CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 18/095,621, filed Jan. 11, 2023, which claims the benefit of priority to U.S. Provisional Application No. 63/298,816, filed Jan. 12, 2022, and U.S. Provisional Application No. 63/386, 113 filed Dec. 5, 2022, each of which is incorporated by reference herein in its entirety for any purpose.

TECHNICAL FIELD

Described herein are crystalline forms of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4] oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide, the process of preparing the forms, pharmaceutical compositions, and methods of use thereof.

BACKGROUND

Receptor-interacting protein kinase 1 (RIPK1) is a key regulator of inflammation, apoptosis, and necroptosis. RIPK1 has an important role in modulating inflammatory responses mediated by nuclear-factor kappa-light chain enhancer of activated B cells (NF-KB). More recent research has shown that its kinase activity controls necroptosis, a form of necrotic cell death. Further, RIPK1 is part of a pro-apoptotic complex indicating its activity in regulating apoptosis. Dysregulation of receptor-interacting protein kinase 1 signaling can lead to excessive inflammation or cell death. Research suggests that inhibition of RIPK 1 is a potential clinical target for diseases involving inflammation or cell death. RIPK1 kinase has emerged as a promising therapeutic target for the treatment of a wide range of human neurodegenerative, autoimmune, and inflammatory diseases.

Compound (I) is a RIPK1 inhibitor and may be useful in the treatment of RIPK1 mediated diseases or disorders. Compound (I) is disclosed in WO2017/136727 (also in U.S. Pat. No. 9,815,850) and has the following structure:

[Image Omitted]

Solid forms (e.g., crystalline forms) of bioactive compounds, such as Compound (I), are of interest in the pharmaceutical industry, where solid forms with specific physical, chemical, or pharmaceutical properties, such as solubility, dissociation, true density, dissolution, melting point, morphology, compaction behavior, particle size, flow properties, or solid-state stability, may be desirable or even required for pharmaceutical development. Although it is known that the preparation of crystalline forms may improve the physical or pharmaceutical properties of a pharmaceutically active compound, it is not possible to predict whether a compound exists in crystalline form(s) or which crystalline form(s) may possess advantages for a particular purpose prior to the actual preparation and characterization of the crystalline form. In particular, such advantages, in a non-limiting manner could include better processability, solubility or shelf-life stability, just to name a few. Other advantages may also include biological properties such as improved bioavailability, reduced adverse reactions at the GI tract (for example irritation of the GI tract, partial degradation of the compound, etc.), or better deliverability of the drug to the intended target site among other advantages.

SUMMARY

The present disclosure relates to various solid state forms of the RIPK1 inhibitor (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (also referred as Compound (I)), the process of preparing the forms, and pharmaceutical compositions and methods of use thereof.

The present disclosure provides a crystalline form of Compound (I), characterized as Form A.

The present disclosure provides a crystalline form of Compound (I), characterized as Form B.

The present disclosure provides a crystalline form of Compound (I), characterized as Form C.

The present disclosure provides a crystalline form of Compound (I), characterized as Form D.

The present disclosure provides a crystalline form of Compound (I), characterized as Form E.

The present disclosure provides a crystalline form of Compound (I), characterized as Form F.

The crystalline Form B of Compound (I) has high melting point and is less hygroscopic and appears to be most suitable for industrial use and storage.

BRIEF DESCRIPTION DRAWINGS

FIG. 1 is an X-ray powder diffractogram of crystalline Form A of Compound (I).

FIG. 2 is a Differential Scanning Calorimetry/Thermal Gravimetric Analysis (DSC/TGA) thermogram of crystalline Form A of Compound (I).

FIG. 3 is an X-ray powder diffractogram of crystalline Form B of Compound (I).

FIG. 4 is a Differential Scanning Calorimetry/Thermal Gravimetric Analysis (DSC/TGA) thermogram of crystalline Form B of Compound (I).

FIG. 5 is an X-ray powder diffractogram of crystalline Form C of Compound (I).

FIG. 6 is ¹HNMR spectrum of Form C of Compound (I).

FIG. 7 is a Differential Scanning Calorimetry/Thermal Gravimetric Analysis (DSC/TGA) thermogram of crystalline Form C of Compound (I).

FIG. 8 is an X-ray powder diffractogram of crystalline Form D of Compound (I).

FIG. 9 is a Differential Scanning Calorimetry/Thermal Gravimetric Analysis (DSC/TGA) thermogram of crystalline Form D of Compound (I).

FIG. 10 is a ¹HNMR spectrum of crystalline Form D of Compound (I).

FIG. 11 is an X-ray powder diffractogram of crystalline Form E of Compound (I).

FIG. 12 is an X-ray powder diffractogram of crystalline Form F of Compound (I).

FIG. 13 Inter-conversion relationship between different forms.

FIG. 14 is thermal ellipsoids drawing of the single crystal of crystalline Form B of Compound (I).

FIG. 15 is the hydrogen bonds in the single crystal structure of crystalline Form B of Compound (I).

FIG. 16 is the calculated XRPD generated from the single crystal structure of crystalline Form B of Compound (I).

FIG. 17 is thermal ellipsoids drawing of the single crystal of crystalline Form E of Compound (I).

FIG. 18 is the calculated XRPD generated from the single crystal structure of crystalline Form E of Compound (I).

DETAILED DESCRIPTION

The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

The present disclosure provides crystalline solid forms of Compound (I). The present disclosure also provides pharmaceutical compositions comprising one or more crystalline solid forms of Compound (I). The disclosure also provides processes for making the crystalline solid forms, and methods for using them.

Herein are also provided pharmaceutical compositions comprising one or more compounds selected from the group consisting of Form A of Compound (I), Form B of Compound (I), Form C of Compound (I), Form D of Compound (I), Form E of Compound (I), and Form F of Compound (I)); and a pharmaceutically acceptable excipient.

Herein are also provided methods of preparing pharmaceutical compositions comprising mixing one or more compounds selected from the group consisting of Form A of Compound (I), Form B of Compound (I), Form C of Compound (I), Form D of Compound (I), Form E of Compound (I), and Form F of Compound (I)); and a pharmaceutically acceptable excipient.

Herein are also provided methods of preparing pharmaceutical compositions comprising mixing Form B of Compound (I) and a pharmaceutically acceptable excipient.

Herein are also provided methods of treating a disease associated with RIPK1 in a patient in need thereof, comprising administering to the patient an effective amount of one or more compounds selected from the group consisting of Form A of Compound (I), Form B of Compound (I), Form C of Compound (I), Form D of Compound (I), Form E of Compound (I), and Form F of Compound (I)).

Herein are also provided methods of treating a disease associated with RIPK1 in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising one or more compounds selected from the group consisting of Form A of Compound (I), Form B of Compound (I), Form C of Compound (I), Form D of Compound (I), Form E of Compound (I), and Form F of Compound (I)).

Herein are also provided methods of inhibiting RIPK1. The method comprises administering to a patient in need thereof, an effective amount of one or more compounds selected from the group consisting of Form A of Compound (I), Form B of Compound (I), Form C of Compound (I), Form D of Compound (I), Form E of Compound (I), and Form F of Compound (I)).

Herein are also provided methods of inhibiting RIPK1 comprising administering to a patient in need thereof, an effective amount of a pharmaceutical composition comprising one or more compounds selected from the group consisting of Form A of Compound (I), Form B of Compound (I), Form C of Compound (I), Form D of Compound (I), Form E of Compound (I), and Form F of Compound (I)).

Another aspect of the disclosure relates to one or more compounds selected from the group consisting of Form A of Compound (I), Form B of Compound (I), Form C of Compound (I), Form D of Compound (I), Form E of Compound (I), and Form F of Compound (I)), for use in treating a disease associated with RIPK1. One aspect of the disclosure relates to pharmaceutical compositions comprising one or more compounds selected from the group consisting of Form A of Compound (I), Form B of Compound (I), Form C of Compound (I), Form D of Compound (I), Form E of Compound (I), and Form F of Compound (I)); and a pharmaceutically acceptable excipient, for use in treating a disease or disorder associated with RIPK1.

Herein is also provided the use of one or more compounds selected from the group consisting of Form A of Compound (I), Form B of Compound (I), Form C of Compound (I), Form D of Compound (I), Form E of Compound (I), and Form F of Compound (I)), in the manufacture of a medicament for treating a disease associated with RIPK1. Another aspect of the disclosure relates to the use of pharmaceutical compositions comprising one or more compounds selected from the group consisting of Form A of Compound (I), Form B of Compound (I), Form C of Compound (I), Form D of Compound (I), Form E of Compound (I), and Form F of Compound (I)); and a pharmaceutically acceptable excipient, in the manufacture of a medicament for treating a disease or disorder associated with RIPK1.

Herein is also provided one or more compounds selected from the group consisting of Form A of Compound (I), Form B of Compound (I), Form C of Compound (I), Form D of Compound (I), Form E of Compound (I), and Form F of Compound (I)), for use as a medicament. Another aspect of the disclosure relates to pharmaceutical compositions comprising one or more compounds selected from the group consisting of Form A of Compound (I), Form B of Compound (I), Form C of Compound (I), Form D of Compound (I), Form E of Compound (I), and Form F of Compound (I)), for use as a medicament. In some embodiments, the medicament is used for treating a disease or disorder mediated by RIPK1.

Provided herein is a method of treating a receptor-interacting protein kinase 1-mediated disease or disorder comprising administering a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein to a patient in need thereof.

In certain embodiments, the disease or disorder is inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, cutaneous lupus erythematosus, Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome, vasculitis, osteoarthritis, non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis, nephritis, Celiac disease, autoimmune ITP, transplant rejection, ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cytokine release syndrome, covid-19 infection, cerebrovascular accident, myocardial infarction, Huntington's disease, Parkinson's disease, allergic diseases, asthma, atopic dermatitis, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, or peridontitis.

In certain embodiments, the disease or disorder is trauma, ischemia, stroke, cardiac infarction, infection, lysosomal storage disease, Gaucher's disease, Krabbe disease, Niemann-Pick disease, sepsis, Parkinson's disease, amyotrophic lateral sclerosis (ALS/Lou Gehrig's Disease), Huntington's disease, HIV-associated dementia, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis or inflammatory bowel disease.

In certain embodiments, the disease or disorder is ALS, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, or spinal muscular atrophy. In certain embodiments, the disease or disorder is brain injury, spinal cord injury, dementia, stroke, ALS, Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathy, poly glutamine (polyQ) diseases, stroke, Fahr disease, Menke's disease, Wilson's disease, cerebral ischemia, or a prion disorder.

The present disclosure also provides compounds and pharmaceutical compositions that are useful in inhibiting RIPK1.

Each embodiment described herein may be taken alone or in combination with any one or more other embodiments.

TERMS

The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

The term “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

The terms “article of manufacture” and “kit” are used as synonyms.

A “pharmaceutically acceptable excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.

As used herein, the term “crystalline” or “crystalline solid form,” refers to a solid form which is substantially free of any amorphous solid-state form. In some embodiments, the crystalline solid form is a single solid-state form, e.g., crystalline Form A.

In some embodiments, “substantially free” means less than about 10% w/w, less than about 9% w/w, less than about 8% w/w, less than about 7% w/w, less than about 6% w/w, less than about 5% w/w, less than about 4% w/w, less than about 3% w/w, less than about 2.5% w/w, less than about 2% w/w, less than about 1.5% w/w, less than about 1% w/w, less than about 0.75% w/w, less than about 0.50% w/w, less than about 0.25% w/w, less than about 0.10% w/w, or less than about 0.05% w/w of other crystalline forms of the compound and the amorphous compound. In some embodiments, “substantially free” means an undetectable amount of other crystalline forms of the compound and the amorphous compound.

As used herein, the term “substantially pure” means that the crystalline form contains at least 90 percent, preferably at least 95 percent, more preferably at least 97 percent, and most preferably at least 99 percent by weight of the indicated crystalline form compared to the total weight of the compound of all forms.

Alternatively, it will be understood that “substantially pure” means that the crystalline form contains less than 10 percent, preferably less than 5 percent, more preferably less than 3 percent, and most preferably less than 1 percent by weight of impurities, including other polymorphic, solvated or amorphous forms compared to the total weight of the compound of all forms.

An “XRPD pattern” or “X-ray powder diffraction pattern” is an x-y graph with diffraction angle (i.e., °2 θ) on the x-axis and intensity on the y-axis. The peaks within this pattern may be used to characterize a crystalline solid form. As with any data measurement, there is variability in XRPD data. The data are often represented solely by the diffraction angle of the peaks rather than including the intensity of the peaks because peak intensity can be particularly sensitive to sample preparation (for example, particle size, moisture content, solvent content, and preferred orientation effects influence the sensitivity), so samples of the same material prepared under different conditions may yield slightly different patterns; this variability is usually greater than the variability in diffraction angles. Diffraction angle variability may also be sensitive to sample preparation. Other sources of variability come from instrument parameters and processing of the raw X-ray data: different X-ray instruments operate using different parameters and these may lead to slightly different XRPD patterns from the same solid form, and similarly different software packages process X-ray data differently and this also leads to variability. These and other sources of variability are known to those of ordinary skill in the pharmaceutical arts. Due to such sources of variability, it is usual to assign a variability of about ±0.2° θ to diffraction angles in XRPD patterns.

SOLID FORMS

Forms A and B are anhydrous polymorphs of Compound (I). Form C is a hydrate of Compound (I), and Form D, Form E and Form, F are solvates of Compound (I).

The preparation and uses of Compound (I) have been previously described (see WO 2017/136727, U.S. Pat. No. 9,815,850).

In some embodiments provided herein, Compound (I) is crystalline.

In some embodiments, the crystallinity of a solid form is characterized by X-Ray Powder Diffraction (XRPD).

In some embodiments, the crystallinity of a solid form is determined by thermo gravimetric analysis (TGA).

In some embodiments, the crystallinity of a solid form is determined by differential scanning calorimeter (DSC).

Herein is provided a crystalline form selected from the group consisting of:

Form A of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide;

Form B of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide;

Form C of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide;

Form D of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide;

Form E of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide; and

Form F of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide.

Herein is provided crystalline Form A of Compound (I).

In some embodiments, crystalline Form A of Compound (I) is characterized as having one or more of:

- a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 1;
- b) an X-ray powder diffraction (XRPD) pattern derived using Cu (Kα) radiation with peaks, in term of 2-theta degrees, at about 6.9, 13.0, 16.6, and 23.4±0.2 degrees;
- c) a Differential Scanning calorimetry (DSC) thermogram substantially the same as shown in FIG. 2;
- d) a Differential Scanning calorimetry (DSC) thermogram with three endothermic events having an onset at about 186.7° C. and a peak at about 188.9° C.;
- e) a Thermogravimetric Analysis (TGA) pattern substantially the same as shown in FIG. 2;
- f) a Thermogravimetric Analysis (TGA) pattern with an about 1.0% w/w loss from about 27.8° C. to about 150° C.; or
- g) combinations thereof.

In one embodiment, the crystalline Form A of Compound (I), having an X-ray powder diffraction pattern derived using Cu (Kα) radiation comprising one, two, three, four, five, six, seven or more peaks selected from the group consisting of: 6.9, 11.5, 13.0, 13.9, 16.6, 19.4, 23.4, and 24.0 (expressed in degrees 2-theta±0.2 degrees 2-theta).

In one embodiment, the crystalline Form A of Compound (I), having an X-ray powder diffraction pattern derived using Cu (Kα) radiation comprising one peak selected from the group consisting of: 6.9, 11.5, 13.0, 13.9, 16.6, 19.4, 23.4, and 24.0 (expressed in degrees 2-theta±0.2 degrees 2-theta).

In one embodiment, the crystalline Form A of Compound (I), having an X-ray powder diffraction pattern derived using Cu (Kα) radiation comprising two peaks selected from the group consisting of: 6.9, 11.5, 13.0, 13.9, 16.6, 19.4, 23.4, and 24.0 (expressed in degrees 2-theta±0.2 degrees 2-theta).

In one embodiment, the crystalline Form A of Compound (I), having an X-ray powder diffraction pattern derived using Cu (Kα) radiation comprising three peaks selected from the group consisting of: 6.9, 11.5, 13.0, 13.9, 16.6, 19.4, 23.4, and 24.0 (expressed in degrees 2-theta±0.2 degrees 2-theta).

In one embodiment, the crystalline Form A of Compound (I), having an X-ray powder diffraction pattern derived using Cu (Kα) radiation comprising four peaks selected from the group consisting of: 6.9, 11.5, 13.0, 13.9, 16.6, 19.4, 23.4, and 24.0 (expressed in degrees 2-theta±0.2 degrees 2-theta).

In one embodiment, the crystalline Form A of Compound (I), having an X-ray powder diffraction pattern derived using Cu (Kα) radiation comprising five peaks selected from the group consisting of: 6.9, 11.5, 13.0, 13.9, 16.6, 19.4, 23.4, and 24.0 (expressed in degrees 2-theta±0.2 degrees 2-theta).

In one embodiment, the crystalline Form A of Compound (I), having an X-ray powder diffraction pattern derived using Cu (Kα) radiation comprising six peaks selected from the group consisting of: 6.9, 11.5, 13.0, 13.9, 16.6, 19.4, 23.4, and 24.0 (expressed in degrees 2-theta±0.2 degrees 2-theta).

In one embodiment, the crystalline Form A of Compound (I), having an X-ray powder diffraction pattern derived using Cu (Kα) radiation comprising seven or more peaks selected from the group consisting of: 6.9, 11.5, 13.0, 13.9, 16.6, 19.4, 23.4, and 24.0 (expressed in degrees 2-theta±0.2 degrees 2-theta).

In one embodiment, the crystalline Form A of Compound (I), having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta degree, at about 6.9 (each time plus or minus 0.2).

In one embodiment, the crystalline Form A of Compound (I), having an X-ray powder diffraction pattern comprising a peak, in term of 2-theta degree, at about 6.9 and about 13.0 (each time plus or minus 0.2).

In one embodiment, the crystalline Form A of Compound (I) having one or more X-ray powder diffraction displaying peaks expressed as degree 2-Theta degrees at about 6.9, 13.0, 16.6 and 23.4 (each time plus or minus 0.2).

In one embodiment, the crystalline Form A of Compound (I), having the X-ray powder diffraction pattern comprises one or more 2-theta degrees selected from the group comprising about 13.9, 16.6, 19.4, and 23.4 (each time plus or minus 0.2).

In one embodiment, the crystalline Form A of Compound (I), having an X-ray powder diffraction pattern is substantially in accordance with that shown in FIG. 1.

Herein is also provided a crystalline Form A of Compound (I), characterized by a differential scanning calorimetry (DSC) curve with an onset at about 186.7° C. and an endothermic peak at 188.9° C.

Herein are also provided processes for the preparation of the crystalline Form A of Compound (I) comprising at least the following steps:

- a) dissolving Compound (I) in a solvent selected from CPME, EtOH, IPA, Acetone, MIBK, EtOAc, IPAc, ACN, MTBE, THF, n-Heptane, MeOAc, 2-MeTHF and toluene, at a set temperature ranging from 50° C. to 70° C.;
- b) slowly cooling to room temperature;
- c) filtering, washing with the solvent and drying to provide the crystalline Form A of Compound (I) formed in step 2.

Herein is provided a crystalline Form B of Compound (I).

In some embodiments, crystalline Form B of Compound (I) is characterized as having one or more of:

- a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 3;
- b) an X-ray powder diffraction (XRPD) pattern derived using Cu (Kα) radiation with peaks, in term of 2-theta degrees, at about 9.6, 11.5, 16.4, 19.2, and 23.8±0.2 degrees;
- c) unit cell parameters substantially the same as shown in Table 25;
- d) a Differential Scanning calorimetry (DSC) thermogram substantially the same as shown in FIG. 4;
- e) a Differential Scanning calorimetry (DSC) thermogram with three endothermic events having an onset at about 189.2° C. and a peak at about 191.9° C.;
- f) a Thermogravimetric Analysis (TGA) pattern substantially the same as shown in FIG. 4;
- g) a Thermogravimetric Analysis (TGA) pattern with a about 1.0% w/w loss from about 23.8° C. to about 150° C.; or
- h) combinations thereof.

Herein is also provided a crystalline form of Compound (I), characterized as Form B.

In one embodiment, the crystalline Form B of compounds (I) consists of one tautomer.

In one embodiment, the crystalline Form B of compounds (I) having at least 90% (w/w) of one tautomer, wherein hydrogen is on 4-position of triazole ring of the tautomer.

In one embodiment, the crystalline Form B of compounds (I) having at least 95% (w/w) of one tautomer, wherein hydrogen is on 4-position of triazole ring of the tautomer.

In one embodiment, the crystalline Form B of compounds (I) having at least 97% (w/w) of one tautomer, wherein hydrogen is on 4-position of triazole ring of the tautomer.

In one embodiment, the crystalline Form B of Compound (I), having an X-ray powder diffraction pattern derived using Cu (Kα) radiation comprising one, two, three, four, five, six or more peaks selected from the group consisting of: 9.6, 11.5, 13.8, 16.4, 19.2, 23.2, and 23.8 (expressed in degrees 2-theta±0.2 degrees 2-theta).

In one embodiment, the crystalline Form B of Compound (I), having an X-ray powder diffraction pattern derived using Cu (Kα) radiation comprising one peak selected from the group consisting of: 9.6, 11.5, 13.8, 16.4, 19.2, 23.2, and 23.8 (expressed in degrees 2-theta±0.2 degrees 2-theta).

In one embodiment, the crystalline Form B of Compound (I), having an X-ray powder diffraction pattern derived using Cu (Kα) radiation comprising two peaks selected from the group consisting of: 9.6, 11.5, 13.8, 16.4, 19.2, 23.2, and 23.8 (expressed in degrees 2-theta±0.2 degrees 2-theta).

In one embodiment, the crystalline Form B of Compound (I), having an X-ray powder diffraction pattern derived using Cu (Kα) radiation comprising three peaks selected from the group consisting of: 9.6, 11.5, 13.8, 16.4, 19.2, 23.2, and 23.8 (expressed in degrees 2-theta±0.2 degrees 2-theta).

In one embodiment, the crystalline Form B of Compound (I), having an X-ray powder diffraction pattern derived using Cu (Kα) radiation comprising four peaks selected from the group consisting of: 9.6, 11.5, 13.8, 16.4, 19.2, 23.2, and 23.8 (expressed in degrees 2-theta±0.2 degrees 2-theta).

In one embodiment, the crystalline Form B of Compound (I), having an X-ray powder diffraction pattern derived using Cu (Kα) radiation comprising five peaks selected from the group consisting of: 9.6, 11.5, 13.8, 16.4, 19.2, 23.2, and 23.8 (expressed in degrees 2-theta±0.2 degrees 2-theta).

In one embodiment, the crystalline Form B of Compound (I), having an X-ray powder diffraction pattern derived using Cu (Kα) radiation comprising six or more peaks selected from the group consisting of: 9.6, 11.5, 13.8, 16.4, 19.2, 23.2, and 23.8 (expressed in degrees 2-theta±0.2 degrees 2-theta).

Herein is also provided a crystalline Form B of Compound (I), having an X-ray powder diffraction pattern comprising a peak, in term of 2-theta degree, at about 9.6 and about 16.4 (each time plus or minus 0.2).

Herein is also provided a crystalline Form B of Compound (I), having the X-ray powder diffraction displaying one or more peaks expressed as 2-theta degrees at about 9.6, 11.5, 16.4, 19.2, 23.2 and 23.8 (each time plus or minus 0.2).

Herein is also provided a crystalline Form B of Compound (I), having the X-ray powder diffraction pattern comprises one or more 2-theta degrees selected from the group comprising about 11.5, 19.2, 23.2, and 23.8 (each time plus or minus 0.2).

Herein is also provided a crystalline Form B of Compound (I), having an X-ray powder diffraction pattern is substantially in accordance with that shown in FIG. 3.

Herein is also provided a crystalline Form B of Compound (I), having cell parameters substantially the same as: a=5.0418(8) Å, b=15.320(3) Å, c=11.599(2) Å, α=90°, β=98.383(5)°, γ=90°, V=886.3(3) Å³.

Herein is also provided a crystalline Form B of Compound (I), having cell parameters substantially the same as: a=5.0418 Å, b=15.320 Å, c=11.599 Å, α=90°, β=98.383°, γ=90°, V=886.3 Å³.

Herein is also provided a crystalline Form B of Compound (I), having cell parameters substantially the same as: a=5.04 Å, b=15.32 Å, c=11.60 Å, α=90°, β=98.38°, γ=90°, V=886.33 Å³.

Herein is also provided a crystalline Form B of Compound (I), characterized by a differential scanning calorimetry (DSC) curve comprises an endotherm at about 189.2° C. and an endothermic peak at 191.9° C.