RU2801355C2 - Polymorphous form of the monoposphate hydrate salt of the known tetrahydroisoquinoline derivative - Google Patents

Abstract

FIELD: chemical industry.

SUBSTANCE: invention relates to a method for obtaining crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha radiation having the following list of PXRD peaks°2θ: 4.5, 5.8, 7.2, 8.9, 10.5, 10.7, 11.5, 12.2, 13.1, 14.7, 15.3, 16.6, 17.5, 18.0, 18.6, 19.3, 21.0, 21.6, 22.7, 23.1, 23.5, 24.8 The method according to the invention is carried out by obtaining a mixture of (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol, 2-propanol and water; subsequent addition of phosphoric acid and 2-propanol to form a solution; heating the solution to a crystallization temperature and adding more 2-propanol to the solution; and maintaining the solution at the crystallization temperature to form crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate.

EFFECT: obtaining crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate having low hygroscopicity.

12 cl, 8 dwg, 7 tbl, 13 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to a new crystalline form of (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol or a pharmaceutically acceptable salt thereof. More specifically, the present invention relates to a novel crystalline form of the pharmaceutically acceptable salt of (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl )hydroxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol. The present invention also relates to formulations and therapeutic uses for such a polymorph.

BACKGROUND OF THE INVENTION

Compound (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H -pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol is represented by formula (I) below.

(I)

Preparation of compound (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol as hydrochloride salt is described in Example 190 of WO2017/212385 and depicted as follows.

In this procedure, with tert-butyl-6-(difluoromethyl)-8-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate is first deprotected in dichloromethane/dioxane/HCl. The precipitated solid is separated, dried and lyophilized to give the hydrochloride salt (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl) hydroxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol as a "light yellow solid". The defined solid form of the resulting hydrochloride salt (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-( 4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol is not listed. (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol can be prepared from this salt by standard basicization methods.

Preparation of compound (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol as hydrochloride salt as described in Example 190 of WO2017/212385 has been reproduced as accurately as possible in Reference Example 1 herein. PXRD and elemental analysis show that the product obtained in Example 190 is an amorphous dihydrochloride containing approximately 1 mole of water per mole of (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1 ,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol.

In WO2017/212385 (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4- methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol has been described as a PRMT5 inhibitor useful in the treatment of abnormal cell growth in mammals, in particular in humans, in particular in the treatment of cancer.

Human cancer includes a wide range of diseases that together are one of the leading causes of death in developed countries around the world (American Cancer Society, Cancer Facts and Figures 2005. Atlanta: American Cancer Society; 2005). Cancer progression is driven by a complex series of multiple genetic and molecular events, including gene mutations, chromosomal translocations, and karyotypic abnormalities (Hanahan & Weinberg, The hallmarks of cancer. Cell 2000; 100: 57-70). Although the underlying genetic causes of cancer are both varied and complex, each type of cancer has been found to exhibit common features and acquired abilities that contribute to its progression. These acquired abilities include dysregulation of cell growth, sustained ability to recruit blood vessels (ie, angiogenesis), and the ability of tumor cells to spread locally as well as metastasize to secondary organ sites (Hanahan & Weinberg 2000 supra). Therefore, the ability to identify new therapeutic agents that inhibit molecular targets that change during cancer progression or target multiple processes that are common to cancer progression in different tumors represents a significant unmet need.

Post-translational modification of arginine residues by methylation is important for many critical cellular processes, including chromatin remodeling, gene transcription, protein translation, signal transduction, RNA splicing, and cell proliferation. Arginine methylation is catalyzed by protein arginine methyltransferase (PRMT) enzymes. There are nine PRMT members in total, and eight have been reported to have enzymatic activity on target substrates.

The protein arginine methyltransferase (PRMT) family of enzymes uses S-adenosylmethionine (SAM) to transfer methyl groups to arginine residues on target proteins. Type I PRMTs catalyze the formation of monomethylarginine and asymmetric dimethylarginines, while type II PRMTs catalyze monomethylarginine and symmetrical dimethylarginines. PRMT5 is a type II enzyme that double-transfers a methyl group from SAM to two of the n-guanidino nitrogen of arginine, resulting in n-NG, N'G asymmetric methylation of protein substrates.

The PRMT5 protein is found in both the nucleus and the cytoplasm and has several protein substrates such as histones, transcription factors, and spliceosomal proteins. PRMT5 has a binding partner, Mep50 (methylosomal protein 50), and functions in a variety of protein complexes. PRMT5 is associated with chromatin remodeling complexes (SWI/SNF, NuRD) and epigenetically controls genes involved in cell development, proliferation, and differentiation, including tumor suppressors, through histone methylation (Karkhanis, V. et al. , Versatility of PRMT5 Induced Methylation in Growth Control and Development, Trends Biochem Sci 36(12) 633-641 (2011)). PRMT5 also controls gene expression through association with protein complexes that recruit PRMT5 to methylate several transcription factors, p53 (Jansson, M. et al. , Arginine Methylation Regulates the p53 Response, Nat. Cell Biol. 10, 1431-1439 (2008) ); E2F1 (Zheng, S. et al. , Arginine Methylation-Dependent Reader-Writer Interplay Governs Growth Control by E2F-1, Mol Cell 52(1), 37-51 (2013)); HOXA9 (Bandyopadhyay, S. et al. , HOXA9 Methylation by PRMT5 is Essential for Endothelial Cell Expression of Leukocyte Adhesion Molecules, Mol. Cell. Biol. 32(7): 1202-1213 (2012)) and NFκB (Wei, H. et al. , PRMT5 dimethylates R30 of the p65 Subunit to Activate NFkB, PNAS 110(33), 13516-13521 (2013)). In the cytoplasm, PRMT5 has a diverse array of substrates involved in other cellular functions, including RNA splicing (Sm proteins), Golgi assembly (gm130), ribosome biogenesis (RPS10), piRNA-mediated gene silencing (Piwi proteins), and EGFR signaling (Karkhanis, 2011).

Additional documents related to PRMT5 include: Aggarwal, P. et al. , (2010) Nuclear Cyclin D1/CDK4 Kinase Regulates CUL4B Expression and Triggers Neoplastic Growth via Activation of the PRMT5 Methyltransferase, Cancer Cell 18; 329-340; Bao, X. et al. , Overexpression of PRMT5 Promotes Tumor Cell Growth and is Associated with Poor Disease Prognosis in Epithelial Ovarian Cancer, J Histochem Cytochem 61: 206-217 (2013); Cho E. et al , Arginine Methylation Controls Growth Regulation by E2F1, EMBO J . 31(7) 1785-1797 (2012); Gu, Z. et al. , Protein Arginine Methyltransferase 5 Functions in Opposite Ways in the Cytoplasm and Nucleus of Prostate Cancer Cells, PLoS One 7(8) e44033 (2012); Gu, Z. et al. , Protein Arginine Methyltransferase 5 is Essential for Growth of Lung Cancer Cells, Biochem J. 446: 235-241 (2012); Kim, J. et al. , Identification of Gastric Cancer Related Genes Using a cDNA Microarray Containing Novel Expressed Sequence Tags Expressed in Gastric Cancer Cells, Clin Cancer Res. 11(2) 473-482 (2005); Nicholas, C. et al. , PRMT5 is Upregulated in Malignant and Metastatic Melanoma and Regulates Expression of MITF and p27(Kip1), PLoS One 8(9) e74710 (2012); Powers, M. et al. , Protein Arginine Methyltransferase 5 Accelerates Tumor Growth by Arginine Methylation of the Tumor Suppressor Programmed Cell Death 4, Cancer Res. 71(16) 5579-5587 (2011); Wang, L. et al. , Protein Arginine Methyltransferase 5 Suppresses the Transcription of the RB Family of Tumor Suppressors in Leukemia and Lymphoma Cells, Mol. Cell biol. 28(20), 6262-6277 (2008).

PRMT5 is overexpressed in many cancers and has been observed in patient samples and cell lines, including B-cell lymphoma and leukemia (Wang, 2008) and the following solid tumors: stomach (Kim 2005), esophagus (Aggarwal, 2010), breast (Powers , 2011), lung (Gu, 2012), prostate (Gu, 2012), melanoma (Nicholas 2012), colon (Cho, 2012) and ovary (Bao, 2013). In many of these cancers, PRMT5 overexpression has been associated with poor prognosis. Aberrant arginine methylation of PRMT5 substrates has been associated with other indications in addition to cancer, such as metabolic disorders, inflammatory and autoimmune diseases, and hemoglobinopathies.

Given its role in the regulation of various biological processes, PRMT5 is an attractive target for modulation by small molecule inhibitors such as (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3, 4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol.

SUMMARY OF THE INVENTION

Polymorphs are different crystalline forms of the same compound. The term "polymorphic form" may or may not include other crystalline solid molecular forms, including hydrates (eg bound water present in the crystal structure) and solvates (eg bound solvents other than water present in the crystal structure) of the same compound. Polymorphs usually have different crystal structures due to different packing of molecules in the lattice. This results in different crystal symmetries and/or unit cell parameters that directly affect its physical properties, such as the X-ray diffraction characteristics of crystals or powders.

Polymorphic forms are of interest to the pharmaceutical industry and especially to those involved in the development of suitable dosage forms. If the polymorphic form is not kept constant during clinical or stability studies, the exact dosage form used or studied may not be comparable from lot to lot. It is also desirable to have processes for preparing a compound with a selected polymorph in high purity when the compound is used in clinical studies or in commercial products, since any impurities present may cause undesirable toxicological effects. Certain polymorphs may also exhibit increased (eg, thermodynamic) stability or are easier to produce in high purity in large quantities and thus are more suitable for inclusion in pharmaceutical formulations. Certain polymorphs may exhibit other preferred physical properties such as no hygroscopic tendencies, improved solubility, and increased dissolution rates due to different lattice energies.

For pharmaceutical development and commercialization, it is necessary to identify the solid form of (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)- 5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol or a pharmaceutically acceptable salt or solvate thereof, which can be easily prepared, processed and formulated. Therefore, there is a need to identify the solid form of (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol or a pharmaceutically acceptable salt or solvate thereof, having desirable physicochemical and technological properties.

The present invention provides a novel crystalline form of the pharmaceutically acceptable salt of (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)- 5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol. More specifically, the present invention relates to crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate having desirable properties such as high crystallinity, high purity and preferable physical stability, chemical stability, dissolution and mechanical properties. In particular, crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4- methyl 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate provides improved physical stability (including low hygroscopicity) compared to the hydrochloride salt (1S,2S,3S,5R) -3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidine -7-yl)cyclopentan-1,2-diol disclosed in WO2017/212385.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the diffraction pattern of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-( 4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate.

Figure 2 shows ¹³ C solid state NMR spectrum of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy )-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate.

Figure 3 shows ¹⁹ F solid state NMR spectrum of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy )-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate.

Figure 4 shows the Fourier-Raman spectrum of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate.

Figure 5 shows the structure of (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4 -methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate (protons on OW3 not shown in Figure 5) as determined by single crystal X-ray diffraction.

Figure 6 shows the diffraction pattern of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-( 4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate synthesized in Example 1A.

Figure 7 shows the diffraction pattern of amorphous (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-( 4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol (di)hydrochloride synthesized in Reference Example 1 and further discussed in Reference Examples 2 and 3.

Figure 8 shows the diffraction patterns of (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4 -methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol (di)hydrochloride synthesized in Reference Example 1 before exposure to 80% RH (amorphous, the only distinct peak is , probably an artifact peak in sample preparation) (A) and after storage at more than 80% RH (crystalline) (B).

DETAILED DESCRIPTION OF THE INVENTION

The present invention can be more easily understood with reference to the following detailed description of the embodiments of the invention, and the Examples and Figures included herein. It should be understood that the terminology used herein is for the purpose of describing certain embodiments only and is not intended to be limiting. In addition, it should be understood that, unless otherwise indicated in the present description, the terminology used in the present description should have its traditional meaning, known in the relevant field of technology.

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate.

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation , containing at least 3 characteristic peaks selected from approximately 5.8, 10.5, 10.7, 11.5, and 17.5 degrees 2-theta (+/- 0.2 degrees 2-theta).

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation , containing characteristic peaks at approximately 5.8, 10.5, and 10.7 degrees 2-theta (+/- 0.2 degrees 2-theta).

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation , containing characteristic peaks at approximately 5.8, 11.5, and 17.5 degrees 2-theta (+/- 0.2 degrees 2-theta).

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation , containing characteristic peaks at approximately 5.8, 10.5, 10.7, and 17.5 degrees 2-theta (+/- 0.2 degrees 2-theta).

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation , containing characteristic peaks at approximately 5.8, 10.5, 10.7, 11.5, and 17.5 degrees 2-theta (+/- 0.2 degrees 2-theta).

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation , containing characteristic peaks at approximately 5.8, 8.9, 10.5, 10.7, 11.5, and 17.5 degrees 2-theta (+/- 0.2 degrees 2-theta).

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation , essentially the same as shown in Figure 1.

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation having a list of PXRD peaks essentially the same as in Table 1.

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a ¹³ C-thNMR spectrum containing characteristic peaks at approximately 123.5 and 149.3 ppm±0.2 ppm

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a ¹³ C-thNMR spectrum containing characteristic peaks at approximately 40.1, 123.5 and 149.3 ppm±0.2 ppm

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a ¹³ C-ttNMR spectrum containing characteristic peaks at approximately 40.1, 121.3 , 123.5 and 149.3 ppm±0.2 ppm

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a ¹³ C-ttNMR spectrum containing characteristic peaks at approximately 40.1, 121.3 , 123.5, 149.3 and 151.3 ppm±0.2 ppm

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by ^{a 13} C-ttNMR spectrum essentially the same as shown in Figure 2.

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-Methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a list of ¹³ C-ttNMR spectrum peaks essentially the same as in Table 2.

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a ¹⁹ F-ttNMR spectrum containing a characteristic peak at approximately -129.6 ppm .±0.2 ppm

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a ¹⁹ F-ttNMR spectrum containing characteristic peaks at approximately -129.6 and -128 .4 ppm±0.2 ppm

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by ^{a 19} F-ttNMR spectrum essentially the same as shown in Figure 3.

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a list of ¹⁹ F-ttNMR spectrum peaks essentially the same as in Table 3.

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a Fourier-Raman spectrum containing characteristic peaks at approximately 702 and 1630 cm ^-1 ± 2 cm ^-1 .

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a Fourier-Raman spectrum containing characteristic peaks at approximately 702, 1604 and 1630 cm ^{- 1} ±2 cm ^-1 .

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate having a Fourier-Raman spectrum essentially the same as shown in Figure 4.

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-Methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate having a Fourier-Raman peak list essentially the same as in Table 4.

Each of the embodiments of the present invention described above may be combined with any other embodiment of the present invention described in this application that does not conflict with the embodiment with which it is combined. Examples of such combinations are provided below.

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation , containing at least 3 characteristic peaks selected from approximately 5.8, 10.5, 10.7, 11.5 and 17.5 degrees 2-theta (+/- 0.2 degrees 2-theta), and ¹³ C-ttNMR spectrum containing characteristic peaks at approximately 123.5 and 149.3 ppm±0.2 ppm.

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation , containing at least 3 characteristic peaks selected from approximately 5.8, 10.5, 10.7, 11.5 and 17.5 degrees 2-theta (+/- 0.2 degrees 2-theta), and ¹⁹ F-ttNMR spectrum containing a characteristic peak at approximately -129.6 ppm±0.2 ppm.

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation , containing at least 3 characteristic peaks selected from approximately 5.8, 10.5, 10.7, 11.5 and 17.5 degrees 2-theta (+/- 0.2 degrees 2-theta), and Fourier-Raman spectrum containing characteristic peaks at approximately 702 and 1630 cm ^-1 ±2 cm ^-1 .

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a ¹³ C-thNMR spectrum containing characteristic peaks at approximately 123.5 and 149.3 ppm±0.2 ppm, and a ¹⁹ F-ttNMR spectrum containing a characteristic peak at approximately -129.6 ppm±0.2 ppm.

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a ¹³ C-thNMR spectrum containing characteristic peaks at approximately 123.5 and 149.3 ppm±0.2 ppm, and a Fourier-Raman spectrum containing characteristic peaks at approximately 702 and 1630 cm ^-1 ±2 cm ^-1 .

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a ¹⁹ F-ttNMR spectrum containing a characteristic peak at approximately -129.6 ppm .±0.2 ppm, and a Fourier-Raman spectrum containing characteristic peaks at approximately 702 and 1630 cm ^-1 ±2 cm ^-1 .

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation , containing at least 3 characteristic peaks selected from approximately 5.8, 10.5, 10.7, 11.5 and 17.5 degrees 2-theta (+/- 0.2 degrees 2-theta), ¹³ C-ttNMR spectrum containing characteristic peaks at approximately 123.5 and 149.3 ppm±0.2 ppm and ¹⁹ F-ttNMR spectrum containing characteristic peak at approximately -129.6 ppm .±0.2 ppm

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation , containing at least 3 characteristic peaks selected from approximately 5.8, 10.5, 10.7, 11.5 and 17.5 degrees 2-theta (+/- 0.2 degrees 2-theta), ¹³ C-ttNMR spectrum containing characteristic peaks at approximately 123.5 and 149.3 ppm ± 0.2 ppm, and Fourier-Raman spectrum containing characteristic peaks at approximately 702 and 1630 cm ^-1 ± 2 cm ^-1 .

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation , containing at least 3 characteristic peaks selected from approximately 5.8, 10.5, 10.7, 11.5 and 17.5 degrees 2-theta (+/- 0.2 degrees 2-theta), ¹⁹ F-ttNMR spectrum containing a characteristic peak at approximately -129.6 ppm ± 0.2 ppm and a Fourier-Raman spectrum containing characteristic peaks at approximately 702 and 1630 cm ^-1 ± 2 cm ^{- 1} .

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a ¹³ C-thNMR spectrum containing characteristic peaks at approximately 123.5 and 149.3 ppm ± 0.2 ppm, ^{a 19} F-ttNMR spectrum containing a characteristic peak at approximately -129.6 ppm ± 0.2 ppm, and a Fourier Raman spectrum containing characteristic peaks at approximately 702 and 1630 cm ^-1 ±2 cm ^-1 .

In one embodiment, the invention provides crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation , containing at least 3 characteristic peaks selected from approximately 5.8, 10.5, 10.7, 11.5 and 17.5 degrees 2-theta (+/- 0.2 degrees 2-theta), ¹³ C-ttNMR spectrum containing characteristic peaks at approximately 123.5 and 149.3 ppm±0.2 ppm, ¹⁹ F-ttNMR spectrum containing characteristic peak at approximately -129.6 ppm. ±0.2 ppm, and a Fourier-Raman spectrum containing characteristic peaks at approximately 702 and 1630 cm ^-1 ±2 cm ^-1 .

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation containing at least 3 characteristic peaks selected from approximately 5.8, 10.5, 10.7, 11.5 and 17.5 degrees 2-theta (+/- 0.2 degrees 2- theta).

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation containing characteristic peaks at approximately 5.8, 10.5 and 10.7 degrees 2-theta (+/- 0.2 degrees 2-theta).

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation containing characteristic peaks at approximately 5.8, 11.5 and 17.5 degrees 2-theta (+/- 0.2 degrees 2-theta).

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation containing characteristic peaks at approximately 5.8, 10.5, 10.7 and 17.5 degrees 2-theta (+/- 0.2 degrees 2-theta).

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation containing characteristic peaks at approximately 5.8, 10.5, 10.7, 11.5 and 17.5 degrees 2-theta (+/- 0.2 degrees 2-theta).

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation containing characteristic peaks at approximately 5.8, 8.9, 10.5, 10.7, 11.5 and 17.5 degrees 2-theta (+/- 0.2 degrees 2-theta).

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation, essentially the same as shown in Figure 1.

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation having a list of PXRD peaks essentially the same as in Table 1.

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by ^{a 13} C-thNMR spectrum containing characteristic peaks at approximately 123.5 and 149.3 ppm±0.2 ppm

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by ^{a 13} C-ttNMR spectrum containing characteristic peaks at approximately 40.1, 123.5 and 149.3 ppm±0.2 ppm

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by ^{a 13} C-ttNMR spectrum containing characteristic peaks at approximately 40.1, 121.3, 123.5 and 149.3 ppm±0.2 ppm

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by ^{a 13} C-ttNMR spectrum containing characteristic peaks at approximately 40.1, 121.3, 123.5, 149.3 and 151.3 ppm±0.2 ppm

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by ^{a 13C} -ttNMR spectrum essentially the same as shown in Figure 2 .

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a list of ¹³ C-ttNMR spectrum peaks essentially the same as in Table 2.

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a ¹⁹ F-ttNMR spectrum containing a characteristic peak at approximately -129.6 ppm±0.2 ppm

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by ^{a 19} F-ttNMR spectrum containing characteristic peaks at approximately -129.6 and -128.4 ppm±0.2 ppm

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by ^{a 19} F-ttNMR spectrum essentially the same as shown in Figure 3 .

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a list of ¹⁹ F-ttNMR spectrum peaks essentially the same as in Table 3.

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a Fourier-Raman spectrum containing characteristic peaks at approximately 702 and 1630 cm ^-1 ±2 cm ^-1 .

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a Fourier-Raman spectrum containing characteristic peaks at approximately 702, 1604 and 1630 cm ^-1 ±2 cm ^-1 .

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate having a Fourier-Raman spectrum substantially the same as shown in Figure 4 .

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a Fourier-Raman peak list essentially the same as in Table 4.

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation containing at least 3 characteristic peaks selected from approximately 5.8, 10.5, 10.7, 11.5 and 17.5 degrees 2-theta (+/- 0.2 degrees 2- theta) and a ¹³ C-ttNMR spectrum containing characteristic peaks at approximately 123.5 and 149.3 ppm±0.2 ppm.

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation containing at least 3 characteristic peaks selected from approximately 5.8, 10.5, 10.7, 11.5 and 17.5 degrees 2-theta (+/- 0.2 degrees 2- theta), and a ¹⁹ F-ttNMR spectrum containing a characteristic peak at approximately -129.6 ppm±0.2 ppm.

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation containing at least 3 characteristic peaks selected from approximately 5.8, 10.5, 10.7, 11.5 and 17.5 degrees 2-theta (+/- 0.2 degrees 2- theta), and a Fourier-Raman spectrum containing characteristic peaks at approximately 702 and 1630 cm ^-1 ±2 cm ^-1 .

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by ^{a 13} C-thNMR spectrum containing characteristic peaks at approximately 123.5 and 149.3 ppm ± 0.2 ppm, and ^{a 19} F-ttNMR spectrum containing a characteristic peak at approximately -129.6 ppm ± 0.2 ppm.

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by ^{a 13} C-thNMR spectrum containing characteristic peaks at approximately 123.5 and 149.3 ppm ± 0.2 ppm, and a Fourier-Raman spectrum containing characteristic peaks at approximately 702 and 1630 cm ^-1 ± 2 cm ^-1 .

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a ¹⁹ F-ttNMR spectrum containing a characteristic peak at approximately -129.6 ppm±0.2 ppm, and a Fourier-Raman spectrum containing characteristic peaks at approximately 702 and 1630 cm ^-1 ±2 cm ^-1 .

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation containing at least 3 characteristic peaks selected from approximately 5.8, 10.5, 10.7, 11.5 and 17.5 degrees 2-theta (+/- 0.2 degrees 2- theta), ^{a 13} C-ttNMR spectrum containing characteristic peaks at approximately 123.5 and 149.3 ppm±0.2 ppm, and ^{a 19} F-ttNMR spectrum containing a characteristic peak at approximately -129.6 ppm±0.2 ppm

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation containing at least 3 characteristic peaks selected from approximately 5.8, 10.5, 10.7, 11.5 and 17.5 degrees 2-theta (+/- 0.2 degrees 2- theta), ¹³ C-ttNMR spectrum containing characteristic peaks at approximately 123.5 and 149.3 ppm±0.2 ppm, and Fourier-Raman spectrum containing characteristic peaks at approximately 702 and 1630 cm ^-1 ±2 cm ^-1 .

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation containing at least 3 characteristic peaks selected from approximately 5.8, 10.5, 10.7, 11.5 and 17.5 degrees 2-theta (+/- 0.2 degrees 2- theta), ¹⁹ F-ttNMR spectrum containing a characteristic peak at approximately -129.6 ppm ± 0.2 ppm, and a Fourier-Raman spectrum containing characteristic peaks at approximately 702 and 1630 cm ^-1 ± 2 cm ^-1 .

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by ^{a 13} C-thNMR spectrum containing characteristic peaks at approximately 123.5 and 149.3 ppm ± 0.2 ppm, ¹⁹ F-ttNMR spectrum containing a characteristic peak at approximately -129.6 ppm ± 0.2 ppm, and Fourier-Raman spectrum containing characteristic peaks at approximately 702 and 1630 cm ^-1 ±2 cm ^-1 .

In one embodiment, the invention provides substantially pure crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha (wavelength 1.54 E) radiation containing at least 3 characteristic peaks selected from approximately 5.8, 10.5, 10.7, 11.5 and 17.5 degrees 2-theta (+/- 0.2 degrees 2- theta), ¹³ C-ttNMR spectrum containing characteristic peaks at approximately 123.5 and 149.3 ppm±0.2 ppm, ¹⁹ F-ttNMR spectrum containing characteristic peak at approximately -129.6 m .d.±0.2 ppm, and a Fourier-Raman spectrum containing characteristic peaks at approximately 702 and 1630 cm ^-1 ±2 cm ^-1 .

The term used in the present description:

"abnormal cell growth", unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (eg, loss of contact inhibition). Abnormal cell growth can be benign (not cancerous) or malignant (cancerous). In frequent embodiments of the methods provided herein, the abnormal cell growth is cancer.

"cancer" refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth. The term "cancer" includes, but is not limited to, primary cancer that originates at a specific location in the body, metastatic cancer that has spread from where it started to other parts of the body, recurrence from the original primary cancer after remission, and second primary cancer, which is a new primary cancer in a person with a history of previous cancer of a different type than the last one.

"approximately" means the presence of a value that falls within the accepted standard error of the mean, when considered by a person skilled in the art.

"crystalline" means the presence of a three-dimensional order, i.e., a regularly repeating arrangement of molecules or planes of the outer surface. Crystal forms (polymorphs) may differ in thermodynamic stability, physical parameters, x-ray structure, and characteristics, and methods of preparation.

"substantially the same" means that the variability inherent in a particular method is taken into account. For example, in relation to the positions of X-ray diffraction peaks, the term "substantially the same" means that characteristic variations in the position and intensity of the peaks are taken into account. One skilled in the art will appreciate that peak positions (2Ɵ) will exhibit some variability, typically ±0.2°. In addition, one of skill in the art will appreciate that relative peak intensities will exhibit variability between devices, as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to one of skill in the art, and should only be taken into account. in the form of quality indicators. Similarly, Fourier-Raman wavenumber values (cm ^-1 ) show variability typically up to ±2 cm ^-1 , while ¹³ C and ¹⁹ F solid state NMR spectral peaks (ppm) show variability typically ± 0 .2 ppm

"mammal" refers to a human or animal. In certain preferred embodiments, the mammal is a human.

"hydrate" in the context of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-( 4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate means the presence of a stoichiometric or non-stoichiometric amount of water bound in the crystal lattice by non-covalent intermolecular bonds. The hydrate state observed for this polymorph includes stoichiometry ranging from about 1.0 to about 1.4 molar equivalents of water per mole of active moiety from 10% RH to 90% RH at 25°C. As an example, this is illustrated by determining the molecular structure of the crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)- 5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate using single crystal X-ray diffraction (see Figure 5), which indicates that the analyzed material is a hydrate of salt of monophosphate (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol. For the crystal 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate used to create the structure of Figure 5, the stoichiometry of water is approximately 1.1 mol water per 1 mol (1S,2S, 3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3 -d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate. The structure contains a water molecule ("O3W" in Figure 5, protons not shown) with low filling. See also Example 9.

"pharmaceutically acceptable", "carrier", "diluent", "filler" or "excipient" refers to a material (or materials) that can be included with a certain active pharmaceutical agent to form a pharmaceutical composition and can be solid or liquid. Examples of solid excipients or carriers are lactose, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water, and the like. Similarly, the carrier or diluent may include a sustained or modified release material known in the art, such as glycerol monostearate or glycerol distearate alone or with wax, ethylcellulose, hydroxypropyl methylcellulose, methyl methacrylate, and the like.

"essentially pure" should be interpreted as the presence of equal to or greater than 90%, equal to or greater than 95%, equal to or greater than 98%, or equal to or greater than 99% wt./mass. crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H -pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate versus any other physical form of (1S,2S,3S,5R)-3-((6-(difluoromethyl) -5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2 -diol or a pharmaceutically acceptable salt or solvate thereof.

"therapeutically effective amount" refers to that amount of a compound administered that will relieve to some extent one or more symptoms of the disorder being treated. With regard to the treatment of cancer, a therapeutically effective amount refers to an amount that has the effect of (1) reducing the size of a tumor, (2) inhibiting (i.e., slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent ( ie, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness and/or (4) alleviating to some extent (or preferably eliminating) one or more of the signs or symptoms associated with cancer.

"treatment" as used herein, unless otherwise indicated, means the treatment, amelioration, inhibition of progression, or prevention (i.e., prophylactic treatment) of the disorder or condition to which such term applies, or one or more of the symptoms of such disorder, or states. Used in the present description, the term "treatment", unless otherwise indicated, refers to the effect of treatment, as "treatment" is defined immediately above. The term "treatment" also includes adjuvant and neoadjuvant treatment of the subject. With regard to cancer in particular, these terms simply mean that the life expectancy of a person affected by cancer will be increased or that one or more of the symptoms of the disease will be reduced.

the term "2-theta value" or "2Ɵ" refers to the position of the peak in degrees based on the experimental setup of an X-ray diffraction experiment and is a common unit of abscissa in diffraction patterns. The experimental setup requires that if the reflection is diffracted when the incoming beam makes an angle of theta (Ɵ) with a certain grating plane, the reflected beam is recorded at an angle of 2-theta (2Ɵ). It should be understood that reference herein to specific 2Ɵ values for a particular polymorph is intended to refer to 2Ɵ values (in degrees) measured using experimental X-ray diffraction conditions as described herein. For example, as described herein, Cu K-alpha 1 (wavelength 1.54E) was used as the radiation source.

The present invention also provides a pharmaceutical composition comprising a crystalline form as described herein and a pharmaceutically acceptable carrier or excipient.

In addition, the present invention provides methods for treating abnormal cell growth in a mammal, comprising administering to the mammal a therapeutically effective amount of a crystalline form as described herein, or a composition thereof.

Additionally, the present invention provides a crystalline form as described herein, or a composition thereof, for use as a drug or for use in the treatment of abnormal cell growth in a mammal.

Moreover, the present invention provides the use of a crystalline form as described herein, or a composition thereof, for the preparation of a medicament useful in the treatment of abnormal cell growth in a mammal.

Abnormal cell growth may represent cancer. The cancer referred to herein may be lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, cancer adrenal glands, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis carcinoma, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brainstem glioma, or pituitary adenoma.

The crystalline form as described herein may be administered alone or as a formulation in combination with one or more pharmaceutically acceptable carriers or excipients. The choice of excipient will largely depend on factors such as the particular route of administration, the effect of the excipient on solubility and stability, and the characteristics of the dosage form.

It should be understood that when the crystalline form, as described in this application, is dissolved for compositional purposes, the crystal lattice is no longer present. In this situation, reference to an active compound in crystalline form as described herein below means a (therapeutically active) compound in crystalline form as described herein.

Pharmaceutical compositions suitable for delivery of the crystalline form as described herein and their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety.

The crystalline form, as described in this application, can be administered orally. Oral administration may include swallowing, so that the crystalline form enters the gastrointestinal tract, or buccal or sublingual administration may be used, in which the crystalline form enters the bloodstream directly from the oral cavity.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particles, liquids or powders, lozenges (including liquid-filled), chewable tablets, multi- and nanoparticles, gels, solid solution, liposomes, films (including mucoadhesive ), capsules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying and/or suspending agents. Liquid formulations can also be prepared by reconstitution of a solid, for example from sachets.

The crystalline form as described herein can also be used in fast dissolving, fast disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001).

For tablet dosage forms, depending on the dose, the crystalline form, as described in this application, may comprise from 0.5 wt.% to 80 wt.% of the dosage form, more typically from 0.5 wt.% to 20 wt.% of the dosage form . In addition to the drug, tablets usually contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Typically, the disintegrant will comprise from 1 wt.% to 25 wt.%, preferably from 2 wt.% to 10 wt.% of the dosage form.

Binders are commonly used to impart cohesive properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.

Tablets may also optionally include surfactants such as sodium lauryl sulfate and polysorbate 80 and glidants such as silica and talc. When present, surfactants are typically present in an amount of 0.2 wt.% to 5 wt.% of the tablet, and glidants are typically present in 0.2 wt.% to 1 wt.% of the tablet.

Tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Glidants are usually present in an amount of from 0.25 wt.% to 10 wt.%, preferably from 0.5 wt.% to 3 wt.% of the tablet.

Other standard ingredients include antioxidants, colors, flavors, preservatives and flavoring agents.

Typical tablets contain up to about 80 wt.% crystalline form, as described in this application, from about 10 wt.% to about 90 wt.% binder, from about 0 wt.% to about 85 wt.% diluent, from about 2 wt.% up to about 10 wt.% baking powder and from about 0.25 wt.% to about 10 wt.% lubricant.

Tablet blends can be compressed directly or with a roller to form tablets. Tablet blends or portions of blends may alternatively be subjected to wet granulation, dry granulation or melt granulation, melt congealing or extrusion prior to tabletting. The final composition may include one or more layers and may be coated or uncoated; or encapsulated.

The composition of tablets is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X).

Solid formulations for oral administration can be prepared as immediate and/or modified release forms. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

Suitable modified release formulations are described in US Pat. No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma et al , Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

The crystalline form as described herein can also be administered directly to the bloodstream, to a muscle, or to an internal organ. Suitable routes of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needleless injectors and infusion devices.

Formulations for parenteral administration are usually aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably up to a pH of 3 to 9), but for some applications they may be more suitable as a sterile non-aqueous solution or as dried form for use in combination with a suitable vehicle such as sterile, pyrogen-free water.

Obtaining parenteral formulations under sterile conditions, for example, by lyophilization, can be easily carried out using standard pharmaceutical techniques, well known to a person skilled in the art.

The solubility of the crystalline form, as described in this application, used in the preparation of parenteral solutions, can be increased by using suitable preparation techniques, such as the inclusion of agents that increase solubility. Compositions for parenteral administration can be formulated with immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release. Thus, the crystalline form as described herein may be formulated as a solid, semi-solid or thixotropic liquid for administration as an implanted depot providing a modified release of the active compound. Examples of such formulations include drug-eluting stents and PGLA microspheres.

The crystalline form as described herein can also be administered topically to the skin or mucosa, ie skin or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, capsules, implants, sponges, fibers, dressings, and microemulsions. You can also use liposomes. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be included; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other methods of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and injections with or without a microneedle ( eg Powderject™, Bioject™ , etc. ).

Compositions for topical administration can be prepared in immediate and/or modified release form. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

The crystalline form as described herein can also be administered intranasally or by inhalation, usually in the form of a dry powder (or alone, as a mixture, for example dry-mixed with lactose, or as mixed component particles, for example mixed with phospholipids , such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, nebulizer (preferably a nebulizer using electrohydrodynamics to produce a fine mist) or nebulizer with or without the use of a suitable propellant such as 1.1 ,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may include a bioadhesive agent such as chitosan or cyclodextrin.

The pressurized container, pump, spray, nebulizer or nebulizer contains a solution or suspension of a crystalline form as described herein, including, for example, ethanol, aqueous ethanol or a suitable alternative agent for dispersing, solubilizing or extending the release of the active substance, propellant(s) as a solvent and an optional surfactant such as sorbitan trioleate, oleic acid or oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by any suitable grinding method such as spiral jet milling, fluidized bed jet milling, supercritical fluid treatment to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropyl methylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mixture of crystalline form as described herein, a suitable powder base such as lactose or starch, and a performance modifier such as l -leucine, mannitol or magnesium stearate. The lactose may be anhydrous or in the form of a monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an electrohydrodynamic fine mist nebulizer may contain 1 µg to 20 mg of the crystalline form as described herein per push, and the push volume may vary from 1 µl to 100 µl. A typical formulation includes the crystalline form as described herein, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerin and polyethylene glycol.

Suitable flavorings such as menthol and levomenthol or sweeteners such as saccharin or sodium saccharin may be added to such inhalation/nasal formulations of the invention.

Formulations for inhalation/nasal administration can be prepared in immediate and/or modified release form using, for example, poly(DL-lactic-coglycolic acid) (PGLA). Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a metered amount. Devices in accordance with the invention are typically adapted to deliver a metered dose or "spray" containing the desired amount of crystalline form as described herein. The total daily dose may be administered as a single dose, or more commonly as divided doses throughout the day.

The crystalline form as described herein may be administered rectally or vaginally, for example in the form of a suppository, pessary or enema. Cocoa butter is the traditional base for suppositories, but various alternatives can be used if necessary. Formulations for rectal/vaginal administration may be in immediate and/or modified release form. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

The crystalline form as described herein can also be administered directly to the eye or ear, usually in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable ( eg , absorbable gel sponges, collagen) and non-biodegradable ( eg , silicone) implants, capsules, lenses, and particulate or vesicle systems such as niosomes or liposomes. A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulose polymer such as hydroxypropyl methylcellulose, hydroxyethylcellulose or methylcellulose, or a heteropolysaccharide polymer such as gelan gum may be included along with a preservative such as benzalkonium chloride. Such formulations can also be delivered by iontophoresis.

Ophthalmic/ear formulations may be prepared in immediate and/or modified release form. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, or programmed release.

The crystalline form as described herein can be combined with soluble macromolecular structures such as cyclodextrin and suitable derivatives thereof or polyethylene glycol containing polymers to improve solubility, dissolution rate, taste masking, bioavailability and/or stability for use in any of the aforementioned methods. introductions.

For example, drug-cyclodextrin complexes have been found to be generally applicable to most dosage forms and routes of administration. Both inclusion complexes and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiliary additive, ie as a carrier, diluent or solubilizer. The most commonly used for this purpose are alpha, beta and gamma cyclodextrins, examples of which can be found in WO 91/11172, WO 94/02518 and WO 98/55148.

The amount of active compound in crystalline form, as described herein, to be administered will depend upon the entity being treated, the severity of the disorder or condition, the rate of administration, the distribution of the compound, and the discretion of the attending physician. However, an effective dosage is usually in the range of about 0.001 to about 100 mg per kg of body weight per day, preferably from about 0.01 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this amount would be from about 0.07 to about 7000 mg/day, preferably from about 0.7 to about 2500 mg/day. In some cases, dosage levels below the lower end of the aforementioned range may be more than adequate, while in other cases even higher doses may be used without causing any adverse side effects, such large doses usually being divided into several smaller doses to administration throughout the day.

Since it may be desirable to administer a combination of a crystalline form as described herein and an additional anti-cancer compound, for example for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains the active compound in crystalline form, as described in this application, can be conveniently combined in the form of a kit suitable for co-administration of the compositions. Thus, the kit of the invention includes two or more separate pharmaceutical compositions, at least one of which contains a crystalline form, as described in this application, and means for separate storage of these compositions, such as a container, a divided bottle or a divided foil bag. An example of such a kit is the familiar blister pack used to pack tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different dosage forms, eg oral and parenteral, for administering separate compositions at different dosing intervals, or for titration of separate compositions against each other. To facilitate adherence to the rules, the kit usually includes instructions for use and may be provided with a reminder.

The present invention is described with reference to the following Examples. It should be understood that the scope of the present invention is not limited by the scope of the following Examples.

EXAMPLE 1A

Synthesis of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate

(1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl -7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol (6.53 g, 14.56 mmol) followed by 2-propanol (9.3 ml/g, 61 ml). Water (4.14 ml/g, 27.0 ml) was then charged at ambient temperature (approx. 25°C) and the resulting solution was heated to 40°C. A solution of phosphoric acid (85% w/w in water, 1.1 mol equiv., 16.02 mmol, 1.1 ml) in 2-propanol (3 ml/g, 19.6 ml) was slowly loaded into for at least 10 minutes. The solution was then heated to 70° C. and 2-propanol (8.78 ml/g, 57.3 ml) was charged via an addition funnel over at least 10 minutes. At this point, crystallization initiated on its own, and the mixture was kept at approximately 65°C for 2 hours. It was then cooled to about 10°C for 4 hours, heated to about 50°C for 2 hours, kept at about 50°C for 2 hours, and finally cooled to 10°C after a ramp of -0.1°C /min After stirring at approximately 10°C for at least 2 hours, the suspension was filtered and the precipitate was washed with cold 2-propanol/water 95:5 v/v. (2 ml/g, 13.1 ml). The precipitate was then allowed to dry on the filter under reduced pressure for at least 1 hour to give the title compound as a white to yellowish or greyish solid (7.73 g, 13.7 mmol, 94%).

EXAMPLE 1B

PXRD analysis of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4- methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate

The material was characterized by powder diffraction performed using a Bruker D2 diffractometer equipped with a Cu radiation source, fixed slits (divergence=0.2) and a Lynxeye detector. Data was collected on a Theta-Theta goniometer at Cu K-alpha (wavelength 1.54E) from 3.0 to 40.0 degrees 2-theta using a step size of 0.0141 degrees and a step time of 0.5 seconds. The voltage and current of the X-ray tube were set to 30 kV and 10 mA, respectively. Samples were prepared by placing in an acrylic sample holder provided by Bruker and rotated during data collection (30 rpm). PXRD data were read and analyzed using Eva Diffraction software version 4.2.1. The peak search was performed manually for all intense peaks in the range from 2 to 25 2-theta. Peak selection was carefully checked to ensure that all major peaks were captured and that the peak position represents the center point of the peak. Peak shoulders were not displayed in the peak selection. Crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H -pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate from Example 1A was characterized by PXRD analysis and had a structure and list of characteristic peaks essentially in accordance with Figure 1 and Table 1 (see Example 4) respectively. In particular, the PXRD chart for this Example is provided in Figure 6. The list of peaks is provided in Table 5.

Table 5 Corner
°2-theta % Relative intensity 4.5 6.2 5.8 100.0 7.2 11.9 8.9 22.5 10.5 66.8 10.7 60.0 11.5 28.6 12.2 15.1 13.1 7.7 14.7 41.4 15.3 15.9 16.6 25.1 17.5 34.2 18.0 31.9 18.6 6.1 19.3 1.7 21.0 31.9 21.6 9.3 22.7 41.8 23.1 58.8 24.8 30.2 25.1 59.3

EXAMPLE 2

Pharmaceutical formulations of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl -7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate

Mixtures of prototype formulations containing crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-( 4-Methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate can be prepared using standard excipients commonly used in pharmaceutical tablet formulations. Tablets usually contain 0.5-30% wt./mass. crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H -pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate. Microcrystalline cellulose and anhydrous dibasic calcium phosphate can be used as tablet fillers and sodium starch glycolate can be used as a disintegrant. Magnesium stearate can be used as a lubricant.

A typical tablet formulation is provided in Table A.

Table A Component Role wt./mass. % Crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H -pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate API 3.8 Cellulose
[Avicel PH 102 (Trademark)] Filler 61.4 Dibasic calcium phosphate
[DiCAFOS A12 (Trademark)] Filler 30.8 sodium starch glycolate
[Explotab (Trademark)] Baking powder 3.0 magnesium stearate sliding substance 1.0

EXAMPLE 3

Synthesis of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate

Solution at ambient conditions (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4 -methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol (2.30 kg, 1.0 equiv., 5.13 mol) in 2-propanol (9, 3 l/kg, 21.3 l) and water (4.14 l/kg, 9.5 l) were heated to 40°C. This warm solution was charged with a solution of phosphoric acid (85% w/w) in water, (0.64 kg, 1.1 equiv.), in 2-propanol (3 L/kg, 6.9 L) through a pressurized reservoir for at least 10 minutes. The container with the phosphoric acid solution was washed with 2-propanol (0.5 L) and this wash solution was loaded into the reactor. At this point, the pH of the solution was within the range of 3.5-4.5. The resulting solution was then heated to 70° C. and 2-propanol (8.78 L/kg, 20 L) was charged through the pressure tank for at least 45 minutes. At this point, granulation occurred and the mixture was kept at 65°C for 2 hours. Then it was cooled to 10°C for at least 4 hours, heated to 50°C for at least 2 hours, held at 50° C. for at least 2 hours and finally cooled to 10° C. after a ramp of -0.1° C./min. After stirring at 10° C. for at least 7 hours, the suspension was filtered on a Nutsche (trade mark) filter and the precipitate was washed with cold 2-propanol/water (95:5 v/v, 4.63 L). The precipitate was then allowed to dry on the filter under reduced pressure for at least 1 hour. Meanwhile, 2-propanol (2.17 L/kg, 5 L) and water (2.17 L/kg, 5 l) and the mixture was heated at 80°C for at least 30 minutes to promote the dissolution of the solids on the walls of the reactor. The solution was kept at 80°C for at least 1 hour, then cooled to 20°C for at least 30 minutes. At this point, 2-propanol (4.35 L/kg, 10 L) was charged into the reactor via a head tank followed by the addition of wet solids and 2-propanol (2.17 L/kg, 5 L) to flush the walls. The mixture was heated at 50°C for at least 30 minutes, kept at 50°C for at least 1 h, cooled to 10°C for at least 2 h, heated to 50° C for at least 30 minutes, held at 50°C for at least 1 hour, cooled to 10°C for at least 2 hours, heated back to 50°C for, at least 30 minutes, kept at 50°C for at least 2 hours and finally cooled to 10°C for at least 5 hours. After keeping the mixture at 10°C for at least water (3.04 L/kg, 7 L) was charged to the reactor for at least 5 hours, and the mixture was heated at 75°C for at least 45 minutes, and kept at this temperature for at least 15 minutes. The mixture was then cooled to 65°C for at least 15 minutes, kept at 65°C for at least 1 hour and cooled to 20°C for at least 2 hours. Then 2- propanol (12.17 L/kg, 28 L) was charged over at least 30 minutes through the pressure tank and stirring was maintained for at least 1 hour, then the mixture was heated at 50° C. for at least at least 2 h, kept at 50°C for at least 1 h and cooled to 10°C for at least 5 h. After stirring at 10°C for at least 5 h the suspension was filtered on a Nutsche (trade mark) filter and the precipitate was washed with cold 2-propanol/water (95:5 v/v, 2.5 L). The wash cake was used to wash the reactor. The solids were placed on three oven trays. The trays were placed in a sealed vacuum oven at ambient temperature for 17 hours (with a covered water tray at the bottom of the oven to ensure wet drying and complete rehydration) to give the title compound (2.60 kg, 4.61 mol, 90 %, white with a grayish or yellowish tint solid).

EXAMPLE 4

PXRD analysis of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4- methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate

A sample of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate prepared using the method of Example 3 was analyzed by PXRD and data collected at Bruker-AXS Ltd. D4 (trademark) X-ray powder diffractometer equipped with automatic sample changer, theta-2 goniometer, motorized beam divergence adjustment slit and Vantec-1 PSD detector. The voltage and current of the X-ray tube were set to 35 kV and 40 mA, respectively. Data was collected at Cu K-alpha (wavelength 1.54 E) using a step size of 0.018 degrees and a scan time of 11.3 hours while scanning from 2.0 to 65.0 degrees 2-theta. The sample was obtained by placing the powder in a low background Si cavity holder. The sample powder was pressed with a glass slide to ensure that the correct sample height was obtained. Data were collected using Bruker DIFFRAC software (trademark) and analysis was performed using DIFFRAC EVA software (version 3.1) (trademark). The assembled PXRD samples were imported into Bruker DIFFRAC EVA (trademark) software. Manual peak selection was checked to ensure that all peaks below 25 degrees 2-theta were captured and that all peak positions were accurately assigned. These data include a typical ±0.2°2-theta error in peak positions. The ±0.2°2-theta error associated with this measurement can result from a variety of factors including: (a) sample preparation (e.g. sample height), (b) device, (c) calibration, (d) operator (including those errors that are present in peak location) and (e) material properties (eg preferred orientation and transparency errors). Therefore, the peaks are considered to have a typical associated error of ±0.2°2-theta. When two peaks in the list are considered to overlap, the less intense peak is removed from the list. Peaks existing as shoulders on an adjacent higher intensity peak were also removed from the peak list. While the arms may be ˃0.2°2-theta from the position of the adjacent peak, they are not considered to be distinct from the adjacent peak. To obtain absolute peak positions, the powder sample must be aligned with the reference. This can be either a Calculated diffraction pattern obtained by determining the structure of a single crystal of the same compound, resolved at room temperature, or an internal standard, such as silica or corundum.

Diffraction pattern of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate of Example 3 is provided in Figure 1. A list of characteristic peaks is provided in Table 1. Certain peaks are selected as characteristic peaks for those indicated in the title compound of Example 1. It should be noted that for the title compound of Example 1, the two characteristic peaks listed in Table 1 occur at 10.5 and 10.7°2-theta. While the separation of these peak positions is within the margin of error of 0.2°2-theta at the peak position as described above, these peaks should be considered as discrete peaks.

Table 1 Corner
°2-theta % Relative intensity 4.5 5.0 ^5.8⃰ 100.0 7.2 11.2 ^8.9⃰ 18.1 ^10.5⃰ 69.5 ^10.7⃰ 71.3 ^11.5⃰ 58.2 12.2 30.4 13.1 2.3 14.7 65.3 15.3 7.3 16.6 13.9 ^17.5⃰ 71.4 18.0 66.2 18.6 16.2 19.3 14.2 21.0 26.7 21.6 13.4 22.7 14.6 23.1 61.1 23.5 86.0 24.8 26.3

(peak positions marked with an asterisk are characteristic peaks)

Comparison of the data in Table 1 with the data presented in Table 1A (see Example 5) for the calculated diffraction pattern of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2, 3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate obtained from structure determination single crystal shows good correlation of characteristic peaks indicating that the sample is crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinoline -8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate. The absence or loss of resolution of some peaks in Figure 1 (compared to Table 1A) should be expected, and this may be due to internal deviation of the experimental data associated with (a) sample preparation (for example, sample height and mass), (b) device, (c) calibration, (d) operator, and/or (e) material properties (eg preferred orientation).

EXAMPLE 5

Calculated diffraction pattern of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl -7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate

The calculated diffraction pattern of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl -7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate was obtained from single crystal structure determination. A single crystal was grown in 2-propanol/water and the crystal structure was determined from this crystal as described in Example 9. A calculated powder diffraction pattern was obtained by calculation using the Reflex/Powder Diffraction Toolbox in Materials Studio 2018 (trademark) software package for a specific crystal structures. Determination of the structure of a single crystal of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4- methyl 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate is shown in Figure 5. The list of peaks for the calculated diffractogram of crystalline (1S,2S,3S,5R)-3- ((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentan-1,2-diol monophosphate hydrate obtained from single crystal structure determination is shown in Table 1A. Calculated diffraction pattern of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl -7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate contains all possible peaks that could be observed in the diffraction pattern for this polymorph. It should be expected that not all possible peaks will be found in the experimentally determined diffractogram. This may be due to internal bias in experimental data related to (a) sample preparation (e.g. sample height and mass), (b) device, (c) calibration, (d) operator, and (e) material properties (e.g., preferred orientation ). Therefore, the peak table for the calculated diffraction pattern usually has more peaks than the experimental diffraction pattern.

Table 1A Corner
°2-theta % Relative intensity 4.5 14.7 5.8 100.0 7.2 6.5 8.9 16.6 10.5 32.7 10.7 46.7 11.6 17.7 11.8 3.1 12.3 13.1 12.5 2.6 13.2 7.0 14.1 6.1 14.4 5.0 14.7 21.2 15.3 23.8 16.4 7.0 16.6 29.4 17.3 2.3 17.5 23.0 17.8 6.0 18.0 16.8 18.1 11.0 18.3 5.6 18.6 6.2 19.3 3.7 21.0 28.0 21.1 6.7 21.6 13.5 21.9 45.1 22.7 44.4 23.1 49.8 23.5 14.7 23.7 19.5 24.2 5.0 24.3 5.5 24.5 3.7 24.8 31.3

EXAMPLE 6

solid state ¹³ C-NMR ( ¹³ C-ttNMR) crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4 -methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate

A sample of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate prepared using the method of Example 3 was analyzed by ¹³ C-ttNMR. The ¹³ C-ttNMR spectrum is provided in Figure 2. The list of peaks is provided in Table 2. ¹³ C-ttNMR analysis was performed on a Bruker-BioSpin Avance III HD 400 MHz NMR spectrometer (frequency 1H) (trademark). Data was collected with a 4 mm MAS probe at a magic angle rotation speed of 10 kHz. The temperature was adjusted to 20°C. Cross-polarization (CP) TOSS sideband suppression spectra were recorded with a CP interaction time of 1 ms and a recirculation delay of 3 seconds. During the collection of spectra, a phase-modulated proton decoupling field of ~70 kHz was used. The number of scans was adjusted to obtain an adequate signal to noise ratio and 3600 scans were collected. The ¹³ C chemical shift scale was examined using an external standard of crystalline adamantane, setting its resonance in the downfield to 38.5 ppm. Automatic peak selection was performed using Bruker-BioSpin TopSpin software version 3.2 (trademark). Typically a threshold of 3% relative intensity was used for peak preselection. The output from the automatic peak selection was visually checked for validity and manual adjustments were made as needed. While specific ¹³ C-ttNMR peaks are given herein, there is a range for these peaks due to differences in instrumentation, samples, and sample preparation. The typical variability of the ¹³ C chemical shift along the x-axis is on the order of plus or minus 0.2 ppm. for a crystalline solid. The ¹³ C-ttNMR peak heights reported herein are relative intensities. The ¹³ C-ttNMR intensities may vary depending on the actual settings of the experimental parameters and the thermal history of the sample.

table 2 ¹³ C chemical shifts [ppm] % Relative intensity 16.2 69 17.9 26 19.9 88 29.7 16 32.4 27 37.9 17 ^40.1⃰ 73 54.5 32 58.9 38 70.6 90 77.0 35 78.7 46 79.8 40 83.1 42 99.9 32 105 25 108.7 33 110.3 34 116.5 68 117.5 69 ^121.3⃰ 94 ^123.5⃰ 109 124.5 65 126.9 20 145.1 26 148.5 26 ^149.3⃰ 96 150.7 59 ^151.3⃰ 100 154.0 57 158.2 55

(peak positions marked with an asterisk are characteristic peaks)

EXAMPLE 7

solid state ¹⁹ F-NMR ( ¹⁹ F-ttNMR) crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4 -methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate

A sample of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate prepared by the method of Example 3 was analyzed by ¹⁹ F-ttNMR. The ¹⁹ F-ttNMR spectrum is provided in Figure 3. The list of peaks is provided in Table 3. The ¹⁹ F-ttNMR analysis was performed using the same spectrometer used for the ¹³ C-ttNMR analysis above. Data was collected using a 3.2 mm MAS probe at a magic angle rotation speed of 20 kHz. The temperature was adjusted to 20°C. Cross polarization (CP) spectra (CP) were recorded at a CP interaction time of 400 μs and a recirculation delay of 3 seconds. During the collection of spectra, a phase-modulated proton decoupling field of ~65 kHz was used. The number of scans was adjusted to obtain an adequate signal-to-noise ratio and 256 scans were collected. The ¹⁹ F chemical shift scale was examined using an external standard of trifluoroacetic acid and water (50/50 v/v), setting its resonance to -76.54 ppm. (relative to CFCl ₃ ). Automatic peak selection was performed using Bruker-BioSpin TopSpin software version 3.2 (trademark). Typically a threshold of 3% relative intensity was used for peak preselection. The output from the automatic peak selection was visually checked for validity and manual adjustments were made as necessary. Although specific ¹⁹ F-ttNMR peaks are given herein, there is a range for these peaks due to differences in instrumentation, sample and sample preparation. The typical variability of the ¹⁹ F chemical shift along the x-axis is on the order of plus or minus 0.2 ppm. for a crystalline solid. ^{The 19} F-ttNMR peak heights reported herein are relative intensities. The ¹⁹ F-ttNMR intensities may vary depending on the actual settings of the experimental parameters and the thermal history of the sample.

Table 3 ¹⁹ F Chemical shifts [ppm] % Relative intensity ^-129.6⃰ 100 ^-128.4⃰ 97 -109.8 52 -108.8 51 -107.8 50 -106.0 43

(peak positions marked with an asterisk are characteristic peaks)

EXAMPLE 8

Fourier-Raman spectroscopy of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4 -methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate

A sample of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate prepared by the method of Example 3 was analyzed by Fourier-Raman spectroscopy. The Fourier Raman spectrum is provided in Figure 4. The list of peaks is provided in Table 4. The Fourier Raman spectra were obtained using a RAM II FT Raman module attached to a Bruker Vertex 70 FTIR (trademark) spectrometer. The device is equipped with a 1064 nm Nd:YAG laser and a liquid nitrogen cooled germanium detector. Prior to data collection, instrument performance and calibration were tested using a white light source and polystyrene and naphthalene standards. Samples were prepared and analyzed in truncated NMR tubes (5 mm diameter). A sample rotator (Ventacon) was used during the measurement to maximize the volume of material exposed to the laser during data acquisition. The Raman backscatter signal from the sample was optimized and data was collected with a spectral resolution of 2 cm ^-1 using a laser power of 500 mW. A 4-term Blackman-Harris apodization function was used to minimize spectral aberrations. Spectra were obtained from 3500 to 200 cm ^-1 with appropriate adjustment of the number of scans to ensure adequate signal-to-noise ratio. The spectra were normalized by setting the intensity of the most intense peak to 1.00. Peaks were then identified using the automatic peak selection feature in GRAMS/AI v9.2 software (Thermo Fisher Scientific) with the threshold set to 0.05. Peak positions and relative peak intensities were extracted and tabulated, and the peaks were then classified as very strong (os), strong (s), medium (av), and weak (w) for intensity ranges of 1.00-0.75 , 0.74-0.50, 0.49-0.25 and ˂0.25, respectively. The variability of peak positions in this experimental configuration is within ±2 cm ^-1 . It is expected that because the techniques for Fourier Raman and dispersive Raman measurements are similar, the peak positions reported in this document for Fourier Raman spectra will be consistent with those that would be observed using dispersive Raman measurements, provided that the instrument is properly calibrated.

Table 4 Peak position
cm ^-1 (± 2cm ^-1 ) Relative intensity 233 Wed 316 Wed 349 Wed 430 Wed 460 Wed 492 Wed 564 Wed 603 Wed 669 Wed ^702⃰ With 718 Wed 827 Wed 850 Wed 907 Wed 960 Wed 1046 Wed 1158 Wed 1239 Wed 1266 Wed 1325 Wed 1342 Wed 1369 Wed 1392 Wed 1438 Wed 1471 Wed 1512 os ^1604⃰ Wed ^1630⃰ Wed 2924 With 2972 Wed 3006 Wed 3023 Wed

(Peak positions marked with an asterisk represent characteristic peaks, and the relative intensity of the peaks is indicated as very strong (oc), strong (s), medium (av), or weak (sl))

EXAMPLE 9

Determination of the structure of a single crystal of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4- methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate

Data collection was carried out on a Bruker D8 Venture diffractometer at room temperature. Data collection consisted of omega and phi scans. Structure was determined by internal phasing using the SHELX software package in monoclinic space group P21 with the following cell parameters: a=15.3572(6) E; b=8.1080(3) E; c=19.9014(8) E; alpha=90°; beta=91.447(2)°; gamma=90°. The structure was subsequently refined by the full-matrix least squares method. All non-hydrogen atoms were found and refined using anisotropic displacement parameters. Hydrogen atoms located on nitrogen and oxygen were found from the difference Fourier map and refined with limited distances. The remaining hydrogen atoms were placed in the calculated positions and allowed to move on their carrier atoms. The final refinement included isotropic displacement parameters for all hydrogen atoms. As noted in the figure, one of the water molecules is given without bound hydrogen atoms. The lattice contains two water molecules in an asymmetric block: one fully filled water and one water position with approximately 0.2 filling. In general, the ratio of API to water is approximately 1:1.1. Absolute structure analysis using likelihood methods (Hooft 2008) was performed using PLATON (Spek 2010). Assuming the sample provided is enantiomerically pure, the results show that the absolute structure was assigned correctly. The final R-index was 3.9%. The last Fourier difference revealed no missing or shifted electron density. Figure 5 shows an asymmetric unit of crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate with displacement parameters obtained with 50% probability. Hydrogen in the water molecule O3W is not shown.

REFERENCE EXAMPLE 1

Repetition of the preparation of compound (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl -7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol hydrochloride salt (ZZZ-16) as described in Example 190 WO2017/212385

To a solution of ZZZ-15 (210 mg, 0.383 mmol) in dichloromethane (2 ml) was added a 4M solution of HCl in dioxane (0.766 ml, 3.06 mmol) at 0° C. in a 25 ml pear-shaped round bottom flask. The ice bath was removed and the mixture was stirred at room temperature (23°C) for 2 hours. A white solid precipitated, adhering to the flask slides. LCMS shows ˃95% conversion. The clear liquid was removed with a pipette and the solid was dried under reduced pressure. The solid was dissolved in 4 ml of water and freeze-dried for 70 hours to give ZZZ-16 as an amorphous white with a yellowish or grayish tint solid (184 mg, 92%). LCMS [M+1] = 449; ¹ H NMR (400 MHz, D ₂ O): d=8.85 (s, 1H), 7.82 (br. s, 1H), 7.18-6.87 (m, 3H), 5.41- 5.31 (m, 1H), 4.86-4.81 (m, 1H), 4.72-4.69 (m, 1H), 4.40 (br. s, 2H), 4.36- 4.33 (m, 1H), 3.53 (t, J=6.0 Hz, 2H), 3.16-3.03 (m, 3H), 2.91 (s, 3H), 2.27 -2.15 (m, 1H)ppm [ZZZ-16 equivalent prepared in Example 190 of WO2017/212385: LCMS [M+1] 449; ¹ H NMR (400 MHz, D ₂ O) d ppm 8.93 (s, 1H), 7.91 (d, J=3.8 Hz, 1H), 7.24-6.88 (m, 3H), 5.41 (q, J=9.0 Hz , 1H), 4.87 (br.dd, J=2.4, 4.4 Hz, 1H), 4.75 (dd, J=5.0, 8.8 Hz, 1H), 4.45 ( s, 2H), 4.39 (br. d, J=5.0 Hz, 1H), 3.58 (t, J=6.3 Hz, 2H), 3.19-3.07 (m, 3H ), 2.99 (s, 3H), 2.35-2.24 (m, 1H).]

REFERENCE EXAMPLE 2

Elemental analysis of hydrochloride salt (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4- methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol Reference Example 1

Based on elemental analysis, the product of Reference Example 1 was shown to contain 2 moles of HCl and ~1 H2O per mole. Elemental analysis was performed using Atlantic Microlab, Inc. (Norcross GA). Samples were weighed on an electronic microbalance (Perkin-Elmer Model AD4 or Model AD6; Mettler Model MT5; Cahn Model 30, Model 31, Model 33, or Model 34) calibrated daily prior to weighing any samples. Carbon, hydrogen and nitrogen analyzes were carried out on automatic analyzers using a method based on a modification of the classical methods of Pregl and Dumas. The analyzers were: Perkin-Elmer Model 2400 Series II auto-analyzers or Carlo Erba Model 1108 analyzers, calibrated daily with UHP standards before any samples were analyzed. The technical specifications of the device indicate an accuracy of +/- 0.3 percent. Samples were weighed and then placed in an autoanalyzer maintained at positive pressure with a helium carrier gas. The content of fluorine, chlorine, bromine and iodine was measured by combustion in a Schoniger flask followed by analysis using ion chromatography. The sample was diluted, filtered and injected into the IC. The data is processed to obtain ppm. of each halogen and then converted to a percentage using the following calculation: ppm S Volume (l)/mass of sample (kg) S 10,000 (10,000 ppm = 1%). Elemental analysis results are presented in Table 6:

Table 6 Element Theory Found (experiment 1) Found (experiment 2) C 48.99 48.75 48.93 H 5.05 5.10 5.10 N 10.39 10.06 10.03 Cl 13.14 12.76 12.79

This elemental analysis shows that the product is (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4- tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol.

REFERENCE EXAMPLE 3

PXRD analysis of hydrochloride salt (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4 -methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol Reference Example 1

PXRD analysis of the product of Reference Example 1 shows that it is amorphous. The analysis was performed using a Rigaku Miniflex 600 diffractometer. Data were collected from 4 to 40 degrees using Cu radiation at 15 mA and 40 kV. The diffractogram shows that an amorphous product was obtained. See Figure 7.

COMPARATIVE EXAMPLE 1

Hygroscopicity -pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol as hydrochloride salt compared to crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)- 5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2- diol monophosphate hydrate

The hygroscopicity of the products of Reference Example 1 and Example 3 was tested using dynamic vapor sorption (DVS). Preferred Dynamic Vapor Sorption Measurement Device Surface Measurement Systems Ltd. used with a 10% RH change at 25°C starting at 40% RH and cycling from 0% RH to 90% RH and back to 0% RH twice. The di-HCl salt-based material of Reference Example 1 was gradually exposed to increasing relative humidity, and the weight of the sample was recorded. Spent two complete cycles from 0% RH to 90% RH. The percentage weight gain relative to the weight of the sample at the first exposure to 0% RH (dry weight) was calculated and presented in Table 7. The crystallinity of the material of Reference Example 1 was checked by PXRD after the DVS run and showed that the material had turned into a crystalline solid . The DVS data for the phosphate hydrate of Example 3 was obtained in a similar manner and is also provided in Table 7. The DVS data suggest that the diHCl salt is very hygroscopic, increasing its mass by 14.7% at 70% RH. In addition, a decrease in mass is noted at 80% RH, which corresponds to the solid state change occurring under these conditions. This is supported by PXRD analysis (Figure 8) after the DVS run confirming that the di-HCl salt is not physically stable, is very hygroscopic and crystallizes when exposed to RH≥80% RH. In contrast to the di-HCl salt, the phosphate salt of Example 3 only increases its mass by 4.57% at 70% RH (monohydrate stoichiometry refers to 3.3%). Hydration (1 mol water equivalent) occurs at 10% RH, and weight gain gradually occurs from 10% RH to 90% RH, which corresponds to the absence of structural changes caused by water sorption.

Table 7 OV di HCl (%wt std dry weight) Phosphate (%wt std. dry weight 0 0.0 0.0 10 2.9 3.4 20 4.0 3.7 thirty 4.9 3.9 40 6.0 4.1 50 7.6 4.3 60 10.4 4.5 70 14.7 4.6 80 12.0 4.7 90 12.0 4.8

The foregoing may be modified without departing from the essential aspects of the invention. Although the invention has been substantially described in detail with reference to one or more specific embodiments, it will be apparent to a person skilled in the art that changes may be made to the embodiments specifically disclosed in this application, and yet these modifications and improvements are within scope and essence of the invention.

Claims (21)

1. Method for obtaining crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4 -methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate, characterized by a diffraction pattern measured using Cu K-alpha radiation having the following list of PXRD peaks: °2θ 4.5 5.8 7.2 8.9 10.5 10.7 11.5 12.2 13.1 14.7 15.3 16.6 17.5 18.0 18.6 19.3 21.0 21.6 22.7 23.1 23.5 24.8 where the method includes: obtaining a mixture of (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol, 2-propanol and water; subsequent addition of phosphoric acid and 2-propanol to form a solution; heating the solution to the crystallization temperature and adding more 2-propanol to the solution; And maintaining the solution at the crystallization temperature to form crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5 -(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate. 2. The method according to claim 1, where crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate has a diffraction pattern measured using Cu K-alpha radiation, the same as shown in FIG. 1. 3. The method according to p. 1 or 2, where crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl) hydroxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate is characterized by ^{a 13} C-ttNMR spectrum containing characteristic peaks at 123.5 and 149.3 ppm ± 0.2 ppm 4. The method according to p. 3, where crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate is characterized by ^{a 13C} -ttNMR spectrum further containing at least one or more characteristic peaks selected from 40.1, 121.3 and 151.3 ppm. ± 0.2 ppm 5. The method according to claim 1 or 2, where crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl) hydroxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate has a ¹³ C-ttNMR spectrum as shown in FIG. 2. 6. The method according to claim 1 or 2, where crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl) hydroxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate is characterized by the following list of ^13C -ttNMR peaks: ¹³ C chemical shifts [ppm] 16.2 17.9 19.9 29.7 32.4 37.9 40.1 54.5 58.9 70.6 77.0 78.7 79.8 83.1 99.9 105 108.7 110.3 116.5 117.5 121.3 123.5 124.5 126.9 145.1 148.5 149.3 150.7 151.3 154.0 158.2 7. The method according to any one of paragraphs. 1-6, where crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-( 4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate is characterized by ^{a 19} F-ttNMR spectrum containing at least one or more characteristic peaks at -129.6 and -128.4 ppm ± 0.2 ppm 8. The method according to claim 7, where crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate has a ¹⁹ F-ttNMR spectrum as shown in FIG. 3. 9. The method according to claim 7, where crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy) -5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate is characterized by the following list of ¹⁹ F-ttNMR peaks: ¹⁹ F chemical shifts [ppm] ^{-129.6⃰ -128.4⃰} -109.8 -108.8 -107.8 -106.0 10. The method according to any one of paragraphs. 1-9, where crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-( 4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate is characterized by a Fourier-Raman spectrum containing at least two or more characteristic peaks at 702, 1604 and 1630 cm ^-1 ± 2 cm ^-1 . 11. The method according to any one of paragraphs. 1-9, where crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-( 4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate has a Fourier-Raman spectrum as shown in FIG. 4. 12. The method according to any one of paragraphs. 1-9, where crystalline (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-( 4-Methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol monophosphate hydrate is characterized by the following list of Fourier Raman peaks: Peak position cm ^-1 (±2 cm ^-1 ) 233 316 349 430 460 492 564 603 669 702 718 827 850 907 960 1046 1158 1239 1266 1325 1342 1369 1392 1438 1471 1512 1604 1630 2924 2972 3006 3023

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