, including feline immunodeficiency virus, bovine immunodeficiency virus, and canine immunodeficiency virus. [00172] When the terms "p38 associated condition" or "p38 associated disease or disorder" are used herein, each is intended to encompass all of the conditions identified above as if repeated at length, as well as any other condition that is affected by p38 kinase activity.

[00173] The present invention thus provides methods for treating such conditions, comprising administering to a subject in need thereof an effective amount of at least one compound of Formula I or a salt thereof. The methods of treating p38 kinase- associated conditions may comprise administering compounds of Formula I alone or in combination with each other and/or other suitable therapeutic agents useful in treating such conditions. Exemplary of such other therapeutic agents include corticosteroids, rolipram, calphostin, CSAIDs, 4-substituted imidazo [1,2- AJquinoxalines as disclosed in U.S. Patent No. 4,200,750; Interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyspergualin (DSG); non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf); cytotoxic drugs such as azathiprine and cyclophosphamide; TNF-α inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof.

[00174] The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. In the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the inventive compounds. [00175] The present invention also provides pharmaceutical compositions capable of treating p38-kinase associated conditions, including TNF-α, IL-I, and/or IL-8 mediated conditions, as described above. The inventive compositions may contain other therapeutic agents as described above and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (e.g., excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation. [00176] The compounds of Formula I may be administered by any means suitable for the condition to be treated, which may depend on the need for site-specific treatment or quantity of drug to be delivered. Topical administration is generally preferred for skin-related diseases, and systematic treatment preferred for cancerous or pre-cancerous conditions, although other modes of delivery are contemplated. For example, the compounds may be delivered orally, such as in the form of tablets, capsules, granules, powders, or liquid formulations including syrups; topically, such as in the form of solutions, suspensions, gels or ointments; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., as sterile injectable aq. or non-aq. solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; rectally such as in the form of suppositories; or liposomally. Dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents may be administered. The compounds may be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved with suitable pharmaceutical compositions or, particularly in the case of extended release, with devices such as subcutaneous implants or osmotic pumps.

[00177] Exemplary compositions for topical administration include a topical carrier such as PLASTIBASE® (mineral oil gelled with polyethylene). [00178] Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The inventive compounds may also be orally delivered by sublingual and/or buccal administration, e.g., with molded, compressed, or freeze- dried tablets. Exemplary compositions may include fast-dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (AVICEL®) or polyethylene glycols (PEG); an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g., GANTREZ®); and agents to control release such as polyacrylic copolymer (e.g., CARBOPOL 934®). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.

[00179] Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents such as those known in the art. [00180] Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

[00181] Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures but liquefy and/or dissolve in the rectal cavity to release the drug. [00182] The effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a mammal of from about 0.05 to 100 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats, horses, and the like. Thus, when the term "patient" is used herein, this term is intended to include all subjects, most preferably mammalian species, that are affected by mediation of p38 enzyme levels.

[00183] Compound 1 is useful for its p38-kinase activity. Compound 1 may be used to treat a variety of medical conditions and/or disorders associated with inflammation.. Compound 1 can modulate the function of p38 kinases. In one embodiment, Compound 1 inhibits p38α/β enzymes. Medical conditions associated with p38 kinase activity include asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, diabetes, inflammatory bowel disease, Alzheimer's disease, osteoporosis, psoriasis, graft vs. host rejection, atherosclerosis, multiple myeloma, pain, myocardial ischemia and arthritis, including rheumatoid arthritis, psoriatic arthritis, traumatic arthritis, rubella arthritis, gouty arthritis and osteoarthritis. Compound 1 can be used to treat all the foregoing conditions. [00184] In one embodiment, a method for treating an inflammatory disorder (disorder as used herein is also intended to be used interchangeably with the term "disease") comprises administering to a patient in need of such treatment a therapeutically effective amount of Compound 1, wherein Compound 1 is provided in a crystalline form comprising at least one form selected from Form Form IA2-1; MIBK2-1; MA2.5-1; TRA-I; SA-3; SB-3; SC-3; TFE-4; TFA-4; TFA-12; IBU2-5; HPA2-6; SA-7; SA-8; SA-9; BY2-10; VA2-10; CP2-10; and SA-I l; optionally administering either simultaneously or sequentially at least one other antiinflammatory agent, and optionally administering either simultaneously or sequentially at least one other anti-inflammatory treatment. Preferably, the inflammatory-associated disease is selected from the group consisting of asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, diabetes, inflammatory bowel disease, Alzheimer's disease, osteoporosis, psoriasis, graft vs. host rejection, atherosclerosis, multiple myeloma, pain, myocardial ischemia and arthritis, including rheumatoid arthritis, psoriatic arthritis, traumatic arthritis, rubella arthritis, gouty arthritis and osteoarthritis; and, more preferably, atherosclerosis, rheumatoid arthritis, and psoriasis. [00185] In a further embodiment, a method for treating at least one inflammatory- associated disease comprises administering to a patient in need of such treatment a therapeutically effective amount of Compound 1, wherein Compound 1 is provided in a crystalline form comprising at least one Form selected from IA2-1; MIBK2-1; MA2.5-1; TRA-I; SA-3; SB-3; SC-3; TFE-4; TFA-4; TFA-12; IBU2-5; HPA2-6; SA- 7; SA-8; SA-9; BY2-10; VA2-10; CP2-10; and SA-11; optionally administering either simultaneously or sequentially at least one other anti-inflammatory agent, and optionally administering either simultaneously or sequentially at least one other antiinflammatory treatment. Preferably, the inflammatory-associated disease is selected from the group consisting of asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, diabetes, inflammatory bowel disease, Alzheimer's disease, osteoporosis, psoriasis, graft vs. host rejection, atherosclerosis, multiple myeloma, pain, myocardial ischemia and arthritis, including rheumatoid arthritis, psoriatic arthritis, traumatic arthritis, rubella arthritis, gouty arthritis and osteoarthritis; and, more preferably, atherosclerosis, rheumatoid arthritis, and psoriasis.

[00186] In another embodiment, the method for treating at least one inflammatory- associated disease involves providing Compound 1 in a substantially pure form. [00187] In another embodiment, a pharmaceutical composition comprises at least one crystalline form of Compound 1 selected from IA2-1; MIBK2-1; MA2.5-1; TRA- 1; SA-3; SB-3; SC-3; TFE-4; TFA-4; TFA-12; IBU2-5; HPA2-6; SA-7; SA-8; SA-9; BY2-10; VA2-10; CP2-10; and SA-I l; optionally at least one component selected from excipients and carriers; and optionally at least one other anti-inflammatory agent. Preferably, the pharmaceutical composition of this embodiment comprises Form HAC-4. [00188] The phrase "other anti-inflammatory agent" includes any known agent useful for treating an inflammatory disorder, preferably atherosclerosis, rheumatoid arthritis, and psoriasis. In treating cancer, a combination of therapeutic agents and/or other treatments is often advantageous. The other anti-inflammatory agent may have the same or different mechanism of action than the primary therapeutic agent. It may be especially useful to employ anti-inflammatory drug combinations wherein the two or more drugs being administered act in different manners or in different phases of the cell cycle, and/or where the drugs being combined each has a demonstrated efficacy in treating the particular disease state manifested by the patient. [00189] The invention herein further comprises use of Form HAC-4, P -2, and/or P- 5 in preparing medicaments for the treatment of inflammatory-associated disorders, and/or it comprises the packaging of a Form selected from IA2-1; MIBK2-1; MA2.5- 1; TRA-I; SA-3; SB-3; SC-3; TFE-4; TFA-4; TFA-12; IBU2-5; HPA2-6; SA-7; SA- 8; SA-9; BY2-10; VA2-10; CP2-10; and SA-11 herein together with instructions that it is to be used in combination with other anti-inflammatory agents and treatments for the treatment of inflammation-associated diseases. [00190] The present invention further comprises combinations of a Form selected from IA2-1; MIBK2-1; MA2.5-1; TRA-I; SA-3; SB-3; SC-3; TFE-4; TFA-4; TFA- 12; IBU2-5; HPA2-6; SA-7; SA-8; SA-9; BY2-10; VA2-10; CP2-10; and SA-I l and one or more additional agents in kit form, e.g., where they are packaged together or placed in separate packages to be sold together as a kit, or where they are packaged to be formulated together. [00191] Additionally, forms of Compound 1 can be formulated or co-administered with other therapeutic agents that are selected for their particular usefulness in addressing side effects associated with the aforementioned conditions. [00192] The above other therapeutic agents, when employed in combination with forms of Compound 1, can be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.

[00193] In one embodiment, Form IA2-1; MIBK2-1; MA2.5-1; TRA-I; SA-3; SB- 3; SC-3; TFE-4; TFA-4; TFA-12; IBU2-5; HPA2-6; SA-7; SA-8; SA-9; BY2-10; VA2-10; CP2-10; SA-11; and/or TFA-12, is used to treat rheumatoid arthritis. [00194] In another embodiment, Form IA2-1; MIBK2-1; MA2.5-1; TRA-I; SA-3; SB-3; SC-3; TFE-4; TFA-4; TFA-12; IBU2-5; HPA2-6; SA-7; SA-8; SA-9; BY2-10; VA2-10; CP2-10; SA-I l; and/or TFA-12, is used to treat psoriasis. [00195] In another embodiment, Form IA2-1; MIBK2-1; MA2.5-1; TRA-I; SA-3;

SB-3; SC-3; TFE-4; TFA-4; TFA- 12; IBU2-5; HPA2-6; SA-7; SA-8; SA-9; BY2-10;

VA2-10; CP2-10; SA-11; and/or TFA-12, is used to treat atherosclerosis.

[00196] In another embodiment, Form IA2-1; MIBK2-1; MA2.5-1; TRA-I; SA-3; SB-3; SC-3; TFE-4; TFA-4; TFA-12; IBU2-5; HPA2-6; SA-7; SA-8; SA-9; BY2-10;

VA2-10; CP2-10; SA-11; and/or TFA-12, is used to treat pain.

[00197] In another embodiment, Form IA2-1; MIBK2-1; MA2.5-1; TRA-I; SA-3;

SB-3; SC-3; TFE-4; TFA-4; TFA-12; IBU2-5; HPA2-6; SA-7; SA-8; SA-9; BY2-10;

VA2-10; CP2-10; SA-11; and/or TFA-12, is used to treat multiple sclerosis.. [00198] Any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral preparations. Exemplary oral preparations, include, but are not limited to, for example, tablets; troches; lozenges; aqueous or oily suspensions; dispersible powders or granules; emulsions; hard or soft capsules; syrups; and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to methods known in the art and can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, demulcents, antioxidants, and preserving agents.

[00199] Exemplary excipients include, but are not limited to, for example, inert diluents, such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as, for example, microcrystalline cellulose, sodium croscarmellose, corn starch, and alginic acid; binding agents, such as, for example, starch, gelatin, polyvinyl-pyrrolidone, and acacia; and lubricating agents, such as, for example, magnesium stearate, stearic acid, and talc. [00200] An aqueous suspension can be prepared, for example, by admixing at least one of Form HAC-4; IA2-1; MIBK2-1; MA2.5-1; TRA-I; SA-3; SB-3; SC-3; TFE-4;

TFA-4; TFA-12; IBU2-5; HPA2-6; SA-7; SA-8; SA-9; BY2-10; VA2-10; CP2-10;

SA-11; TFA-12, P-2 and/or P-5 of Compound 1 with at least one excipient suitable for the manufacture of an aqueous suspension. Exemplary excipients suitable for the manufacture of an aqueous suspension, include, but are not limited to, for example, suspending agents, such as, for example, sodium carboxymethylcellulose or methylcellulose. Oily suspensions can, for example, be prepared by suspending at least one of Form HAC-4; IA2-1; MIBK2-1; MA2.5-1; TRA-I; SA-3; SB-3; SC-3; TFE-4; TFA-4; TFA-12; IBU2-5; HPA2-6; SA-7; SA-8; SA-9; BY2-10; VA2-10; CP2-10; SA-11; TFA-12, P-2 and/or P-5 of Compound 1 in either a vegetable oil, such as, for example, arachis oil; olive oil; sesame oil; and coconut oil; or in mineral oil, such as, for example, liquid paraffin.

[00201] Any pharmaceutical composition contemplated herein can, for example, also be delivered intravenously, subcutaneously, and/or intramuscularly via any pharmaceutically acceptable and suitable injectable form. Exemplary injectable forms include, but are not limited to, for example, sterile aqueous solutions comprising acceptable vehicles and solvents, such as, for example, water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oleaginous suspensions.

[00202] A sterile injectable oil-in-water microemulsion can, for example, be prepared by 1) dissolving at least one crystalline form of Compound 1 in an oily phase, such as, for example, a mixture of soybean oil and lecithin; 2) combining the Compound 1 containing oil phase with a water and glycerol mixture; and 3) processing the combination to form a microemulsion.

[00203] Any pharmaceutical composition contemplated herein can, for example, further be administered via any acceptable and suitable rectal preparation, including, but not limited to, for example, a suppository. A suppository can be prepared by mixing at least one crystalline form of Compound 1 with at least one suitable non- irritating excipient that is liquid at rectal temperatures but solid at a temperature below rectal temperature. [00204] Any pharmaceutical composition contemplated herein can, for example, be administered via any acceptable and suitable topical preparations including, but not limited to, for example, creams; ointments; jellies; solutions; suspensions, transdermal patches; and intranasal inhalers. For purposes of this application, topical preparations include mouth washes and gargles. [00205] Exemplary compositions for nasal aerosol or inhalation administration include solutions that may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents such as those known in the art. [00206] An "effective amount" of Compound 1 may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a mammal of from about 0.05 to about 300 mg/kg/day, preferably less than about 200 mg/kg/day, in a single dose or in 2 to 4 divided doses. The specific dose level and frequency of dosage for any particular subject, however, may be varied and generally depends on a variety of factors, including, but not limited to, for example, the bioavailability of Compound 1 in the administered form; metabolic stability and length of action of Compound 1; species, age, body weight, general health, sex, and diet of the subject; mode and time of administration; rate of excretion; drug combination; and severity of the particular condition.

[00207] In one embodiment, the patient is an animal.

[00208] In another embodiment, the patient is a mammalian species including, but not limited to, for example, humans and domestic animals, such as, for example, dogs, cats, and horses.

BIOLOGICAL ASSAYS Generation of p38 Kinases

[00209] cDNAs of human p38α, β and γ isozymes were cloned by PCR. These cDNAs were subcloned in the pGEX expression vector (Pharmacia). GST-p38 fusion protein was expressed in E. CoIi and purified from bacterial pellets by affinity chromatography using glutathione agarose. p38 fusion protein was activated by incubating with constitutively active MKK6. Active p38 was separated from MKK6 by affinity chromatography. Constitutively active MKK6 was generated according to Raingeaud et al. [MoL Cell. Biol., 1247-1255 (1996)].

TNF-α Production by LPS-Stimulated PBMCs

[00210] Heparinized human whole blood was obtained from healthy volunteers. Peripheral blood mononuclear cells (PBMCs) were purified from human whole blood by Ficoll-Hypaque density gradient centrifugation and resuspended at a concentration of 5 x 10⁶/ml in assay medium (RPMI medium containing 10% fetal bovine serum). 50 μl of cell suspension was incubated with 50 μl of test compound (4X concentration in assay medium containing 0.2% DMSO) in 96-well tissue culture plates for 5 minutes at RT. 100 μ of LPS (200 ng/ml stock) was then added to the cell suspension and the plate was incubated for 6 hours at 37°C. Following incubation, the culture medium was collected and stored at -20⁰C. TNF-α concentration in the medium was quantified using a standard ELISA kit (Pharmingen-San Diego, CA). Concentrations of TNF-α and IC50 values for test compounds (concentration of compound that inhibited LPS-stimulated TNF-α production by 50%) were calculated by linear regression analysis.

p38 Assay [00211] The assays were performed in V-bottomed 96-well plates. The final assay volume was 60 μl prepared from three 20 μl additions of enzyme, substrates (MBP and ATP) and test compounds in assay buffer (50 mM Tris pH 7.5, 10 mM MgCl₂, 50 mM NaCl and 1 mM DTT). Bacterially expressed, activated p38 was pre-incubated with test compounds for 10 min. prior to initiation of reaction with substrates. The reaction was incubated at 25°C for 45 min. and terminated by adding 5 μl of 0.5 M EDTA to each sample. The reaction mixture was aspirated onto a pre-wet filtermat using a Skatron Micro96 Cell Harvester (Skatron, Inc.), then washed with PBS. The filtermat was then dried in a microwave oven for 1 min., treated with MeltilLex A scintillation wax (Wallac), and counted on a Microbeta scintillation counter Model 1450 (Wallac). Inhibition data were analyzed by nonlinear least-squares regression using Prizm (GraphPadSoftware). The final concentration of reagents in the assays are ATP, 1 μM; [γ-³³P]ATP, 3 nM; MBP (Sigma, #M1891), 2μg/well; p38, 10 nM; and DMSO, 0.3%.

TNF-α Production by LPS-Stimulated Mice

[00212] Mice (Balb/c female, 6-8 weeks of age, Harlan Labs; n=8/treatment group) were injected intraperitoneally with 50ug/kg lipopolysaccharide (LPS; E coli strain 0111:B4, Sigma) suspended in sterile saline. Ninety minutes later, mice were sedated by CO₂: 0₂ inhalation and a blood sample was obtained. Serum was separated and analyzed for TNF-alpha concentrations by commercial ELISA assay per the manufacturer's instructions (R&D Systems, Minneapolis, MN). [00213] Test compounds were administered orally at various times before LPS injection. The compounds were dosed either as suspensions or as solutions in various vehicles or solubilizing agents.

METHODS OF PREPARATION AND CHARACTERIZATION

[00214] Crystalline forms may be prepared by a variety of methods, including, but not limited to, for example, crystallization or recrystallization from a suitable solvent mixture; sublimation; growth from a melt; solid state transformation from another phase; crystallization from a supercritical fluid; and jet spraying. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, but are not limited to, for example, evaporation of the solvent; decreasing the temperature of the solvent mixture; crystal seeding a supersaturated solvent mixture of the compound and/or a salt from thereof; freeze drying the solvent mixture; and adding antisolvents (countersolvents) to the solvent mixture. High throughput crystallization techniques may be employed to prepare crystalline forms including polymorphs. Crystals of drugs, including polymorphs, methods of preparation, and characterization of drug crystals are discussed in Byrn, S. R. et al., Solid-State Chemistry of Drugs, 2^nd Edition, SSCI, West Lafayette, Indiana (1999). [00215] In a crystallization technique in which solvent is employed, the solvent(s) are typically chosen based on one or more factors including, but not limited to, for example, solubility of the compound; crystallization technique utilized; and vapor pressure of the solvent. Combinations of solvents may be employed. For example, the compound may be solubilized in a first solvent to afford a solution to which antisolvent is then added to decrease the solubility of the Compound In the solution and precipitate the formation of crystals. An antisolvent is a solvent in which a compound has low solubility.

[00216] In one method that can be used in preparing crystals, a Compound Is suspended and/or stirred in a suitable solvent to afford a slurry, which may be heated to promote dissolution. The term "slurry", as used herein, means a saturated solution of the compound, wherein such solution may contain an additional amount of compound to afford a heterogeneous mixture of compound and solvent at a given temperature. [00217] Seed crystals may be added to any crystallization mixture to promote crystallization. Seeding may be employed to control growth of a particular polymorph and/or to control the particle size distribution of the crystalline product. Accordingly, calculation of the amount of seeds needed depends on the size of the seed available and the desired size of an average product particle as described, for example, in Mullin, J. W. et al, "Programmed Cooling of Batch Crystallizers", Chemical Engineering Science, 26:369-377 (1971). In general, seeds of small size are needed to effectively control the growth of crystals in the batch. Seeds of small size may be generated by sieving, milling, or micronizing large crystals, or by micro- crystallizing a solution. In the milling or micronizing of crystals, care should be taken to avoid changing crystallinity from the desired crystalline form (i.e., changing to an amorphous or other polymorphic form).

[00218] A cooled crystallization mixture may be filtered under vacuum and the isolated solid product washed with a suitable solvent, such as, for example, cold recrystallization solvent. After being washed, the product may be dried under a nitrogen purge to afford the desired crystalline form.

[00219] The product may be analyzed by a suitable spectroscopic or analytical technique including, but not limited to, for example, solid state nuclear magnetic resonance; differential scanning calorimetry (DSC); and powder x-ray diffraction (PXRD) to assure the preferred crystalline form of the compound has been formed. The resulting crystalline form may be produced in an amount greater than about 70 wt. % isolated yield, based on the weight of the compound originally employed in the crystallization procedure, and preferably greater than about 90 wt. % isolated yield. Optionally, the product may be delumped by being comilled or passed through a mesh screen.

[00220] Crystalline forms of Compound 1 including, but not limited to, for example, the Forms described herein, may be prepared directly from the reaction medium produced via the final process step employed in preparing Compound 1. For example, crystalline form(s) of Compound 1 could be produced by employing a solvent or a mixture of solvents in the final process step employed in preparing

Compound 1. Alternatively, crystalline forms of Compound 1 may be obtained by distillation or solvent addition techniques. Suitable solvents for this purpose include, but are not limited to, for example, the aforementioned nonpolar and polar solvents, wherein polar solvents include, but are not limited to, for example, protic polar solvents, such as, for example, alcohols and aprotic polar solvents, such as, for example, ketones. [00221] The presence of more than one crystalline form and/or polymorph in a sample may be determined by techniques, including, but not limited to, for example, PXRD and solid state nuclear magnetic resonance spectroscopy. For example, the presence of extra peaks when an experimentally measured PXRD pattern is compared to a simulated PXRD pattern may indicate more than one crystalline form and/or polymorph in the sample. The simulated PXRD may be calculated from single crystal x-ray data. See, for example, Smith, D. K., "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns" Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963). [00222] Crystalline forms of Compound 1 , including, but not limited to, those described herein according to the invention may be characterized using a variety of techniques well known to person(s) of ordinary skill in the art. For example, the single x-ray diffraction technique may, under standardized operating conditions and temperatures, be used to characterize and distinguish crystalline form(s) of Compound 1. Such characterization may, for example, be based on unit cell measurements of a single crystal of the desired form at a fixed analytical temperature. The approximate unit cell dimensions in Angstroms (A), as well as the crystalline cell volume, space group, molecules per cell, and crystal density may be measured, for example, at a sample temperature of 25°C. A detailed description of unit cells is provided in Stout et al, X-Ray Structure Determination: A Practical Guide, Chapter 3, Macmillan Co., New York (1968), which is hereby incorporated herein by reference.

[00223] Additionally, the unique spatial arrangement of atoms in a crystalline lattice may be characterized according to the observed fractional atomic coordinates of such atoms. [00224] Another means of characterizing the crystalline structure of the subject form is by PXRD analysis, the actual diffraction profile of such form is compared to a simulated profile representing pure powder material. Preferably, the actual and simulated profiles are both run at the same analytical temperature, and the subsequent measurements characterized as a series of 2Θ values (usually four or more). [00225] Other means of characterizing a crystalline form that may be used include, but are not limited to, for example, solid state nuclear magnetic resonance (NMR); DSC; thermography; gross examination of the crystalline or amorphous morphology; and combinations thereof.

[00226] At least one crystalline form of Compound 1 described herein was analyzed using at least one of the testing methods described hereinbelow.

EXAMPLES

[00227] The following Examples illustrate embodiments of the inventive compounds and stability information of said embodiments and are not intended to limit the scope of the claims.

[00228] Various crystal forms of ((((4-((5-(cyclopropylcarbamoyl)-2- methylphenyl)amino)-5-methylpyrrolo[2, 1 -J] [ 1 ,2,4]triazin-6- yl)carbonyl)(propyl)carbamoyl)oxy)methyl (4-(phosphonooxy)phenyl)acetate, were prepared and characterized as described below.

PROCEDURES FOR CHARACTERIZING THE FORMS Single Crystal Data

[00229] Data were collected on a Bruker-Nonius (BRUKER AXS, Inc., 5465 East Cheryl Parkway Madison, WI 53711 USA) CAD4 serial diffractometer. Unit cell parameters were obtained through least-squares analysis of the experimental diffractometer settings of 25 high-angle reflections. Intensities were measured using Cu Ka radiation (λ = 1.5418 A) at a constant temperature with the Θ-2Θ variable scan technique and were corrected only for Lorentz-polarization factors. Background counts were collected at the extremes of the scan for half of the time of the scan. Alternately, single crystal data were collected on a Bruker-Nonius Kappa CCD 2000 system using Cu Ka radiation (λ = 1.5418 A). Indexing and processing of the measured intensity data were carried out with the HKL2000 software package

(Otwinowski, Z. et al., Macromolecular Crystallography, Carter, Jr., W.C. et al., eds. (Academic, NY), 276:307-326 (1997)) in the Collect program suite. (Collect Data collection and processing user interface: Collect: Data collection software, R. Hooft, Nonius B.V. (1998)). Alternately, single crystal data were collected on a Bruker- AXS APEX2 CCD system using Cu Ka radiation (λ = 1.5418 A). Indexing and processing of the measured intensity data were carried out with the APEX2 software package/program suite (APEX2 Data collection and processing user interface: APEX2 User Manual, vl.27; BRUKER AXS, Inc., 5465 East Cheryl Parkway Madison, WI 5371 I USA).

[00230] When indicated, crystals were cooled in the cold stream of an Oxford cryo system (Oxford Cryosystems Cryostream cooler: Cosier, J. et al, J. Appl. Cryst, 19: 105 (1986)) during data collection.

[00231] The structures were solved by direct methods and refined on the basis of observed reflections using either the SDP (SDP, Structure Determination Package, Enraf-Nonius, Bohemia NY 11716. Scattering factors, including/' and/", in the SDP software were taken from the "International Tables for Crystallography", Kynoch Press, Birmingham, England (1974), Vol. IV, Tables 2.2A and 2.3.1) software package with minor local modifications or the crystallographic packages MAXUS (maXus solution and refinement software suite: S. Mackay, CJ. Gilmore, C. Edwards, M. Tremayne, N. Stewart, K. Shankland. maXus: a computer program for the solution and refinement of crystal structures from diffraction data or SHELXTL (APEX2 Data collection and processing user interface: APEX2 User Manual,

Vol.27; BRUKER AXS, Inc., 5465 East Cheryl Parkway Madison, WI 53711 USA). The derived atomic parameters (coordinates and temperature factors) were refined through full matrix least-squares. The function minimized in the refinements was

∑wflFol " l^Fcl)² R is defined as Σ ||F₀| - |F_C||/Σ |F₀| while R_w = [∑_w( |F₀| - |F_C|)²/Σ_W

2 1/2 |F₀| ] where w is an appropriate weighting function based on errors in the observed intensities. Difference maps were examined at all stages of refinement. Hydrogens were introduced in idealized positions with isotropic temperature factors, but no hydrogen parameters were varied.

X-ray Powder Diffraction Data (PXRD) [00232] X-ray powder diffraction (PXRD) data were obtained using a Bruker GADDS (General Area Detector Diffraction System) manual chi platform goniometer. Powder samples were placed in thin walled glass capillaries of lmm or less in diameter; the capillary was rotated during data collection. The sample-detector distance was 17 cm. The radiation was Cu Ka (λ = 1.5418 Ang). Data were collected for 3<2Θ <35° with a sample exposure time of at least 300 seconds.

Hybrid PXRD Patterns (from Low Temp)

[00233] "Hybrid" simulated powder X-ray patterns were generated as described in the literature (Yin, S. et al., American Pharmaceutical Review , 6(2):80 (2003)). The room temperature cell parameters were obtained by performing a cell refinement using the CellRefine.xls program. Input to the program includes the 2-theta position of ca. 10 reflections, obtained from the experimental room temperature powder pattern; the corresponding Miller indices, hkl, were assigned based on the single- crystal data collected at low temperature. A new (hybrid) PXRD was calculated (by either of the software programs, Alex or LatticeView) by inserting the molecular structure determined at low temperature into the room temperature cell obtained in the first step of the procedure. The molecules are inserted in a manner that retains the size and shape of the molecule and the position of the molecules with respect to the cell origin, but, allows intermolecular distances to expand with the cell.

Hybrid PXRD (from Isostructural Analog)

[00234] "Hybrid" simulated powder X-ray patterns were generated as described in the literature (Yin, S. et al., American Pharmaceutical Review , 6(2):80 (2003)). The room temperature cell parameters were obtained by performing a cell refinement using the CellRefine.xls program. Input to the program includes the 2-theta position of ca. 10 reflections, obtained from the experimental room temperature powder pattern; the corresponding Miller indices, hkl, were assigned based on the single- crystal data collected for an isostructural analog. A crystal structure for the molecule of interest was generated in a two step process: (1) by replacing the analog molecule in the experimental analog crystal structure with the molecule of interest. This step fixes the orientation and position of the molecule of interest in the unit cell of the analog compound; (2) Inserting the molecule of interest into the room temperature cell obtained from the experimental PXRD of the molecule of interest, as described above. In this step, the molecules are inserted in a manner that retains the size and shape of the molecule and the position of the molecules with respect to the cell origin, but, allows intermolecular distances to expand/contract with the cell. A new (hybrid) PXRD was calculated (by either of the software programs, Alex or LatticeView) based on the crystal structure generated as described above.

EXAMPLE 1 Preparation of Form IA2-1

[00235] Compound 1 was dissolved with warming in a minimal volume of

2,2,2-trifluoroethanol. Isopropylacetate was added drop-wise to the warm solution. Crystals appeared upon standing at room temperature to afford the diisopropylacetate solvate of Compound 1 (Form IA2-1).

Characterization of Form IA2-1

[00236] The IA2-1 Form is a diisopropylacetate solvate form of Compound 1 and was characterized by the unit cell parameters listed in Table 1, wherein the unit cell parameters of Form IA2-1 were measured at -50⁰C:

TABLE 1 Crystal Properties of Form IA2-1

[00237] The fraction atomic coordinate data of Form IA2-1 were measured according to the procedure described above and are presented in Table 2. Occupancies are 1. unless otherwise indicated.

TABLE 2 Positional Parameters for Form IA2-1 at -50⁰C

Occupancies are 1 unless otherwise noted.

[00238] The simulated and observed PXRD powder x-ray diffraction (PXRD) were measured according to the above described procedures to afford the patterns shown in Figure 1, wherein the PXRD pattern (CuKa λ= 1.5418 A at a temperature of about 25°C) had 2 theta ("2Θ") values of 6.4, 8.0, 8.3, 10.6, 15.6, 18.3, 18.7, 20.5, 22.7, 23.3, and 25.7 (degrees 2Θ ±0.1) which were measured at a temperature of about 25°C. EXAMPLE 2 Preparation of Form MIBK2-1

[00239] Compound 1 was dissolved with warming in a minimal volume of 2,2,2- trifluoroethanol. Dimethylisobutylketone (MIBK) was added drop-wise to the warm solution. Crystals appeared upon standing at room temperature to afford the MIBK solvate of Compound 1 (Form MIBK2-1).

Characterization of Form MIBK2-1

[00240] The MIBK2-1 Form is the dimethylisobutylketone solvate form of Compound 1.

[00241] Form MIBK2-1 was characterized by unit cell parameters (measured according to the procedures described above) listed in Table 3, wherein the unit cell parameters of Form MIBK2-1 were measured at room temperature:

TABLE 3 Crystal Properties of Form MIBK2-1 (di-MIBK Solvate)

[00242] The fractional atomic coordinates for Form MIB K2- 1 were measured according to the procedure described above and are shown as follows in Table 4. Occupancies are 1. unless otherwise indicated. TABLE 4 Fractional Atomic Coordinates for Form MIBK2-1 at -50⁰C

[00243] The simulated and observed powder x-ray diffraction (PXRD) patterns of the MIBK2-1 Form were measured according to the procedures described above and are shown in Figure 2. The PXRD patterns (CuKa λ= 1.5418 A at a temperature of about 25°C) have 2 theta ("2Θ") values of 6.4, 8.2, 9.5, 10.5, 12.8, 13.2, 15.70 and 25.6 (degrees 2Θ ±0.1), wherein the PXRD pattern of Form MIBK2-1 is measured at a temperature of about 25°C.

EXAMPLE 3 Preparation of Form MA2.5-1

[00244] Compound 1 was dissolved in a minimal volume of formic acid. Methyl acetate was added dropwise until a cloudy solution was formed. Crystals of form MA2.5-1 (a methyl acetate solvate form of Compound 1) appeared upon standing at room temperature. The crystals were unstable when isolated.

Characterization of Form MA2.5-1 [00245] The unit cell parameters of Form MA2.5-1 were measured at about -100⁰C according to the procedure described above, and are presented in Table 5:

TABLE 5 Crystal Properties of Form MA2.5-1 (2.5 Methyl Acetate Solvate)

[00246] The fractional atomic coordinates of Form MA2.5 were measured according to the procedure described above and are presented in Table 6. Occupancies are 1 unless otherwise indicated:

TABLE 6 Positional Parameters for Form MA2.5 at -100°C

[00247] The simulated PXRD curves of the Form MA2.5 form was measured as described in the procedures above and are shown in Figure 3.

EXAMPLE 4

Preparation of Form TRA-I

[00248] Compound 1 was dissolved in excess triacetin with warming. Crystals of Form TRA-I (a monotriacetin solvate) were formed upon cooling.

Characterization of Form TRA-I

[00249] The TRA-I form was measured at -60⁰C according to the procedures described above to give the unit cell parameters listed in Table 7. TABLE 7

Crystal Properties of Form TRA-I (Triacetin) (Monotriacetin Solvate)

[00250] The fraction atomic coordinates of Form TRA-I were measured as described above in the procedures section and are presented in Table 8. Occupancies are 1 unless otherwise indicated:

TABLE 8 Positional Parameter for Form TRA-I at -60⁰C

[00251] The simulated PXRD curve of the Form TRA-I form was measured as described in the procedures above and are shown in Figure 4.

EXAMPLE 5

Preparation of Form SA-3

[00252] Compound 1 was dissolved with warming in a minimal volume of 2,2,2- trifluoroethanol. Ethyl formate contaminated with formic acid was added as the anti- solvent. Crystals of the ethyl formate solvate formed initially, followed by the formation of relatively stable plates of a mono formic acid/monoethylformate mixed solvate of compound 1, form SA-3.

Characterization of Form SA-3

[00253] The unit cell parameters of form SA-3 were measured at -50⁰C according to the procedures described above and are listed in Table 9.

TABLE 9 Crystal Properties of Form SA-3

[00254] The fractional atomic coordinates of Form SA-3 were measured according to the procedures described above and are presented in Table 10. Occupancies are 1 unless otherwise indicated:

TABLE 10 Positional Parameters for Form SA-3 at -50⁰C

[00255] The simulated and observed PXRD curves of the SA-3 Form were measured as described in the procedures above and are shown in Figure 5. The PXRD patterns (CuKa λ=1.5418A at a temperature of about 25°C) have 2 theta ("2Θ") values of 6.7, 7.2, 8.2, 10.5, 13.5, 16.5, 19.6, 21.6, 22.5, 23.7 and 25.8 (degrees 2Θ ±0.1), when measured at a temperature of about 25°C.

EXAMPLE 6 Preparation of Form SB-3 [00256] Compound 1 was dissolved in formic acid. Propylene glycol and butyl acetate were added to the solution dropwise. Crystals of the diformic acid/monohydrate solvate form of Compound 1 (Form SB-3) formed upon standing. Characterization of Form SB-3

[00257] The unit cell parameters of form SB-3 were measured at -70⁰C according to the procedures described above and are listed in Table 11.

TABLE 11 Crystal Properties of Form SB-3

[00258] The fractional atomic coordinate data of Form SB-3 were measured according to the procedure described above and are presented in Table 12. Occupancies are 1 unless otherwise indicated.

TABLE 12 Positional Parameters for Form SB-3 at -70⁰C

[00259] The simulated PXRD curves of the SB-3 form was measured as described in the procedures above and is shown in Figure 6.

EXAMPLE 7

Preparation of Form SC-3

[00260] Compound 1 was dissolved in a minimum amount of glacial acetic acid. Acetonitrile was added drop-wise to the warm solution until the solution turned cloudy. Crystals of the mono acetic acid/monoacetonitrile solvate of Compound 1 (Form SC-3) formed upon standing.

Characterization of Form SC-3

[00261] The unit cell parameters of form SC-3 were measured at -60⁰C according to the procedures described above and are listed in Table 13.

TABLE 13 Crystal Properties of Form SC-3

[00262] The fractional atomic coordinate data of Form SC-3 were measured according to the procedure described above and are presented in Table 14. Occupancies are 1 unless otherwise indicated.

TABLE 14 Positional Parameters for Form SC-3 at -60⁰C

[00263] The simulated and observed PXRD curves of the SC-3 Form were measured as described in the procedures above and are shown in Figure 7. The PXRD patterns (CuKa λ=1.5418A at a temperature of about 25°C) have 2 theta ("2Θ") values of 6.63, 7.1, 10.8, 13.1, 16, 18.7, 20.0, 24.2 and 26.3 (degrees 2Θ ±0.1), when measured at a temperature of about 25°C.

EXAMPLE 8

Preparation of Form TFE-4 [00264] Compound 1 (100 mg) was dissolved in about 0.5 ml of TFE with warming. About 2 ml of butyl acetate was added dropwise. Crystals of the monotrifluoroethanol solvate (Form TFE-4) formed upon standing.

Characterization of Form TFE-4

[00265] The unit cell parameters of form TFE-4 were measured at -50⁰C according to the procedures described above and are listed in Table 15.

TABLE 15 Crystal Properties of Form TFE-4 at -50⁰C

[00266] The fractional atomic coordinate data of Form TFE-4 were measured according to the procedure described above and are presented in Table 16. Occupancies are 1 unless otherwise indicated.

TABLE 16 Positional Parameters for Form TFE-4 at -50⁰C

[00267] The simulated and observed PXRD curves of the TFE-4 Form were measured as described in the procedures above and are shown in Figure 8. The PXRD patterns (CuKa λ=1.5418A at a temperature of about 25°C) have 2 theta ("2Θ") values of 7.27, 9.0, 9.9, 11.3, 12.9, 15.4, 16.9, 21.6, 23.8, 24.8 and 26.0 (degrees 2Θ ±0.1), when measured at a temperature of about 25°C.

EXAMPLE 9 Preparation of Form TFA-4 [00268] Compound 1 was dissolved in a minimal amount of trifluoroacetic acid. Butyl acetate was added dropwise until the solution clouded. Crystals of the monotrifluoroacetic acid solvate (Form TFA-4) formed upon standing.

Characterization of Form TFA-4 [00269] The unit cell parameters of form TFA-4 were measured at -25°C according to the procedures described above and are listed in Table 17.

TABLE 17 Crystal Properties of Form TFA-4 (Trifluoroacetic Acid)

[00270] The fractional atomic coordinate data of Form TFA-4 were measured according to the procedure described above and are presented in Table 18. Occupancies are 1 unless otherwise indicated.

TABLE 18

Positional Parameters for Form TFA-4 (Solid State from TFA-12) at Room Temperature

[00271] The simulated powder x-ray diffraction (PXRD) pattern of theTFA-4 Form was measured according to the procedures above and is shown in Figure 9.

EXAMPLE 10

Preparation of Form IBU2-5 [00272] Compound 1 was dissolved in isobutanol with warming and the solution allowed to cool Crystals of the di-isobutanol solvate (Form IBU2-5) formed upon standing.

Characterization of Form IBU2-5

[00273] The unit cell parameters of form IBU2-5 were measured at -30⁰C according to the procedures described above and are listed in Table 19.

TABLE 19 Crystal Properties of Form IBU2-5 (Di-isobutyl Alcohol)

[00274] The fractional atomic coordinate data of Form IBU2-5 were measured according to the procedure described above and are presented in Table 20. Occupancies are 1 unless otherwise indicated.

TABLE 20 Positional Parameters for Form IBU2-5 at -30⁰C

[00275] The simulated and observed PXRD curves of the IBU2-5 Form were measured as described in the procedures above and are shown in Figure 10. The PXRD patterns (CuKa λ=1.5418A at a temperature of about 25°C) have 2 theta ("2Θ") values of 5.7, 7.8, 9.9, 10.7, 17.8, 18.9, 19.9 and 20.9 (degrees 2Θ ±0.1), when measured at a temperature of about 25°C.

EXAMPLE 11 Preparation of Form HPA2-6 [00276] Compound 1 was dissolved in previously prepared saturated solution of succinic acid in proprionic acid with warming. Butyl acetate was added dropwise to the warm solution and the solution was allowed to cool Crystals of the di-proprionic acid solvate of compound 1 (Form HPA2-6) formed upon standing.

Characterization of Form HPA2-6

[00277] The unit cell parameters of form HPA2-6 were measured at -70⁰C according to the procedures described above and are listed in Table 21.

TABLE 21 Crystal Properties of Form HPA2-6

[00278] The fractional atomic coordinate data of Form HPA2-6 were measured according to the procedure described above and are presented in Table 22. Occupancies are 1 unless otherwise indicated.

TABLE 22 Positional Parameters for Form HPA2-6 at-70°C

[00279] The simulated powder x-ray diffraction (PXRD) pattern of the HPA2-6 Form was calculated as described in the procedures above and is shown in Figure 11

EXAMPLE 12 Preparation of Form SA-7

[00280] Compound 1 was dissolved in a minimal amount of formic acid. A previously prepared saturated solution of succinic acid in proprionic acid was added to the formic acid solution of compound 1. Butyl acetate was added dropwise to the solution until it clouded. Crystals of the 3 formic acid and 1 proprionic acid solvate of compound 1 (Form SA-7) formed upon standing.

Characterization of Form SA-7

[00281] The unit cell parameters of form SA-7 were measured at -50⁰C according to the procedures described above and are listed in Table 23.

TABLE 23 Crystal Properties of SA-7

[00282] The fractional atomic coordinate data of Form SA-7 were measured according to the procedure described above and are presented in Table 24. Occupancies are 1 unless otherwise indicated.

TABLE 24 Positional Parameters for Form SA-7 at -50⁰C

[00283] The simulated and observed PXRD curves of the SA-7 Form were measured as described in the procedures above and are shown in Figure 12. The PXRD patterns (CuKa λ=1.5418A at a temperature of about 25°C) have 2 theta ("2Θ") values of 6.1, 7.2, 7.9, 10.5, 11.1, 12.1, 15.9, 19.0, 21.0, 23.7 and 29.9 (degrees 2Θ ±0.1), when measured at a temperature of about 25°C.

EXAMPLE 13

Preparation of Form SA-8 [00284] Compound 1 was dissolved in a solution of benzoic acid in butanol at 80⁰C. The solution was cooled slowly over 2 hours to room temperature. Crystals of the benzoic acid and butyl acetate solvate of compound 1 (Form SA-8) formed upon standing.

Characterization of Form SA-8

[00285] The unit cell parameters of form SA-8 were measured at -50⁰C according to the procedures described above and are listed in Table 25.

TABLE 25 Crystal Properties of Form SA-8 at -50⁰C

[00286] The fractional atomic coordinate data of Form SA-8 were measured according to the procedure described above and are presented in Table 26. Occupancies are 1 unless otherwise indicated.

TABLE 26 Positional Parameters for Form SA-8 (Benzoic Acid and BuOAc) at -50⁰C

[00287] The simulated and observed PXRD curves of the SA-8 Form were measured as described in the procedures above and are shown in Figure 13. The PXRD patterns (CuKa λ=1.5418A at a temperature of about 25°C) have 2 theta ("2Θ") values of 5.6, 8.8, 11.2, 12.5, 14.1, 15.6, 21.7 and 23.5 (degrees 2Θ ±0.1), when measured at a temperature of about 25°C.

EXAMPLE 14 Preparation of Form SA-9 [00288] Compound 1 was dissolved in a solution of adipic acid in formic acid with warming. Butyl acetate was added dropwise until the solution began to cloud. Crystals of the 3 formic acid and BuOAc solvate of compound 1 (Form SA-9) formed upon standing.

Characterization of Form SA-9

[00289] The unit cell parameters of form SA-9 were measured at -100⁰C according to the procedures described above and are listed in Table 27. TABLE 27 Crystal Properties of Form SA-9 (3 Formic Acid and BuOAc)

[00290] The fractional atomic coordinate data of Form SA-9 were measured according to the procedure described above and are presented in Table 28. Occupancies are 1 unless otherwise indicated.

TABLE 28 Positional Parameters for Form SA-9

[00291] The simulated powder x-ray diffraction (PXRD) pattern of SA-9 Form was calculated according to the procedure described above and is as shown in Figure 14.

EXAMPLE 15 Preparation of Form BY2-10

[00292] Compound 1 was dissolved in a minimal amount of butyric acid.. Butyl acetate was added dropwise until the solution began to cloud. Crystals of the di- butyric acid solvate of compound 1 (Form BY2-10) formed upon standing.

Characterization of Form BY2-10

[00293] The unit cell parameters of form BY2-10 were measured at -50⁰C according to the procedures described above and are listed in Table 29.

TABLE 29 Crystal Properties of Form BY2-10 (Dibutyric Acid)

[00294] The fractional atomic coordinate data of Form BY2-10 were measured according to the procedure described above and are presented in Table 30. Occupancies are 1 unless otherwise indicated.

TABLE 30 Positional Parameters for Form BY2-10 at-50°C

[00295] The simulated powder x-ray diffraction (PXRD) pattern of BY2- 10 Form was measured according to the procedure described above and is as shown in Figure 15. EXAMPLE 16 Preparation of Form VA2-10

[00296] Compound 1 was dissolved in a minimal amount of valeric acid.. Butyl acetate was added dropwise until the solution began to cloud. Crystals of the di- valeric acid solvate of compound 1 (Form VA2-10) formed upon standing.

Characterization of Form VA2-10

[00297] The unit cell parameters of form VA2-10 were measured at -70⁰C according to the procedures described above and are listed in Table 31.

TABLE 31 Crystal Properties of Form VA2-10 (Di-valeric Acid)

[00298] The fractional atomic coordinate data of Form VA-10 were measured according to the procedure described above and are presented in Table 32. Occupancies are 1 unless otherwise indicated.

TABLE 32 Positional Parameters for Form VA2-10 at-70°C

[00299] The simulated and observed PXRD curves of the VA2-10 Form were measured as described in the procedures above and are shown in Figure 16. The PXRD patterns (CuKa λ=1.5418A at a temperature of about 25°C) have 2 theta ("2Θ") values of 5.6, 9.7, 11.9, 15.9, 16.8, 20.6 and 23.7 (degrees 2Θ ±0.1), when measured at a temperature of about 25°C.

EXAMPLE 17 Preparation of Form CP2-10 [00300] Compound 1 was dissolved in a minimal amount of caproic acid.. Butyl acetate was added dropwise until the solution began to cloud. Crystals of the di- caproic acid solvate of compound 1 (Form CP2-10) formed upon standing. Characterization of Form CP2-10

[00301] The unit cell parameters of form CP2-10 were measured at -50⁰C according to the procedures described above and are listed in Table 33.

TABLE 33 Crystal Properties of Form CP2-10

[00302] The fractional atomic coordinate data of Form CP2-10 were measured according to the procedure described above and are presented in Table 34. Occupancies are 1 unless otherwise indicated.

TABLE 34 Positional Parameters for Form CP2-10 at -50⁰C

[00303] The simulated and observed PXRD curves of the CP2- 10 Form were measured as described in the procedures above and are shown in Figure 17. The PXRD patterns (CuKa λ=1.5418A at a temperature of about 25°C) have 2 theta ("2Θ") values of 5.3, 11.6, 15.9, 16.5, 19.1, 21.1 and 28.6 (degrees 2Θ ±0.1), when measured at a temperature of about 25°C.

EXAMPLE 18 Preparation of Form SA-Il [00304] Compound 1 was dissolved in a minimal amount of trifluoroacetic acid. Butyl acetate was added dropwise until the solution began to cloud. Crystals of the monotrifluoroacetic acid and 1/3 BuOAc solvate of compound 1 (Form SA-I l) formed upon standing.

Characterization of Form SA-Il

[00305] The unit cell parameters of form SA-11 were measured at -50⁰C according to the procedures described above and are listed in Table 35. TABLE 35 Crystal Properties of Form SA-Il

[00306] The fractional atomic coordinate data of Form SA- 11 were measured according to the procedure described above and are presented in Table 36. Occupancies are 1 unless otherwise indicated.

TABLE 36 Positional Parameters for Form SA-Il at-50°C

[00307] The simulated and observed PXRD curves of the SA- 11 Form were measured as described in the procedures above and are shown in Figure 18. The PXRD patterns (CuKa λ=1.5418A at a temperature of about 25°C) have 2 theta ("2Θ") values of 6.3, 8.1, 10.6, 11.3, 12.6, 13.7, 16.0, 18.4, 20.5, 21.3 and 23.5 (degrees 2Θ ±0.1), when measured at a temperature of about 25°C.

EXAMPLE 19 Preparation of Form TFA-12

[00308] Compound 1 was dissolved in a minimal amount of trifluoroacetic acid. Butyl acetate was added dropwise until the solution clouded. Crystals of the monotrifluoroacetic acid solvate (Form TFA-4) formed upon standing. Upon standing in the solid state, crystals of form TFA-12 transformed to the monotrifluoroacetic acid solvate (Form TFA-12).

Characterization of Form TFA-12

[00309] The unit cell parameters of form TFA-12 were measured at -70⁰C according to the procedures described above and are listed in Table 37.

TABLE 37 Crystal Properties of Form TFA-12

[00310] The fractional atomic coordinate data of Form TFA- 12 were measured according to the procedure described above and are presented in Table 48. Occupancies are 1 unless otherwise indicated.

TABLE 38 Positional Parameters for Form TFA-12 at -70⁰C

[00311] The simulated and observed PXRD curves of the TFA- 12 Form were measured as described in the procedures above and are shown in Figure 19. The PXRD patterns (CuKa λ=1.5418A at a temperature of about 25°C) have 2 theta ("2Θ") values of 7.3, 9.1, 11.3, 12.5, 16.5, 18.1, 21.4, 23.9, 25.1 and 28.0 (degrees 2Θ ±0.1), when measured at a temperature of about 25°C.

Claims

WHAT IS CLAIMED IS:

1. A compound, that is a crystalline form of ((((4-((5- (cyclopropylcarbamoyl)-2-methylphenyl)amino)-5-methylpyrrolo[2,l-/|[l,2,4]triazin- 6-yl)carbonyl)(propyl)carbamoyl)oxy)methyl (4-(phosphonooxy)phenyl)acetate.

2. The crystalline form according to claim 1, comprising the IA2-1 form.

3. The crystalline form according to claim 1, comprising the MIBK2-1 form.

4. The crystalline form according to claim 1, comprising the MA2.5-1 form.

5. The crystalline form according to claim 1, comprising the TRA-I form.

6. The crystalline form according to claim 1, comprising the SA-3 form.

7. The crystalline form according to claim 1, comprising the SB-3 form.

8. The crystalline form according to claim 1, comprising the SC-3 form.

9. The crystalline form according to claim 1, comprising the TFE-4 form.

10. The crystalline form according to claim 1, comprising the TFA-4 form.

11. The crystalline form according to claim 1, comprising the IBU2-5 form.

12. The crystalline form according to claim 1, comprising the HPA2-6 form.

13. The crystalline form according to claim 1, comprising the SA-7 form.

14. The crystalline form according to claim 1, comprising the SA-8 form.

15. The crystalline form according to claim 1, comprising the SA-9 form.

16. The crystalline form according to claim 1, comprising the BY2-10 form.

17. The crystalline form according to claim 1, comprising the VA2-10 form.

18. The crystalline form according to claim 1, comprising the CP2-10 form.

19. The crystalline form according to claim 1, comprising the SA-11 form.

20. The crystalline form according to claim 1, comprising the TFA- 12 form.