EA045683B1 - SOLID FORMS OF STIMULANT sGC - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to solid forms of a soluble guanylate cyclase (sGC) stimulator. Also provided herein are methods for preparing these solid forms. The invention also relates to pharmaceutical compositions and dosage forms containing these solid forms, and their use, alone or in combination with one or more additional agents, for the treatment and/or prevention of various diseases or disorders; these diseases or disorders are diseases or disorders that may benefit from stimulation of sGC or increased concentrations of nitric oxide (NO) and/or cyclic guanosine monophosphate (cGMP).

BACKGROUND OF THE INVENTION sGC is the main receptor for NO in vivo. sGC can be activated through both NO-dependent and NO-independent mechanisms. In response to this activation, sGC converts guanosine 5'triphosphate (GTP) to the second messenger cGMP. Elevated cGMP levels, in turn, modulate the activity of downstream effectors including protein kinases, phosphodiesterases (PDEs), and ion channels.

In the body, NO is synthesized from arginine and oxygen by various nitric oxide synthase (NOS) enzymes and through the sequential reduction of inorganic nitrates. Three different isoforms of NOS have been identified: inducible NOS (iNOS or NOS II), found in activated macrophage cells; constitutive neuronal NOS (nNOS or NOS I), involved in neurotransmission and long-term potentiation, and constitutive endothelial NOS (eNOS or NOS III), which regulates smooth muscle relaxation and blood pressure. Experimental and clinical evidence suggests that decreased NO concentrations or bioavailability and/or decreased sensitivity to endogenously produced NO contributes to disease development.

NO-independent, heme-dependent Sgc stimulators have demonstrated several important distinctive characteristics compared to sGC activators, including the critical dependence of their activity on the presence of a reduced prosteric heme moiety, strong synergistic activation of the enzyme when combined with NO, and stimulation of cGMP synthesis by direct stimulation sGC, independent of NO. The benzylindazole compound YC-1 was the first sGC stimulator to be identified. Since then, additional sGC stimulators have been developed with increased potency and specificity for sGCs.

Compounds that stimulate sGCs in an NO-independent manner offer significant advantages over other current alternative therapies that target the aberrant NO pathway. There is a need to develop new well-characterized sGC stimulators. Compound I is an sGC stimulator that has demonstrated efficacy for the treatment of a number of NO-related disorders in preclinical models. Compound I was previously described in WO2014144100, example 1, as a light orange solid. Compound I may be present in various crystalline forms and may also form several pharmaceutically acceptable salts.

The properties of a solid relevant to its effectiveness as a drug may depend on the form of the solid. For example, in a drug substance, a change in solid form may result in differences in properties such as solubility and dissolution rate, surface properties (e.g. wettability), powder properties (flow, cohesion, bulk density, mixability, compressibility, static, etc.) .etc.), tablet properties (hardness, uniformity, friability, disintegration, resistance to heat and humidity, etc.), oral absorption, bioavailability, storage properties (caking, hygroscopicity), toxicology results and clinical trial results.

Characterization of polymorphs is useful to prevent the occurrence of certain problems during clinical trials and/or commercial use of drug products, for example, to avoid drug substance and product incompatibility (e.g., batch-to-batch inconsistency), hydration or dehydration of hydrates, chemical degradation, amorphization, or polymorphic transformation in a drug. A polymorph may also be preferred if it improves solubility and/or bioavailability compared to another polymorph of the compound or an amorphous form thereof. It may also be preferred because it imparts increased physical or chemical stability, provides a higher melting point (resulting in improved mechanical properties), has a more acceptable taste or odor, or a more neutral pH, and so on.

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The essence of the invention

In one aspect, the invention provides crystalline solid forms of Compound I, depicted below:

compound I

For purposes of this description, compound I, unless otherwise indicated, refers to the free base or hydrochloric acid salt of the structure designated above. Compound I, as its crystalline free base, is highly polymorphic and is known to have seven crystalline forms (forms A, B, D, E, F, G and H) as well as several solvates. Compound I was previously described in WO2014144100, example 1, as a light orange solid.

In one embodiment, the crystalline solid forms of Compound I disclosed herein are free base polymorphs. In another embodiment, the crystalline solid form of Compound I is a hydrochloric acid salt. In one embodiment, the polymorphs of Compound I are free base crystalline forms. In another embodiment, they are solvates.

In another aspect, methods for preparing the above-described crystalline free forms and salts of Compound I are also provided herein.

In another aspect, the invention relates to pharmaceutical compositions containing one or more polymorphs of Compound I disclosed herein, or a hydrochloric acid salt of Compound I, and at least one pharmaceutically acceptable excipient or carrier. In another embodiment, the invention relates to pharmaceutical dosage forms containing said pharmaceutical compositions.

In another embodiment, the invention relates to a method of treating a disease, health condition or disorder in a subject in need thereof, comprising administering, alone or in combination therapy, a therapeutically effective amount of a polymorph of Compound I disclosed herein, or a mixture of polymorphs thereof, or its salts of hydrochloric acid, subject; wherein the disease or disorder is a disease that may benefit from stimulation of sGC or from increasing the concentration of NO and/or cGMP.

Description of the figures

Fig. 1 shows a powder X-ray diffraction pattern of the amorphous form of compound I.

Fig. 2 shows superimposed powder X-ray diffraction patterns (from bottom to top, scaled, offset) of Form A, Form B, Form D, and Form E, at 2-theta angles ranging from 5 to 45.

Fig. 3A shows a powder X-ray diffraction pattern of Form A, at a 2-theta angle ranging from 5 to 45.

Fig. 3B shows a powder X-ray diffraction pattern of Form A before and after storage for 14 months.

Fig. 3C shows a powder X-ray diffraction pattern of Form A, at a 2-theta angle ranging from 3 to 40.

Fig. 4A shows a powder X-ray diffraction pattern of Form B, at a 2-theta angle ranging from 5 to 45.

Fig. 4B shows a powder X-ray diffraction pattern of Form B before and after storage for 14 months.

Fig. 4C shows a powder X-ray diffraction pattern of Form B, at a 2-theta angle ranging from 3 to 40.

Fig. 5A shows a powder X-ray diffraction pattern of Form D, at a 2-theta angle ranging from 5 to 45.

Fig. 5B shows a powder X-ray diffraction pattern of Form D before and after storage for 14 months.

Fig. 5C shows a powder X-ray diffraction pattern of Form D, with a 2-theta angle ranging from 3 to 40.

Fig. 6 shows a powder X-ray diffraction pattern of Form E, at a 2-theta angle ranging from 5 to 45.

Fig. 7 shows a powder X-ray diffraction pattern of Form F, at a 2-theta angle ranging from 3 to 40.

Fig. 8 shows a powder X-ray diffraction pattern of Form G, at an angle of 2-theta in the range of values from 3 to 40.

Fig. 9 shows a powder X-ray diffraction pattern of Form H, at a 2-theta angle ranging from 3 to 40.

Fig. 10 shows superimposed FT-Raman spectra (from bottom to top, scaled, offset) of Form A, Form B, Form D and Form E over the wavenumber range from 1800 to 200 cm ^-1 .

Fig. 11 shows a powder X-ray diffraction pattern of the HCl salt of compound I, at a 2-theta angle ranging from 0 to 40.

Fig. 12 shows the relationships between crude compound I, polymorph Form A, Form B, Form D, Form E, Form F, Form G and Form H.

The drawings are provided as examples and are not intended to limit the scope of the present invention.

Detailed Description of the Invention

The following will be a detailed description of certain embodiments of the present invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in combination with the listed embodiments, it should be understood that the invention is not limited to the listed embodiments. On the contrary, the invention covers all alternatives, modifications and equivalents that may be included within the scope of the present invention as defined by the claims. The present invention is not limited to the methods and substances described herein, but includes any methods and substances similar or equivalent to those described herein that may be used in the practice of the present invention. In the event that one or more of the included literature references, patents or similar materials differ from or conflict with the present description, including, but not limited to, certain terms, terms of use, methods described, etc., the present description shall control.

Definitions and general terminology

For the purposes of the present invention, chemical elements are identified in accordance with the periodic table of elements, CAS version and Handbook of Chemistry and Physics, 75th ed. 1994 In addition, the general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry, ^5th Ed., Smith, M.B. and March, J., eds. John Wiley & Sons, New York: 2001, which are incorporated herein by reference in their entirety.

The present invention also includes isotopically labeled compounds that are identical to those described herein, wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. All isotopes of any particular atom or element are provided for by the compounds within the scope of the present invention and their applications. Examples of isotopes that may be included in the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, ^chlorine and iodine, such as ^2H , ^3H , 11C, ^13C , ^14C , ¹³ N, ¹⁵ N, ¹⁵ 0, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I and ¹²⁵ I, respectively. Certain isotopically labeled compounds of the present invention (eg, ³ H and ¹⁴ C labeled) are used in compound and/or tissue substrate distribution assays. Tritium (ie ^3H ) and carbon-14 (ie ^14C ) labeled isotopes can be used to facilitate their production and detection. In addition, substitution with heavier isotopes such as deuterium (eg, ^2H ) may provide certain therapeutic benefits as a result of greater metabolic stability (eg, increased in vivo half-life or reduced dosing requirements) and therefore may be preferred in some circumstances. Positron-emitting isotopes such as ¹⁵ O, ¹³ N, 11 C and ¹⁸ F are used in positron emission tomography (PET) analyzes to examine the extent of receptor occupancy by a substrate. The isotopically labeled compounds of the present invention can be prepared by the following methods, similar to those described in the diagrams and/or examples below in the present description, replacing the non-isotope-labeled reagent with the isotope-labeled reagent.

As used herein, the term solid form of compound I characterizes or refers to a particular solid phase crystal lattice (unit cell scale) of the specified compound.

A compound such as Compound I may be present in its pure or free base form, and the free base form may be either crystalline or amorphous. The free base form of a compound is formed only by molecules of the said compound.

As used herein, the term amorphous or amorphous form is a solid form without long-range molecular order, which therefore does not have a characteristic X-ray powder diffraction (XRPD) pattern.

A crystal or crystalline form is a homogeneous solid that is formed by a repeating three-dimensional structure of atoms, ions or molecules having fixed distances between their constituent parts. The term crystal can also be used to designate a unit cell of such a structure.

As used herein, the term crystallization is a process that results in the formation of solid crystals from a solution, melt, vapor, other solid phase, or, less commonly, precipitation directly from a gas. Crystallization can be a natural or artificial process. Crystallization is also a chemical method of solid-liquid separation that involves the mass transfer of solute from a liquid solution to a pure solid crystalline phase.

As used herein, the term polymorphism refers to the ability of a compound (eg, Compound I) to exist in more than one crystalline form or to crystallize into different crystal structures. A polymorph represents each of the different crystal structures of a compound (eg, compound I). Polymorphs are crystal structures of the free form of a compound (ie, crystalline free forms) or solvates thereof (ie, multicomponent crystalline forms) in which a compound, such as compound I, crystallizes with a solvent. In some embodiments, when the solvent that crystallizes is water, the solvates are hydrates.

As used herein, the term solvate refers to the combination or complex of one or more solvent molecules (molecules of a substance that are liquid at room temperature) with a compound (eg, Compound I) in crystalline form, resulting in the formation of a new characteristic crystalline solid . This disclosure describes several ansolvates of the free base form of Compound I (ie, solid forms of Compound I that are crystalline free forms and are not solvates).

There are other types of solid shapes that can be formed. For example, when both compounds in a multicomponent crystalline form will be independently solids when present at room temperature, the resulting solid form is called a cocrystal.

When one of the components in a solid form has visibly transferred a proton to another component, and the resulting components of the multicomponent crystal form are ionic, the resulting solid form is called a salt.

In cocrystals, there is no transfer of ions between the different components of the solid form, so that the resulting components are present in non-ionic form. In cocrystals, two (or more) components of a multicomponent crystal form are solid and nonionic when present independently of each other at room temperature.

Whether a salt or a cocrystal is formed when two substances are mixed will depend on how large the difference is between the pKas of the two components.

The present disclosure describes one solid form of compound I, which is a salt (hydrochloric acid salt).

There are many crystallization techniques available that allow one skilled in the art to obtain crystalline materials. In order for crystallization to occur from solution, the solution must be supersaturated. This means that the solution must contain more solutes (molecules or ions) than are dissolved under thermodynamic equilibrium conditions (saturated solution). This can be achieved by various methods, for example: 1) crystallization by cooling; 2) adding a second solvent to reduce the solubility of the solute (a technique known as antisolvent crystallization); 3) chemical reactions; 4) change in pH; and 5) suspension conversion in organic and/or aqueous solvent systems is the most common method used in industrial practice. Other methods such as solvent evaporation crystallization may also be used. The term supersaturation as used here is the difference between the concentration (C) of a solution and the concentration (C*) at equilibrium at the same temperature. Measured in units of concentration.

The term chemically stable to characterize a solid form of Compound I (e.g., polymorph or salt) indicates that it does not decompose into one or more different new chemical compounds when exposed to certain conditions, e.g., 40°C/75% relative humidity, within a specified period of time, for example, 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or longer. In some embodiments, less than 25% of the Compound I polymorph is degraded; in some embodiments, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the Compound I polymorph is degraded under specified conditions. In some embodiments, no detectable amount of a given compound I polymorph degrades under certain conditions (as determined by the lowest detection limit of the analytical method used) after a certain period of time.

The term physically stable to characterize the crystalline solid form of compound I (e.g., polymorph or salt) means that the crystalline solid form does not convert into one

- 4 045683 or several other crystalline solid forms of compound I (for example, the transformation of a polymorph into another polymorph of compound I, as determined by an analytical method such as XRPD, etc.), or into an amorphous form when exposed to certain conditions, for example 40° C/75% RH, for a specified period of time, e.g. 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months or longer. In some embodiments, less than 25% of the crystalline solid form of Compound I is converted to one or more other solid forms (another crystalline solid form or an amorphous form) when exposed to certain conditions. In some embodiments, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the crystalline solid form of Compound I is converted to one or more other crystalline solid forms of Compound I or an amorphous form when exposed to specified conditions. In some embodiments, no detectable amount of a given solid form of Compound I is converted to one or more other solid forms of Compound I under specified conditions.

The term substantially pure when referring to a specified crystalline solid form of compound I (e.g., a polymorph or salt of compound I described herein) means that the specified crystalline solid form contains less than 20% (by weight) of residual components (such as an alternative polymorph( s) compound I, or amorphous form or additional solvent molecules or impurities). In other embodiments, the substantially pure crystalline solid form of Compound I contains less than 10% (by weight) of alternative polymorphs of Compound I, or amorphous form, or additional solvent molecules or impurities. In other embodiments, it contains less than 5% (by weight) of alternative polymorphs of Compound I, either amorphous form or additional solvent molecules or impurities. In yet other embodiments, it contains less than 1% (by weight) of alternative polymorphs of Compound I, or an amorphous form, or additional solvent molecules or impurities.

A term substantially similar, as used herein, to the spectrum, impurities, thermogram, etc., characteristic of the designated solid form of Compound I (e.g., the polymorph or salt of Compound I described herein) means that the spectrum, traces , thermogram, etc., referred to, contains less than 10% of the peaks that are different from the peaks in the spectrum, impurity or thermogram shown in the figure herein and attributed to the specific solid form of the subject compound I. In other embodiments implementation, it contains less than 5% of the peaks that are different. In yet other embodiments, it contains less than 1% of the peaks that are different.

When comparing XRPD spectra, the spectrum will be substantially similar to the spectrum shown in this disclosure for a particular solid form of compound I, where the characteristic peaks in said spectrum are measured at the same °2θ values as those shown in the figure of the present disclosure, or in within + or -0.5 units of °2θ, from those peaks that are shown in the indicated figure. The XRPD of a solid form of Compound I will be considered substantially unchanged after a specified period of time under specified conditions if the XRPD of said solid form before and after a specified period of time under specified specified conditions is substantially similar.

This disclosure often relates to the assessment of a chemical, physical or biological parameter disclosed herein. One skilled in the art will appreciate that such parameters may be replaced by other chemical, physical or biological parameters which, although not disclosed herein, are substantially similar from a solid form identification standpoint.

Embodiments

In one aspect, the invention provides crystalline solid forms of Compound I depicted below:

Compound I is an sGC stimulator that has demonstrated efficacy for the treatment of a number of NO-related disorders in preclinical models. Compound I may be present in various crystalline forms or polymorphs. Some of these polymorphs are free base crystalline forms. Others are solvates. In some embodiments, the solvate is a hydrate. Compound I can also form

- 5 045683 several pharmaceutically acceptable salts, including its hydrochloric acid salt.

In one embodiment, the solid forms of Compound I disclosed herein are polymorphs. In another embodiment, the solid form of compound I is its hydrochloric acid salt. Compound I exists in at least seven pure polymorphs or crystalline free forms: Form A, Form B, Form D, Form E, Form F, Form G and Form H. Compound I was previously described in WO2014144100, Example 1. as a light orange solid.

In one embodiment, the crystalline solid form of Compound I is a polymorph of Form E. Form E is formed when crude Compound I, prepared as described in the Examples section, is dissolved in MeOH at >60°C (eg, >70°C) to give solution, followed by filtration, heating the filtrate at >60°C, adding water and cooling to room temperature, then filtering and drying in vacuum at 80°C for 72 hours.

In another embodiment, the crystalline solid form of Compound I is a polymorph of Form A. Form A is formed when Compound I is dissolved in ethyl acetate, at >70° C., to form a solution, followed by filtration, further stirring the filtrate at a temperature of 20 to 25° C for 16 hours to obtain a suspension, concentrate the suspension under vacuum, add heptane, further concentrate the resulting suspension, filter and dry in vacuum at 100°C for 3 hours.

In another embodiment, polymorph A is formed when polymorph E is dissolved in ethyl acetate, at >70°C, to obtain a solution, followed by filtration, further stirring the filtrate at 20-25°C for 16 hours, to obtain a suspension, concentrating the suspension under vacuum, adding heptane, further concentrating the resulting suspension, filtering and drying in vacuum at 100°C for 3 hours.

In another embodiment, polymorph Form A can be prepared directly from crude compound I by heating in DMSO at above 60° C., followed by adding water to form a slurry and filtering the slurry.

In another embodiment, polymorph Form A is also isolated when crude compound I is suspended in a solvent at room temperature and allowed to stir for 14-30 hours. In some embodiments, the solvent is selected from heptane, isopropyl acetate (IPAC), ethanol, ethyl acetate, or decane or mixtures thereof. Then the suspension is filtered and dried in vacuum.

In another embodiment, the solid form of Compound I is polymorph Form D. Form D is formed when Form E, prepared as described above, is mixed with n-decane at 145-155°C for 45 minutes to form a suspension, followed by cooling suspension up to 2030°C for 1 hour, filtering and drying in vacuum at 80°C for 72 hours.

In another embodiment, Form D can be formed by heating any of the polymorphic forms of Form E, Form B, Form F, Form G or Form H, or mixtures thereof, alone (in the absence of solvent) at 180°C.

In another embodiment, the solid form of Compound I is a polymorph of Form B. Form B is formed when crude Compound I, prepared as described in the Examples section, is mixed with acetonitrile at 70-75° C. to form a solution, followed by filtration, further heating the filtrate at 70-75°C, adding water, cooling to 52-62°C to form a suspension, cooling the suspension to 0-5°C for more than 4 hours, filtering and drying in vacuum at 90-100°C for at least 30 h.

In another embodiment, the solid form of compound I is the polymorph Form F. Form F is obtained when Form A, prepared as described in the Examples section, is heated neat at 160°C.

In another embodiment, the solid form of Compound I is a polymorph of Form G. Form G is prepared when crude Compound I, prepared as described in the Examples section, is suspended in acetone at ambient temperature for 2 hours, followed by filtration and drying in vacuo at 30-40°C. In another embodiment, polymorph form G is obtained when polymorph form H is stirred in acetone at room temperature, followed by filtration and drying in vacuo at 30-40°C.

In another embodiment, the solid form of Compound I is a polymorph of Form H. Form H is prepared when crude Compound I, prepared as described in the Examples section, is mixed with acetone at 45-50° C. to form a solution, followed by filtration, cooling to room temperature to form a suspension, then stirring at room temperature for 5 hours, followed by filtration and drying in vacuum at 30-40°C.

In one aspect, the solid form of Compound I is a polymorph of Form A.

In some embodiments, Form A exhibits an FT Raman spectrum that is substantially similar to the FT Raman spectrum presented in FIG. 10.

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In some embodiments, Form A is characterized in that its IR spectrum exhibits a band with a maximum at 1730 cm ^-1 .

In some embodiments, Form A has a powder x-ray diffraction pattern substantially similar to that shown in FIG. 2 or 3A.

In other embodiments, Form A is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 6.0, 18.3, 19.3, 20.2 and 22.0 °2θ.

In other embodiments, Form A is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 6.0, 8.5, 9.5, 12.4-12.9, 13.4, 17.1, 18, 3, 19.3, 20.2, 22.0, 30.1 and 34.1 °2θ.

In other embodiments, Form A is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 6.0, 6.7, 8.5, 9.5, 10.9, 12.4-12.9, 13. 4, 16.2, 17.1, 18.3, 19.3, 20.2, 22.0, 23.0, 24.1 to 24, 8, 25, 8, 30, 1 and 34.1° 2θ.

In some embodiments, Form A has a powder x-ray diffraction pattern substantially similar to that shown in FIG. 3C.

In other embodiments, Form A is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 6.1 (80.81% relative intensity or relative int.), 18.4 (53.57%), 19.4 (100.00%), 20.3 (57.01%) and 22.0 (56.64) °2θ.

In other embodiments, Form A is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 6.1 (80.81% rel.int.), 9.6 (40.35%), 12.6 (41. 26%), 13.6 (43.19%), 18.4 (53.57%), 19.4 (100.00%), 20.3 (57.01%) and 22.0 (56. 64) °2θ.

In other embodiments, Form A exhibits a substantially unchanged powder X-ray diffraction pattern after storage for 14 months under stable conditions at 40° C. and 75% relative humidity. Powder X-ray diffraction patterns for Form A before and after storage under these conditions are shown in FIG. 3B.

In one aspect, the solid form of Compound I is polymorph Form B.

In some embodiments, Form B exhibits an FT Raman spectrum that is substantially similar to the FT Raman spectrum presented in FIG. 10.

In some embodiments, Form B is characterized in that its IR spectrum exhibits a maximum peak of 1200 cm ^-1 .

In some embodiments, Form B has a powder x-ray diffraction pattern substantially similar to that shown in FIG. 2 or 4A.

In other embodiments, Form B is characterized by one or more peaks in the X-ray powder diffraction pattern at 18.8-19.1 °2θ.

In another embodiment, Form B is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 8.8, 16.4, 17.2, 18.8-19.1, 20.1, and 21, 1-21 , 6°2θ.

In another embodiment, Form B is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 8.8, 10.6, 12.6-13.0, 14.6, 16.4, 17.2, 18, 8-19.1, 20.1, 21.1-21.6, 24.5, 25.3, 27.0-27.5, 28.9, 29, 8 and 30.5 °2θ.

In some embodiments, Form B has a powder x-ray diffraction pattern substantially similar to that shown in FIG. 4C.

In other embodiments, Form B is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 8.9 (7 6.55% rel.int.), 17.4 (57.67%), 19.1 (100 .00%) and 25.5 (52.26) °2θ.

In other embodiments, Form B is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 7.0 (44.44% rel.int.), 8.9 (76.55%), 17.4 (57. 67%), 19.1 (100.00%), 20.3 (49.78%), 21.8 (36, 16%) and 25.5 (52.26) °2θ.

In other embodiments, Form B exhibits a substantially unchanged powder X-ray diffraction pattern after storage for 14 months under stable conditions at 40° C. and 75% relative humidity. Powder X-ray diffraction patterns for Form B before and after storage under these conditions are shown in FIG. 4B.

In one aspect, the solid form of Compound I is the D polymorph.

In some embodiments, Form D exhibits an FT Raman spectrum that is substantially similar to the FT Raman spectrum presented in FIG. 10.

In some embodiments, Form D is characterized in that its IR spectrum exhibits a band with a maximum at 1665, 1639 and 968 cm ^-1 . In some embodiments, Form D is characterized in that its IR spectrum exhibits a band with a maximum at 1665 cm ^-1 . In other embodiments, Form D is characterized in that its IR spectrum exhibits a band with a maximum at 1639 cm ^-1 . In other embodiments, Form D is characterized in that its IR spectrum exhibits a band with a maximum at 968 cm ^-1 .

In some embodiments, Form D has a powder x-ray diffraction pattern substantially similar to that shown in FIG. 2 or 5A.

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In other embodiments, Form D exhibits a substantially unchanged powder X-ray diffraction pattern after storage for 14 months under stable conditions at 40° C. and 75% relative humidity. Powder X-ray diffraction patterns for Form D before and after storage under these conditions are shown in FIG. 5V.

In other embodiments, Form D has a peak in the X-ray powder diffraction pattern at 18.8°2θ.

In another embodiment, Form D is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 17.1, 18.1, 18.8 and 25.0 °2θ.

In another embodiment, Form D is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 8.8, 17.1, 18.1, 18.8 and 25.0°2θ.

In some embodiments, Form D has a powder x-ray diffraction pattern substantially similar to that shown in FIG. 5C.

In other embodiments, Form D is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 4.7 (97.11% rel.int.), 18.1 (80.97%), 18.6 (100. 00%) and 26.8 (65.25) °2θ.

In other embodiments, Form D is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 4.7 (97.11% rel.int.), 8.3 (64.04%), 18.1 (80. 97%), 18.6 (100.00%) and 26.8 (65.25) °2θ.

In one aspect, the solid form of Compound I is a polymorph of Form E.

In some embodiments, Form E exhibits an FT-Raman spectrum that is substantially similar to the FT-Raman spectrum presented in FIG. 10.

In some embodiments, Form E is characterized in that its IR spectrum exhibits a band with a maximum at 1690 and 1515 cm ^-1 . In some embodiments, Form E is characterized in that its IR spectrum exhibits a maximum peak at 1690 cm ^-1 . In some embodiments, Form E is characterized in that its IR spectrum exhibits a maximum peak at 1515 cm ^-1 .

In some embodiments, Form E has a powder x-ray diffraction pattern substantially similar to that shown in FIG. 2 or 6.

In other embodiments, Form E is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 7.4, 18.8-19.3, 21.1, 24.8 and 25.5°2θ.

In other embodiments, Form E is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 7.4, 13.9, 15.1, 16.3, 17.6, 18.8-19.3, 21. 1, 22.322.5, 24.8, 25.5 and 27.1 °2θ.

In one aspect, the solid form of Compound I is a polymorph of Form F.

In some embodiments, Form F is characterized by a powder x-ray diffraction pattern substantially similar to the diffraction pattern shown in FIG. 7.

In other embodiments, Form F is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 5.3 (100.00% RH), 8.6 (58.80%), and 16.4 (62. 95%) °2θ.

In another embodiment, Form F is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 5.3 (100.00% rel. int.), 8.6 (58.80%), 16.4 (62. 95%) and 19.0 (48.51%) °2θ.

In one aspect, the solid form of compound I is the polymorphic form G.

In some embodiments, Form G is characterized by a powder x-ray diffraction pattern substantially similar to the diffraction pattern shown in FIG. 8.

In other embodiments, Form G is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 10.7 (55.47% rel. int.) and 18.33 (100.00% %) °2θ.

In another embodiment, Form G is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 10.7 (55.47% rel.int.), 13.9 (42.47%), 18.33 (100. 00%) and 21.6 (40.73%) °2θ.

In one aspect, the solid form of Compound I is the polymorphic form H.

In some embodiments, Form H has a powder x-ray diffraction pattern substantially similar to that shown in FIG. 9.

In other embodiments, Form H is characterized by one or more peaks in a powder X-ray diffraction pattern selected from: 5.77 (89.22% rel.int.), 6.39 (100.00% rel.), 9.1 (84 .17%) and 18.5 (67.04%) °2θ.

In another embodiment, Form H is characterized by one or more peaks in the X-ray powder diffraction pattern selected from: 5.77 (89.22% rel.int.), 6.39 (100.00% rel.), 9.1 (84 .17%), 18.5 (67.04%), and 18.83 (67.04%) °2θ.

Pharmaceutically acceptable salts of the invention.

The phrase pharmaceutically acceptable salt as used herein refers to

- 8 045683 pharmaceutically acceptable organic or inorganic salts of compound I. Pharmaceutically acceptable salts of compound I can be used in medicine. Salts which are not pharmaceutically acceptable may, however, be useful as intermediates in the preparation of other solid forms of Compound I.

A pharmaceutically acceptable salt includes the inclusion of another atom or molecule to act as a counterion. The counterion can be any organic or inorganic moiety that stabilizes the charge of the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged atom in its structure. In cases where multiple charged atoms are part of a pharmaceutically acceptable salt, it may have multiple counterions. In some cases, the counterions may be the same. In other cases they may be different for each charged atom. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions.

The preparation of the pharmaceutically acceptable salts described herein and other typical pharmaceutically acceptable salts is more fully described by Berg et al., Pharmaceutical Salts, J. Pharm. Sci., 1977:66:1-19, incorporated herein by reference in its entirety.

In one embodiment, the pharmaceutically acceptable salt of Compound I is the hydrochloric acid salt of Compound I.

The hydrochloric acid salt of compound I can be prepared by suspending compound I in its polymorph form D, prepared as described above, in 1 M HCl, mixing it with iPrOH, stirring with temperature cycling from 20 to 40°C at a heating rate of 40° S/h and cooling rate 5°C/h.

The hydrochloric acid salt of compound I has a melting point of 256°C.

The hydrochloric acid salt of compound I is characterized by a solubility in water of 0.5 mg/ml at pH 1.4. Solubility in water was determined at the pH of the saturated solution. The salt was shaken in water for 24 hours at 25°C. After filtration, the concentration was determined by HPLC as 0.5 mg/ml at pH 1.4.

The hydrochloric acid salt of compound I has a powder x-ray diffraction pattern substantially similar to that shown in FIG. eleven.

Pharmaceutical compositions and methods of administration

The crystalline solid forms described herein may be prepared as pharmaceutical compositions or formulations.

A typical formulation is prepared by mixing the crystalline solid form of Compound I and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient used will depend on the means and purpose for which the polymorph or pharmaceutically acceptable salt of Compound I is formulated. Solvents are generally selected based on solvents generally recognized as safe (GRAS) by those skilled in the art for administration to a mammal. Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that dissolve or mix with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (eg, PEG400, PEG300), etc. and mixtures thereof. The compositions may also contain other types of excipients, such as one or more buffers, stabilizing agents, antiblocking agents, surfactants, wetting agents, lubricants, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (eg, intestinal or slow release), preservatives, antioxidants, coating agents, glidants, excipients used in the manufacturing process, colors, sweeteners, flavorings, flavorings and other known additives that provide elegant presentation of a drug or assist in the manufacture of a pharmaceutical product (i.e. medicine).

The compositions can be prepared using conventional dissolution and mixing methods. For example, the bulk drug (ie, the polymorph or pharmaceutically acceptable salt of Compound I) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound having the desired degree of purity is optionally mixed with a pharmaceutically acceptable diluent, carrier, excipient or stabilizer, in the form of a lyophilized formulation, milled powder or aqueous solution. The composition can be prepared by mixing at ambient temperature at the appropriate pH and in the desired degree of purity, with physiologically acceptable carriers. The pH of the formulation will generally depend on the specific application and concentration of the compound, but may vary from about 3 to about 8. When the formulation described herein is a solid amorphous dispersion formed by a dissolution process, additives may be added directly to the solution for drying by atomizing to form a mixture so that the additives are dissolved or suspended in solution as a slurry, which can then be spray dried. Additionally, additives may be added after the spray drying process to assist in the formation of the final formulated product.

A polymorph or pharmaceutically acceptable salt of Compound I is typically formulated into pharmaceutical dosage forms to provide easily controlled dosage of the drug and to ensure patient compliance. Pharmaceutical formulations of the polymorph or pharmaceutically acceptable salt of Compound I can be prepared for various routes and types of administration. There may be different dosage forms for the same compound because different diseases may require different routes of administration.

The amount of active ingredient that can be combined with the carrier material to form a unit dosage form will vary depending on the subject being treated and the particular route of administration. For example, a time-release formulation intended for oral administration to a human may contain about 1-1000 mg of active agent admixed with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95 wt.% of the total composition (wt. :wt.). The pharmaceutical composition can be prepared to provide administration of easily measurable amounts. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of active ingredient per milliliter of solution to allow for infusion at a suitable volume at a rate of about 30 ml/hour. As a general suggestion, the initial pharmaceutically effective amount of inhibitor administered will be in the range of about 0.01 to 100 mg/kg per dose, that is, from about 0.1 to 20 mg/kg of patient body weight per day, with a typical initial range of the compound used from 0.3 to 15 mg/kg/day.

The term therapeutically effective amount, as used herein, means that amount of an active compound or pharmaceutical agent that produces a biological or medical response in a tissue, system, animal or human being sought by a researcher, veterinarian, physician or other practitioner. A therapeutically or pharmaceutically effective amount of a compound to be administered will be determined by such considerations, and is the minimum amount necessary to ameliorate, treat, or treat a disease or disorder or one or more symptoms thereof.

Pharmaceutical compositions of the polymorph or pharmaceutical acceptable salt of Compound I will be formulated, dosed and administered in such a manner that the amount, concentration, schedules, course, vehicles and routes of administration are consistent with good medical practice. Factors to consider in this context include the particular disease being treated, the particular mammal being treated, the clinical condition of the particular patient, the cause of the disorder, the site of delivery of the agent, the route of administration, the schedule of administration, as well as other factors known to the practitioner, such as age, weight and reactions of a particular patient.

The term prophylactically effective amount refers to an amount effective to prevent or substantially reduce the chance of acquiring a disease or disorder, or reduce the severity of a disease or disorder before it is acquired, or reduce the severity of one or more of its symptoms before symptoms develop. In short, preventive measures are divided between primary prevention (to prevent the disease from developing) and secondary prevention (when the disease has already developed and the patient is protected from worsening the process).

Acceptable diluents, excipients, carriers and stabilizers are those that are non-toxic to recipients at the doses and concentrations used and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkylparabens such as methyl or propylparaben, catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol); proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trihalose or sorbitol; salt-forming counterions such as sodium; metal complexes (eg Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Active pharmaceutical ingredients can also be enclosed in microcapsules obtained, for example, by coacervation methods or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such methods are described in Remington's: The Science and Practice of Pharmacy, 21 ^st Edition, University of the Sciences in Philadelphia, Eds., 2005 (hereinafter Remington's).

- 10 045683

The terms administer, administration or administered in relation to a solid form, composition or composition of the invention mean the introduction of a compound into the body of an animal in need of treatment.

When a compound of the invention is provided in combination with one or more other active agents, the term administration and variations thereof imply simultaneous and/or sequential administration of the compound and other active agents.

The compositions described herein may be administered systemically or topically, for example, orally (e.g., capsules, powders, solutions, suspensions, tablets, sublingual tablets, etc.), by inhalation (e.g., aerosol, gas , inhaler, nebulizer or the like), in the ear (for example, using ear drops), topically (for example, using creams, gels, liniments, lotions, ointments, pastes, transdermal patches, etc.), ophthalmologically (eg, eye drops, eye gels, eye ointments), rectal (eg, using an enema or suppository), nasal, buccal, vaginal (eg, using douching, intrauterine devices, vaginal suppositories, vaginal rings or tablets, etc. .), through an implanted reservoir, etc., or parenterally, depending on the type and severity of the disease being treated.

The term parenteral as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

The pharmaceutical compositions described herein can be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, wheat germ, olive, castor and sesame oils), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and/or a) excipients or diluents, such as starches, lactose, sucrose, glucose, mannitol and silicic acid b) binding agents such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants such as glycerin, d) disintegrants such as agar-agar, calcium carbonate, potato starch or starch tapioca, alginic acid, some silicates and sodium carbonate, e) dissolution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h ) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. Tablets may be uncoated or may be coated by known methods, including microencapsulation, to mask the unpleasant taste or delay disintegration and absorption in the gastrointestinal tract and thereby provide prolonged action over a longer period. For example, a temporary release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax, can be used. Water-soluble taste-masking agents such as hydroxypropyl methylcellulose or hydroxypropylcellulose may be used.

Formulations of a polymorph of Compound I or a pharmaceutically acceptable salt of Compound I that are suitable for oral administration may be formulated in discrete units such as tablets, pills, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft. capsules, for example gelatin capsules, syrups or elixirs. Compound formulations intended for oral administration can be prepared according to any method known in the art for the production of pharmaceutical compositions.

Formulations for oral administration may also be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules, wherein the active ingredient is mixed with a water-soluble carrier such as such as polyethylene glycol, or an oily medium such as peanut oil, liquid paraffin or olive oil.

The active solid forms may also be in microencapsulated form with one or more excipients as described above.

When aqueous suspensions for oral administration are required, the active ingredient is combined with emulsifying and suspending agents. If necessary, some sweetening and/or flavoring agents may be added. Syrups and elixirs can be prepared with sweeteners such as glycerin, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring agent, a colorant, and an antioxidant.

Sterile injectable forms of the compositions described herein (eg, for parenteral administration) may be an aqueous or oily suspension. These suspensions can be prepared according to methods known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as, for example, a solution in 1,3-butanediol or PEG400. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as a solvent or suspending medium. Any soft, fixed oil can be used for this purpose, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectable preparations, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylene versions. These oily solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethylcellulose or similar dispersing agents, which are commonly used in pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans and other emulsifiers or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for injectable formulation purposes.

Oily suspensions can be prepared by suspending a polymorph of Compound I, or a pharmaceutically acceptable salt thereof, in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent such as beeswax, paraffin wax or cetyl alcohol. Sweeteners, such as those noted above, and flavoring agents may be added to provide flavor to the oral formulation. These compositions can be preserved by the addition of an antioxidant such as butylated hydroxyanisole or alpha-tocopherol.

Aqueous suspensions of a polymorph of Compound I, or a pharmaceutically acceptable salt of Compound I, contain the active substances in admixture with excipients suitable for preparing aqueous suspensions. Such excipients include a suspending agent such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia, and dispersing or wetting agents such as natural phosphatides (eg, lecithin), the condensation product of an alkylene oxide with a fatty acid. acid (eg, polyoxyethylene stearate), condensation products of ethylene oxide with a long chain aliphatic alcohol (eg, heptadecaethyleneoxycetanol), condensation products of ethylene oxide with a partial fatty acid ester, and hexitic anhydride (eg, polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

Injectable solutions or microemulsions can be introduced into the patient's bloodstream by local bolus injection. On the other hand, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the compound of the present invention. In order to maintain such a constant concentration, continuous intravenous delivery devices can be used. An example of such a device is the Deltec CADD-PLUS™ Model 5400 IV Pump.

Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the solid forms described herein with suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or suppository wax that is solid at ambient temperature. environment, but liquid at body temperature and therefore melts in the rectal or vaginal cavity and releases the active compound. Other compositions suitable for vaginal administration may be in the form of vaginal suppositories, tampons, creams, gels, pastes, foams or sprays.

The pharmaceutical compositions described herein can also be administered topically, particularly when the target of treatment involves sites or organs readily accessible for topical application, including diseases of the eye, ear, skin or lower intestine. Suitable topical compositions can be readily prepared for each of these areas or organs.

Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be required. Ophthalmic compositions, ear drops and eye drops are also considered to be within the scope of the present invention. In addition, the present invention provides for the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in an appropriate medium. Appropriate agents can also be used to increase the flux of the compound through the skin. The rate can be controlled either by a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel. Topical administration to the lower intestinal tract can be done with rectal suppositories (see above) or a suitable type of enema. Topical transdermal patches may also be used.

For topical use, the pharmaceutical compositions may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more vehicles. Carriers for topical administration of the solid forms of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated as a suitable lotion or cream containing the active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ether waxes, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions can be formulated as micronized suspensions in isotonic, pH sterile saline or, preferably, as solutions in isotonic, pH sterile saline with or without a preservative such as benzylalkonium chloride. Additionally, for ophthalmic use, the pharmaceutical compositions may be formulated as an ointment such as Vaseline. For treating the eyes or other external tissues, such as the mouth and skin, the compositions may be applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w. When formulated as an ointment, the active ingredients may be used with or in an oil-based, paraffin-based, or water-miscible ointment base.

Alternatively, the active ingredients can be formulated in an oil-injected cream base. If desired, the aqueous phase of the cream base may include a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may optionally include a compound that enhances the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

The oil phase of emulsions prepared using a polymorph of Compound I or a pharmaceutically acceptable salt of Compound I may be composed of known ingredients in a known manner. While the phase may contain only an emulsifier (otherwise known as an emulsifier), it desirably contains a mixture of at least one emulsifier with a fat or an oil, or both a fat and an oil. The hydrophilic emulsifier may be included along with a lipophilic emulsifier which acts as a stabilizer. In some embodiments, the emulsifier includes both oil and fat. The emulsifier(s) with or without stabilizer(s) form(s) the so-called emulsifying wax, and the wax together with the oil and fat form the so-called emulsifying ointment base, which forms the oil dispersed phase of cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the composition of a polymorph of Compound I or a pharmaceutically acceptable salt of Compound I include Tween™-60, Span™-80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

The pharmaceutical compositions may also be administered as a nasal aerosol or by inhalation. Such compositions are prepared according to methods well known in the pharmaceutical art and can be formulated as solutions in saline using benzyl alcohol or other suitable absorption promoting preservatives

- 13 045683 to increase bioavailability, fluorocarbons and/or other traditional solubilizing or dispersing agents. Compositions suitable for intrapulmonary or nasal administration have a particle size, for example, in the range from 0.1 to 500 microns (including particles in the range from 0.1 to

500 microns with micron increments of 0.5, 1, 30, 35 microns, etc.), which are administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.

The pharmaceutical composition (or composition) for use may be packaged in various ways depending on the method used to administer the drug. Typically, a commercial preparation includes a container containing the pharmaceutical preparation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders and the like. The container may also include sealing elements to prevent accidental access to the contents of the package. In addition, the container contains a label that describes the contents of the container. The label may also include appropriate warnings.

The compositions may be packaged in single or multiple dose containers, such as ampoules and vials, and may be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as water, for injection immediately prior to use. Immediate injection solutions and suspensions are prepared from sterile powders, granules and tablets of the type described above. Preferred unit dosage formulations contain a daily dose, or a unit daily subdose as described above, or an appropriate portion thereof, of the active ingredient.

In another aspect, a polymorph of Compound I or a pharmaceutically acceptable salt of Compound I can be formulated in a veterinary composition containing a veterinary carrier. Veterinary carriers are the substances used to administer the composition and may be solid, liquid or gaseous substances that are otherwise inert or veterinary acceptable and compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally, or any other desired route.

Therapeutic methods.

In another aspect, the invention relates to the treatment of certain disorders using crystalline solid forms of Compound I disclosed herein, either alone or in combination, or pharmaceutical compositions containing them, in a patient in need thereof.

The present invention relates to crystalline solid forms of Compound I and their pharmaceutical compositions and their use, alone or in combination with one or more additional agents, for the treatment and/or prevention of various diseases where increasing the concentration of NO or increasing the concentration of cGMP is desired.

Increased production of NO or increased concentration of cGMP in tissue results in vasodilation, inhibition of platelet aggregation and adhesion, antihypertensive effects, antiremodeling effects, antifibrotic, antiapoptotic effects, anti-inflammatory effects, and effects on neuronal signal transduction, among other effects.

In other embodiments, the crystalline solid forms of Compound I disclosed herein are useful for the prevention and/or treatment of diseases and disorders characterized by an undesirable reduction in the bioavailability and/or sensitivity to NO in a biological system (eg, the human body), such as associated with conditions of oxidative stress or nitrosative stress.

The term cardiovascular disease (or cardiovascular disorder), as used herein, refers to a disease based on abnormal symptoms of the circulatory organs, such as the heart, blood vessels (arteries, capillaries and veins) or both. The term also includes any disease that affects the cardiovascular system as a whole, including heart disease, cerebrovascular disease, vascular disease of the kidneys, liver and related organs, or lungs, and peripheral arterial disease, among others.

sGC-related cardiovascular disease is a disease in which the NO/sGC/cGMP system is known or suspected to be involved and is a cardiovascular disease that can be treated or prevented by sGC activation/stimulation, by NO synthase activation, or by NO supplementation or an NO donor or NO precursor such as L-arginine or L-citrulline, or by inhibiting the PDE (phosphodiesterase) enzyme responsible for cGMP degradation, or a combination of any of the above.

The term vasodilation, as used herein, refers to the dilation of blood vessels. This occurs as a result of relaxation of smooth muscles in the walls of blood vessels, particularly in large veins, large arteries and small arterioles. In essence, this process is the opposite of vasoconstriction, which is the narrowing of blood vessels. When blood vessels dilate, blood flow increases due to decreased vascular resistance. Consequently, dilation of arterial blood vessels (mainly arterioles) reduces blood pressure. The reaction can be internal (due to local processes in the surrounding tissue) or external (due to

- 14 045683 hormones or nervous system). In addition, the reaction may be localized to a specific organ (depending on the metabolic needs of a particular tissue, such as during intense exercise), or it may be systemic (seen throughout the entire circulatory system).

The term vasoconstriction as used herein refers to the narrowing of a blood vessel due to muscle contraction. Vasoconstriction is one of the mechanisms by which the body regulates and maintains mean arterial pressure (MAP).

Generalized vasoconstriction usually results in an increase in systemic blood pressure, but can also occur in certain tissues, causing a local decrease in blood flow.

As used herein, the term bronchoconstriction is used to define narrowing of the airways in the lungs due to constriction of the surrounding smooth muscle, resulting in cough, wheezing and shortness of breath. The condition has a number of causes, the most common of which is asthma. Exercise and allergies can cause symptoms in an individual who is asymptomatic. Other conditions, such as chronic obstructive pulmonary disease (COPD), can also cause bronchoconstriction.

As used herein, the terms hypertension, arterial hypertension, or high blood pressure (HBP) are used interchangeably and refer to an extremely common and easily preventable chronic condition in which the blood pressure (BP) in the arteries is higher than normal or desirable. If not properly controlled, it poses a significant risk factor for several serious cardiovascular and kidney diseases. Hypertension may be a primary disease, called essential hypertension or idiopathic hypertension, or it may be caused by or associated with other diseases, in which case it is classified as secondary hypertension. Essential hypertension accounts for 90-95% of all cases.

As used herein, the term resistant hypertension refers to hypertension that remains above target blood pressure (usually less than 140/90 mmHg, although a lower value of less than 130/80 is recommended for patients with comorbid diabetes or kidney disease mmHg), despite the simultaneous use of three antihypertensive drugs belonging to different classes of antihypertensive drugs. People who require four or more medications to control their blood pressure also have resistant hypertension. Hypertension is an extremely common comorbidity of diabetes, affecting approximately 20-60% of patients with diabetes, depending on obesity, ethnicity and age. This type of hypertension is referred to herein as diabetic hypertension. In type 2 diabetes mellitus, hypertension is often present as part of the metabolic syndrome of insulin resistance, including central obesity and dyslipidemia. In type 1 diabetes, hypertension may reflect the onset of diabetic nephropathy.

Pulmonary hypertension (PH), as used herein, is a disease characterized by persistently high blood pressure in the pulmonary vessels (pulmonary artery, pulmonary veins, and pulmonary capillaries), leading to hypertrophy of the right heart, ultimately leading to right ventricular failure. failure and death. Common symptoms of PH include shortness of breath, dizziness and fainting, which are aggravated by exercise. Without treatment, the average life expectancy after diagnosis is 2.8 years. PH exists in many different forms, which are classified according to their etiology. Categories include pulmonary arterial hypertension (PAH), PH with left heart disease, PH associated with pulmonary disease and/or hypoxia, PH due to chronic, thrombotic and/or embolic disease, and other PH. PAH is a rare disease in the general population, but the prevalence is increasing due to certain common conditions such as HIV infection, scleroderma and sickle cell disease. Other forms of PH tend to be more common than PAH, and, for example, the association of PH with chronic obstructive pulmonary disease (COPD) is of particular interest. Current treatment of pulmonary hypertension depends on the stage and mechanism of the disease.

The term coronary artery disease refers to a condition in which the blood supply to the heart muscle is partially or completely blocked (cardiac muscle or myocardial ischemia).

This reduction in blood supply to the myocardium can lead to a number of acute myocardial syndromes: chest pain (angina, also called angina pectoris, stable or unstable) and various types of heart attacks (myocardial infarction or MI). One common cause of coronary artery disease is atherosclerosis, which refers to hardening of the arteries due to fatty deposits in the artery walls, which can then progress through the formation of atherosclerotic plaques to narrowing and ultimately blocking blood flow in the artery. This process of atherosclerosis can affect other arteries, not just the heart. A blood clot is the most common cause of a blocked artery, as usually the artery is already partially blocked due to atherosclerotic plaque (atheroma); atheroma may rupture or rupture,

- 15 045683 which will lead to the formation of a clot. Sometimes coronary artery disease is caused by spasm of the coronary artery, which can occur spontaneously or as a result of the use of certain medications (eg, cocaine, nicotine). Rarely, coronary artery disease is caused by a birth defect, a viral infection (such as Kawasaki disease), systemic lupus erythematosus (lupus), inflammation of the arteries (arteritis), a blood clot that has moved from a chamber of the heart into one of the coronary arteries, or physical injury (such as from trauma or radiation therapy).

Unstable angina, as used herein, refers to a change in the nature of angina symptoms, including prolonged or worsening angina and new onset of severe symptoms.

MI (myocardial infarction) can be divided into two types: non-ST-segment elevation MI and ST-segment elevation MI. Complications of acute coronary syndromes depend on how many, how long, and where the coronary artery is blocked. If the blockage affects a large area of the heart muscle, the heart will not pump efficiently. If a blockage cuts off blood flow to the heart's electrical system, it can affect the heart's rhythm. When a heart attack occurs, part of the myocardium dies. Dead tissue and the scar tissue that replaces it does not shrink. The scar tissue sometimes even expands or bulges as the rest of the heart tries to shrink. Therefore, there are fewer muscles to pump blood. If enough muscle dies, the pumping function of the heart can be so reduced that the heart cannot meet the body's needs for oxygen and blood. Then heart failure, low blood pressure, or both develop. If more than half of the myocardium is damaged or dies, the heart usually cannot function and severe disability or death is possible.

As used herein, the term heart failure (HF) is a progressive disorder of left ventricular (LV) myocardial remodeling that results in a complex clinical syndrome in which cardiac and circulatory dysfunction are the defining features and result in insufficient delivery of blood and nutrients to the heart. body tissues. The condition occurs when the heart is damaged or overworked and cannot pump out all the blood that returns to it from the circulatory system. As less blood is pumped out, blood returns to the heart and fluid accumulates in other parts of the body. Heart failure also impairs the kidneys' ability to utilize sodium and water, making fluid retention even more difficult. Heart failure is characterized by autonomic dysfunction, neurohormonal activation, and overproduction of cytokines that contribute to progressive circulatory failure. Symptoms of heart failure include: shortness of breath (shortness of breath) during exercise or rest and waking at night due to sudden shortness of breath, both signs of pulmonary edema; general fatigue or weakness; swelling of the feet, ankles and legs; rapid increase in weight; or chronic cough, chronic cough, including one that produces mucus or blood. Depending on the clinical presentation, heart failure is classified as de novo, transient, acute, post-acute or chronic. Acute heart failure, that is, the rapid or gradual onset of symptoms requiring urgent treatment, can develop de novo or as a result of decompensation of chronic heart failure. The term heart failure is often used to refer to chronic heart failure. The terms congestive circulatory failure (CHF) or congestive heart failure (CHF) are often used interchangeably with chronic heart failure. Common causes of heart failure include coronary artery disease including myocardial infarction (heart attack), high blood pressure, atrial fibrillation, heart valve disease, and cardiomyopathy. They cause heart failure by changing the structure or functioning of the heart.

There are two main types of heart failure: heart failure with reduced ejection fraction (HFREF), also known as heart failure caused by left ventricular systolic dysfunction or systolic heart failure, and heart failure with preserved ejection fraction (HFPEF), also known as diastolic heart failure or heart failure with normal ejection fraction (HFNEF). The ejection fraction is the volume of blood pumped out of the heart during one contraction. This is a percentage with a normal level of 50 to 75%.

The term acute (as in acute HF) is used to indicate rapid onset, and chronic refers to long duration. Chronic heart failure is a long-term condition, usually with stable symptomatic treatment. Acute decompensated heart failure is progressive or decompensated heart failure, referring to episodes in which a person may be characterized by a change in the signs and symptoms of heart failure leading to the need for emergency treatment or hospitalization. Heart failure can also occur in situations with a high heart rate (then called hypersystolic heart failure), when ventricular systolic function is normal, but the heart cannot cope with the

- 16 045683 venous increase in blood volume.

In cardiovascular physiology, the term ejection fraction (EF) is defined as the fraction of blood in the left and right ventricles that is pumped out with each heartbeat or cardiac cycle. In the final mathematics allowed by medical imaging, EF applies to both the right ventricle, which ejects blood through the pulmonary valve into the pulmonary circulation (pulmonary circulation), and the left ventricle, which ejects blood through the aortic valve into the cerebral and systemic circulation.

The term heart failure with preserved ejection fraction (HPPEF) is generally understood to refer to the manifestation of signs and symptoms of heart failure with an ejection fraction greater than 55%. It is characterized by a decrease in left ventricular compliance, which leads to increased pressure in the left ventricle. Increased left atrial size is often seen with HFPEF as a result of poor left ventricular function. There is an increased risk of congestive circulatory failure, atrial fibrillation, and pulmonary hypertension. Risk factors include hypertension, hyperlipidemia, diabetes, smoking and obstructive sleep apnea. With this type of heart failure, the heart muscle contracts well, but the ventricle is poorly filled with blood during the relaxation phase.

The term heart failure with reduced ejection fraction (HFREF) refers to heart failure in which the ejection fraction is less than 40%.

Diabetes is a common comorbidity in patients with heart failure and is associated with poorer outcomes and potentially compromising the effectiveness of treatments. Other important comorbidities include systemic hypertension, chronic airway obstruction, sleep apnea, cognitive dysfunction, anemia, chronic kidney disease, and arthritis. Chronic left ventricular failure is often associated with the development of pulmonary hypertension. The incidence of some comorbidities varies by gender: women are more likely to have hypertension and thyroid disease, while men are more likely to have chronic obstructive pulmonary disease (COPD), peripheral vascular disease, coronary artery disease, and renal failure. Depression is a common comorbidity of heart failure, and the two conditions can and often do complicate each other. Cachexia has long been recognized as a serious and common complication of heart failure, affecting up to 15% of all patients with heart failure and associated with a poor prognosis. Cardiac cachexia is defined as non-edematous, involuntary loss of at least 6% of body weight over a period of six months.

The term arrhythmia, as used herein, refers to irregular heartbeats that occur in more than 90% of people who have had a heart attack. Sometimes the problem is in the part of the heart that starts the heartbeat and the heart rate may be too slow, other times problems may cause the heart to beat too fast or irregularly. Sometimes the beat signal is not transmitted from one part of the heart to another, and the heartbeat may slow or stop. In addition, areas of the myocardium that have not died but have poor blood flow may be irritable. This causes heart rhythm problems such as ventricular tachycardia or ventricular fibrillation. This can lead to cardiac arrest if the heart stops pumping altogether.

The pericardium is a sac or membrane that surrounds the heart. Pericarditis, or inflammation of this membrane, can develop as a result of a heart attack and can lead to fever, pericardial effusion, inflammation of the membranes lining the lungs (the pleura), pleural effusion, and joint pain. Other complications after a heart attack may include mitral valve dysfunction, rupture of the heart muscle, a bulge in the wall of the ventricle (ventricular aneurysm), blood clots, and low blood pressure.

The term cardiomyopathy refers to the progressive deterioration of the structure and function of the muscular walls of the chambers of the heart. The main types of cardiomyopathies are dilated, hypertrophic and restrictive. Cardiomyopathies often cause symptoms of heart failure and can also cause chest pain, loss of consciousness, and sudden death.

The terms mitral valve regurgitation, mitral regurgitation, mitral regurgitation, or mitral incompetence refer to a situation in which the heart's mitral valve does not close tightly, allowing blood to flow back into the heart. As a result, blood cannot move through the heart or to the rest of the body as efficiently, leading to fatigue or shortness of breath.

The term sleep apnea refers to the most common breathing disorder during sleep. This condition is characterized by periodic, cyclical reduction or complete cessation of airflow, which may or may not involve upper airway obstruction. There are three types of sleep apnea: obstructive sleep apnea, the most common form, central sleep apnea, and mixed sleep apnea.

Central sleep apnea (CSA) is caused by a disruption of the brain's normal signal to breathe, rather than a physical blockage of the airway. Lack of respiratory effort leads to an increase in carbon dioxide levels in the blood, which can awaken the patient. CSA is rare in the general population but is relatively common in patients with systolic heart failure.

As used herein, the term metabolic syndrome, insulin resistance syndrome, or syndrome X refers to a group or clustering of metabolic conditions (abdominal obesity, elevated fasting blood glucose, dyslipidemia (i.e., elevated lipid levels), and elevated blood pressure ( HBPs) that occur together more often than by chance alone, and that together contribute to the development of type 2 diabetes and cardiovascular disease.As used herein, the term metabolic syndrome, insulin resistance syndrome, or syndrome X refers to a group or clustering of metabolic conditions ( abdominal obesity, elevated fasting blood glucose, dyslipidemia (i.e. elevated lipid levels) and high blood pressure (HBP), which occur together more often than by chance alone, and which together contribute to the development of type 2 diabetes and cardiovascular disease Metabolic syndrome is characterized by a specific lipid profile of elevated triglycerides, decreased high-density lipoprotein cholesterol (HDL-cholesterol) and, in some cases, mildly elevated low-density lipoprotein cholesterol (LDL-cholesterol) levels, and accelerated progression of atherosclerotic disease due to pressure components of risk factors. There are several types of dyslipidemias: Hypercholesterolemia refers to elevated cholesterol levels. Familial hypercholesterolemia is a specific form of hypercholesterolemia associated with a defect in chromosome 19 (19p13.1-13.3). Hyperglyceridemia refers to elevated glyceride levels (eg, hypertriglyceridemia includes elevated triglyceride levels).

Hyperlipoproteinemia refers to elevated levels of lipoproteins (usually LDL unless otherwise noted).

The term steatosis refers to the abnormal retention of lipids in a cell. This usually reflects a disruption of the normal processes of triglyceride synthesis and elimination. Excess fat accumulates in vesicles, which displace the cell cytoplasm. In severe cases, the cell may explode. Steatosis is usually observed in the liver, since this organ is mainly associated with fat metabolism. This can also be observed in the heart, kidneys and muscle tissue.

As used herein, the term peripheral vascular disease (PVD), also commonly referred to as peripheral arterial disease (PAD) or peripheral arterial occlusive disease (PAOD), refers to obstruction of large arteries not located within the coronary artery, aortic arch vasculature, or brain brain PVD can result from atherosclerosis, inflammatory processes leading to stenosis, embolism, thrombus formation, or other types of occlusion. This causes acute or chronic ischemia (lack of blood supply). Often PVD is the term used to refer to atherosclerotic blockages found in the lower extremity. PVD also includes a subset of diseases classified as microvascular diseases that result from episodic narrowing of the arteries (eg, Raynaud's phenomenon) or dilatation (erythromelalgia), i.e. vascular spasms. Peripheral arterial diseases include occlusive thrombotic vasculitis, peripheral artery occlusive disease, Raynaud's disease, and Raynaud's syndrome. Common symptoms are cold leg or feet, intermittent claudication, lower extremity pain, and critical limb ischemia (leg ulcers and necrosis). Guidance on the diagnosis and treatment of peripheral artery disease can be found in Eur. J. Vasco Endovasc. Surg, 2007, 33(1), SI.

The term stenosis, as used herein, refers to an abnormal narrowing of a blood vessel or other tubular organ or structure. It is also sometimes called a stricture (as in urethral stricture). The term coarctation is a synonym, but is usually used only in the context of coarctation of the aorta. The term restenosis refers to recurrence of stenosis after a procedure.

The term thrombosis refers to the formation of a blood clot (thrombus) inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is damaged, the body uses platelets (platelets) and fibrin to form a blood clot to prevent blood loss. Alternatively, even if the blood vessel is not damaged, blood clots can form in the body if the right conditions are present. If the thickening is too strong and the clot breaks loose, the moving clot is now known as an embolus. The term thromboembolism refers to the combination of thrombosis and its main complication, embolism. When a clot occupies more than 75% of the lumen surface of an artery, blood flow to the supplied tissue is reduced enough to cause symptoms due to decreased oxygen (hypoxia) and accumulation of waste products such as lactic acid (gout). More than 90% of obstruction can lead to anoxia, complete oxygen deprivation and infarction, a form of cell death.

Embolism (multiple emboli) is a case of sedimentation of an embolus (an isolated intravascular mass capable of blocking bloodstreams at a sufficiently large distance from the site of occurrence) in a narrow capillary vessel of the arterial bed, which causes a blockage (vascular occlusion) in a distant part of the body. This should not be confused with a blood clot that is blocking at the site of origin. The material forming an embolus can have different origins: if the material is blood, the emboli are called thrombi; the solid material may also contain fat, bacterial debris, infected tissue, etc.

Ischemia is a restriction in the blood supply to tissues, causing a shortage of oxygen and glucose needed for cellular metabolism (to keep tissues alive). Ischemia is typically caused by problems with the blood vessels, leading to tissue damage or dysfunction. It also means local anemia in a given part of the body, sometimes resulting from congestion (eg, vasoconstriction, thrombosis, or embolism). If ischemia occurs in the heart muscle (or myocardium), the ischemia is called myocardial ischemia. Other types of ischemia are, for example, cerebral ischemia, critical limb ischemia and the like.

Reperfusion occurs when blood supply returns to tissue after a period of ischemia. When blood circulation is restored, inflammatory processes and oxidative stress processes can develop in the tissue. One example of this chain of events is ischemia-reperfusion injury associated with organ transplantation.

Reperfusion injury is tissue damage caused by the return of blood supply to the tissue after a period of ischemia, and inflammation and oxidative damage rather than restoration of normal function. Reperfusion of ischemic tissues is often associated with microvascular injury, particularly due to increased capillary and arteriolar permeability, which results in increased diffusion and filtration of fluid through tissues. Activated endothelial cells produce more reactive oxygen species but less NO after reperfusion, and the imbalance leads to a subsequent inflammatory response. White blood cells carried into the area by the returning bloodstream release a variety of inflammatory factors and free radicals in response to tissue damage. The restored blood flow brings with it oxygen, which damages cellular proteins, DNA and plasma membranes. This ischemia-reperfusion process is also thought to be responsible for the formation and failure to heal chronic wounds (eg, pressure ulcers or diabetic ulcers).

The term angiopathy, as used herein, is a general term for disease of the blood vessels (arteries, veins and capillaries). The most common and most common angiopathy is diabetic angiopathy, a common complication of chronic diabetes. Another common type of angiopathy is cerebral amyloid angiopathy (CAA), also known as congophilic angiopathy, in which amyloid deposits form in the walls of blood vessels in the central nervous system. The term congophilic is used because the presence of abnormal amyloid accumulations can be demonstrated by microscopic examination of brain tissue after application of a special dye called Congo red.

Amyloid material is found only in the brain, and as such the disease is not associated with other forms of amyloidosis.

Stroke, or cerebrovascular accident (CVA), is a rapid loss of brain function(s) due to disruption of the blood supply to the brain. This may be due to ischemia (lack of blood flow with resulting insufficient supply of oxygen and glucose to tissues) caused by an obstruction (thrombosis, arterial embolism, fat accumulation or spasm), or hemorrhage (leakage of blood). As a result, the affected area of the brain cannot function, which may result in the inability to move one or more limbs on one side of the body, the inability to understand or formulate speech, or the inability to see on one side of the visual field. Risk factors for stroke include old age, hypertension, previous stroke or transient ischemic attack (TIA), diabetes, high cholesterol, cigarette smoking and atrial fibrillation. High blood pressure is the most important modifiable risk factor for stroke. Ischemic strokes are sometimes treated in the hospital with thrombolysis (also known as a clot buster), and some hemorrhagic strokes benefit from neurosurgery. Prevention of relapse may include antiplatelet medications such as aspirin and dipyridamole, control and reduction of hypertension, and use of statins. Some patients may benefit from carotid endarterectomy and the use of anticoagulants.

Vascular dementia is the second most common cause of dementia among older adults. It is more common among men and usually begins after age 70. It is more common in people with vascular risk factors (eg, hypertension, diabetes, hyperlipidemia, smoking) and in those who have had multiple strokes. Many people suffer from both vascular dementia and Alzheimer's disease. Vascular dementia usually occurs when multiple small cerebral infarcts (or sometimes hemorrhages) result in the loss of enough neurons or axons to impair brain function. Vascular dementias include the following types: multiple lacunar infarction (which affects small blood vessels and

- 19 045683 heart attacks occur deep inside the white and gray matter of the hemisphere); multi-infarct dementia (which affects medium-sized blood vessels); single infarcts in strategic areas (where a single infarct occurs in a functionally significant area of the brain such as the angular gyrus or thalamus; Binswanger dementia or subcortical arteriosclerotic encephalopathy (where small vessel dementia is associated with severe, poorly controlled hypertension and systemic vascular disease, and causes diffuse and irregular loss of axons and myelin with widespread gliosis, tissue death due to infarction or loss of blood supply to the white matter of the brain).

The term glioma refers to a type of tumor that begins its development in the brain or spinal cord. It is called a glioma because it arises from glial cells. The most common area of such tumors is the brain. Gliomas make up about 30% of all tumors of the brain and central nervous system and 80% of all malignant brain tumors.

According to the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), the term sexual dysfunction covers a range of conditions characterized by disturbances of sexual desire and psychophysiological changes associated with the sexual response cycle; while problems of this type are common, sexual dysfunction is thought to exist only when the problems cause distress in the patient. Sexual dysfunction can be physical or psychological in origin. It can exist as a primary condition, usually hormonal in nature, although most often it is secondary to other medical conditions or drug therapy for said conditions. All types of sexual dysfunction can be classified as congenital, acquired, situational or generalized (or combinations thereof).

The DSM-IV-TR defines five main categories of female sexual dysfunction: disturbance of sexual desire/interest; sexual arousal disorders (including genital, subjective and combined); orgasm disorder; dyspareunia and vaginismus; and persistent sexual arousal disorder.

Female sexual arousal disorder (FSAD) is defined as a persistent or recurrent inability to achieve or maintain sufficient levels of sexual arousal, resulting in personal distress. FSAD encompasses both the absence of subjective sensations of arousal (i.e., subjective sexual arousal disorder) and the absence of somatic reactions such as lubrication and swelling (i.e., sexual/physical sexual arousal disorder). FSAD can be strictly psychological in origin, although it is usually caused or complicated by medical or physiological factors. Hypoestrogenism is the most common physiological condition associated with FSAD, resulting in genitourinary atrophy and decreased vaginal secretions (lubrication).

As used herein, erectile dysfunction (ED) is a male sexual dysfunction characterized by the inability to develop or maintain penile erection during sexual activity. Penile erection is a phenomenon of hydraulic pressure of blood, which is retained in the corpus spongiosum of the penis. The process often begins as a result of sexual arousal, when signals are transmitted from the brain to nerves in the penis. Erectile dysfunction means that it is difficult to get an erection. The most important organic causes are cardiovascular disease and diabetes, neurological problems (eg, trauma from prostatectomy surgery), hormonal deficiency (hypogonadism), and drug side effects.

In one embodiment, the polymorphs and pharmaceutically acceptable salts of Compound I described herein are therefore useful for the prevention and/or treatment of the following types of cardiac, pulmonary, peripheral, hepatic, renal or cerebral vascular/endothelial disorders, conditions and diseases associated with blood circulation:

disorders associated with high blood pressure and decreased coronary blood flow; increased acute and chronic coronary blood pressure; arterial hypertension; vascular disorders resulting from cardiac and renal complications; vascular disorders resulting from heart disease, stroke, cerebral ischemia or renal failure; resistant hypertension; hypertension in diabetes mellitus; essential hypertension; secondary hypertension; gestational hypertension; preeclampsia; portal hypertension; myocardial infarction;

heart failure, HFPEF, HFREF; acute and chronic heart failure; more specific forms of heart failure: acute decompensated heart failure, right ventricular failure, left ventricular failure, general heart failure, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, heart failure with valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis

- 20 045683 pan, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valve insufficiency, combined heart defects; diabetic heart failure; alcoholic cardiomyopathy or storage cardiomyopathy; diastolic heart failure, systolic heart failure; acute phases of existing chronic heart failure (worsening heart failure);

diastolic or systolic dysfunction; coronary insufficiency; arrhythmias; reducing ventricular preload; cardiac hypertrophy; heart failure/cardiorenal syndrome; portal hypertension; endothelial dysfunction or damage; disorders of atrial and ventricular rhythm and conduction disorders: atrioventricular block I-III degree (AVB I-III), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, bidirectional ventricular tachycardia, atrial and ventricular extrasystoles, extrasystoles from the AV junction, tachybradycardia syndrome, reciprocal AV nodal tachycardia; Wolff-Parkinson-White syndrome or acute coronary syndrome; boxer cardiomyopathy; premature contraction of the ventricles; cardiomyopathy; cardiomyopathy caused by cancer; chemotherapy-induced cardiotoxicity;

thromboembolic disorders and ischemia; myocardial ischemia; heart attack; myocardial infarction; heart attack; myocardial failure; endothelial dysfunction; stroke;

transient ischemic attack (TIAs); obstructive thromboangitis; stable or unstable angina; spasms of the coronary arteries or spasms of the peripheral arteries; variant of angina pectoris; Prinzmetal's angina; cardiac hypertrophy; preeclampsia; thrombogenic disorders; ischemia-reperfusion injury; ischemia-reperfusion associated with organ transplantation; ischemia-reperfusion associated with lung transplantation, pulmonary transplantation, heart transplantation, vein graft rejection; canned blood replacement solution for trauma patients;

peripheral vascular diseases; peripheral arterial disease; peripheral arterial occlusive disease; hypertension; syndrome or Raynaud's phenomenon (primary and secondary); Raynaud's disease; critical limb ischemia; peripheral embolism; intermittent claudication; vaso-occlusive crises; muscular dystrophy, Duchenne muscular dystrophy, Becker muscular dystrophy; microcirculation disorders; control of vascular leakage or permeability; lumbar spinal stenosis; occlusive thrombotic vasculitis;

thrombotic vasculitis; peripheral perfusion disorders; arterial and venous thrombosis;

microalbuminuria; peripheral and autonomic neuropathies; neuropathic pain in diabetes; diabetic microangiopathies; vaso-occlusive liver disease; vaso-occlusive crisis in sickle cell anemia; hypertensive crisis;

swelling; renal edema due to heart failure;

Alzheimer's disease; Parkinson's disease; vascular dementias; vascular cognitive impairment; spasm of cerebral vessels; congenital myasthenic syndrome;

subarachnoid hemorrhage; traumatic brain injury; improving perception, concentration, learning or memory performance after cognitive impairment, such as those occurring in mild cognitive impairment, age-related learning and memory impairment, age-related memory loss, vascular dementia, head injury, stroke, post-stroke dementia, post-traumatic brain injury head trauma, general concentration problems and concentration problems in children with learning and memory problems; dementia with Lewy bodies; dementia with frontal lobe degeneration, including Pick's syndrome; progressive nuclear palsy; dementia with corticobasal degeneration; amyotrophic lateral sclerosis (ALS); Huntington's disease; demyelination; multiple sclerosis; thalamic degeneration; Creutzfeldt-Jakob dementia; HIV dementia; schizophrenia with dementia or Korsakoff psychosis; multiple system atrophy and other forms of parkinsonism-plus; motor disorders; neuroprotection; anxiety, tension and depression or post-traumatic stress disorder (PTSD); bipolar disorder; schizophrenia; CNS-related sexual dysfunction and sleep disturbances; pathological eating disorders and the use of delicacies and addictive drugs; control of cerebral perfusion; migraine; prevention and control of the consequences of cerebral infarction (cerebral apoplexy); prevention and control of the consequences of stroke, cerebral ischemia and head injury; neuropathies associated with central nervous system disease; neuropathic pain associated with PC;

chemotherapy-induced neuropathic pain; neuropathic pain associated with herpes zoster; neuropathic pain associated with spinal surgery;

shock; cardiogenic shock; sepsis; septic shock; anaphylactic shock; aneurysms; control of leukocyte activation; inhibition or modulation of platelet aggregation; polyor syndrome

- 21 045683 genetic dysfunction (MODS); multiple organ failure (MOF);

pulmonary/respiratory diseases: pulmonary hypertension (PH); pulmonary arterial hypertension (PAH) and associated pulmonary vascular remodeling; vascular remodeling in the form of localized thrombosis and hypertrophy of the right heart; pulmonary hypertension; primary pulmonary hypertension; secondary pulmonary hypertension; hereditary pulmonary hypertension; sporadic pulmonary hypertension; precapillary pulmonary hypertension; idiopathic pulmonary hypertension; other forms of RN; ROP associated with left ventricular disease, HIV, SCD, thromboembolism (STERN), sarcoidosis, COPD, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), acute lung injury, alpha-1 antitrypsin deficiency (AATD), emphysema, smoking-induced emphysema and cystic fibrosis (MB); thrombotic pulmonary arteriopathy; plexogenic pulmonary arteriopathy; cystic fibrosis; bronchoconstriction or pulmonary bronchoconstriction; acute respiratory syndrome; pulmonary fibrosis, lung transplantation; asthmatic diseases;

pulmonary hypertension associated with or in connection with: left ventricular dysfunction, hypoxemia, WHO group I, II, III, IV hypertension, mitral valve disease, constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, pulmonary fibrosis, abnormal drainage of the pulmonary veins, veno-occlusive pulmonary disease, pulmonary vasculitis, collagen vascular diseases, congenital heart defects, pulmonary venous hypertension, interstitial lung disease, sleep disordered breathing, sleep apnea, alveolar hypoventilation disorders, chronic exposure to high altitude, neonatal lung disease, alveolar capillary dysplasia, crescentic cellular anemia, other coagulation disorders, chronic thromboembolism, pulmonary embolism; pulmonary embolism caused by a tumor, parasites, or foreign material; connective tissue diseases, lupus, schitozomyasis, sarcoidosis, chronic obstructive pulmonary disease, asthma, emphysema, chronic bronchitis, pulmonary capillary hemangiomatosis; histiocytosis X, lymphangiomatosis, pulmonary vascular compression; pulmonary vascular compression due to lymphadenopathy, tumor, or fibrosing mediastinitis;

atherosclerotic disease or condition:

atherosclerosis; atherosclerosis associated with endothelial damage, adhesion and aggregation of platelets and monocytes, proliferation or migration of smooth muscles; restenosis; restenosis that developed after treatment with thrombolysis, percutaneous transluminal angioplasty (PTA), transluminal coronary angioplasty (PTCA), heart transplantation, bypass surgery or inflammatory processes;

micro- and macrovascular damage (vasculitis); elevated fibrinogen levels and low DLD density; increased concentration of plasminogen activator inhibitor 1 (PA-1);

metabolic syndrome; metabolic diseases or diseases associated with metabolic syndrome: obesity; excess subcutaneous fat; excess obesity; diabetes; high blood pressure; disorders associated with lipid metabolism, hyperlipidemia, dyslipidemia, hypercholesterolemia, decreased levels of high-density lipoprotein cholesterol (HDL-cholesterol), moderately elevated levels of low-density lipoprotein cholesterol (LDL-cholesterol), hypertriglyceridemia, hyperglyceridemia, hypolipoproteinemia, sitosterolemia, fatty liver, alcoholic fatty liver disease (AFLD), non-alcoholic fatty liver disease (NAFLD), hepatitis; preeclampsia; progression of polycystic kidney disease; hepatic steatosis, or abnormal accumulation of lipids in the liver; non-alcoholic steatohepatitis (NASH); steatosis of the heart, kidneys or muscles; alpha-beta lipoproteinemia;

sitosterolemia; xanthomatosis; Tangier disease; hyperammonemia and related diseases; hepatic encephalopathy; other toxic encephalopathies; Reye's syndrome;

sexual, gynecological and urological disorders: erectile dysfunction; impotence; premature ejaculation; female sexual dysfunction; dysfunction of female sexual arousal; hypoactive sexual arousal disorder; vaginal atrophy; dyspaneuria; atrophic vaginitis; benign prostatic hyperplasia (BPH), prostatic hypertrophy, prostate enlargement; bladder outlet obstruction; painful bladder syndrome (PBS);

interstitial cystitis (IC); overactive bladder; neurogenic bladder and incontinence; diabetic nephropathy; primary and secondary dysmenorrhea; lower urinary tract syndromes (LUTS); endometriosis; pelvic pain;

benign and malignant diseases of the male and female genitourinary system;

chronic kidney disease; acute and chronic renal failure; acute and chronic renal failure; lupus nephritis; underlying or related kidney diseases: hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, nephropathic diseases, primary and congenital kidney diseases, nephritis; diseases characterized

- 22 045683 abnormally reduced secretion of creatinine and/or water; diseases characterized by abnormally elevated concentrations of urea, nitrogen, potassium and/or creatinine in the blood; diseases characterized by altered activity of renal enzymes, diseases characterized by altered activity of glutamyl synthetase; diseases characterized by altered urine osmolarity or urine volume; diseases characterized by increased microalbuminuria, diseases characterized by macroalbuminuria; diseases characterized by damage to the glomeruli and arterioles, tubular dilatation, hyperphosphatemia and/or the need for dialysis; complications of renal failure; renal failure associated with pulmonary enema; renal failure associated with HF; renal failure associated with uremia or anemia; electrolyte disturbances (hyperkalemia, hyponatremia); disorders of bone and carbohydrate metabolism; acute kidney injury;

eye diseases or disorders such as glaucoma, retinopathy and diabetic retinopathy.

The term inflammation refers to the complex biological response of vascular tissues to noxious stimuli, such as pathogens, damaged cells, or irritants. Classic signs of acute inflammation are pain, heat, redness, swelling and loss of function. Inflammation is the body's protective attempt to eliminate harmful stimuli and begin the healing process. Inflammation is not synonymous with infection, although the two concepts are often correlated (the former is often a consequence of the latter). Inflammation can also occur in the absence of infection, although such types of inflammation are usually insufficiently adaptive (for example, in atherosclerosis). Inflammation is a stereotyped response and is therefore considered a mechanism of innate immunity, as compared to adaptive immunity, which is specific to each pathogen. Progressive tissue destruction in the absence of inflammation can compromise the survival of the organism. On the other hand, chronic inflammation can lead to a variety of diseases such as hay fever, periodontitis, atherosclerosis, rheumatoid arthritis and even cancer (eg gallbladder carcinoma). It is for this reason that inflammation tends to be tightly regulated by the body. Inflammation can be classified as acute or chronic. Acute inflammation is initially the body's response to noxious stimuli and is achieved by increasing the movement of plasma and white blood cells (especially granulocytes) from the blood into damaged tissues. A cascade of biochemical events spreads and an inflammatory response matures involving the local vascular system, the immune system, and various cells in the affected tissue. Long-term inflammation, known as chronic inflammation, results in a progressive shift in the type of cells present at the site of inflammation and is characterized by simultaneous destruction and healing of tissue as a result of the inflammatory process.

In another embodiment, the polymorphs and pharmaceutically acceptable salts of Compound I described herein are therefore useful for the prevention and/or treatment of the following types of cardiac, pulmonary, peripheral, hepatic, renal conditions or diseases, digestive system or central nervous system conditions or diseases systems that may involve inflammation or inflammatory processes:

inflammation of the heart muscle (myocarditis); chronic myocarditis; acute myocarditis; viral myocarditis;

vasculitis; pancreatitis; peritonitis; rheumatoid diseases;

inflammatory kidney disease; immunological kidney diseases: kidney transplant rejection, immune complex-induced kidney disease, toxin-induced nephropathy, contrast agent-induced nephropathy; diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome;

chronic interstitial inflammation. inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis (UC);

inflammatory skin diseases;

inflammatory eye diseases, blepharitis, dry eye syndrome and Sjogren's syndrome; fibrosis of the eyes.

The term wound healing refers to the complex process by which the skin (or other organ or tissue) repairs itself after injury. For example, in intact skin, the epidermis (surface layer) and dermis (inner or deeper layer) exist in a stable balance, forming a protective barrier against environmental influences. Once the protective barrier is broken, the normal (physiological) wound healing process is immediately set in motion. The classical model of wound healing is divided into three or four sequential but overlapping phases: (1) hemostasis (not considered a phase by some authors), (2) inflammation, (3) proliferation, and (4) remodeling. When the skin is damaged, a series of complex biochemical events occur in a carefully orchestrated cascade to repair the damage. During the first few minutes after injury, platelets attach to the site of injury, become activated and aggregate (combine), after which the coagulation cascade is activated, which forms a clot of aggregated thrombocytes

- 23 045683 cyts in a network of cross-linked fibrin protein. This clot stops active bleeding (hemostasis). During the inflammatory phase, bacteria and cellular debris are phagocytosed and removed from the wound by white blood cells. Platelet-derived growth factors (stored in platelet alpha granules) are released into the wound, causing cell movement and separation during the proliferative phase. The proliferation phase is characterized by angiogenesis, collagen deposition, granulation tissue formation, epithelialization, and wound contraction. During angiogenesis, vascular endothelial cells form new blood vessels. During fibroplasia and granulation tissue formation, fibroblasts grow and form a new temporary extracellular matrix (ECM), releasing collagen and fibronectin. At the same time, re-epithelialization of the epidermis occurs, in which epithelial cells proliferate and crawl along the wound bed, providing closure for new tissue. During wound contraction, myofibroblasts reduce the size of the wound by grasping the edges of the wound and contracting, using a mechanism that is similar to that in smooth muscle cells. When the cells' roles are near completion, the unwanted cells undergo apoptosis. During maturation and remodeling, collagen is remodeled and aligned along stretch lines, and cells that are no longer needed are eliminated by apoptosis. However, this process is not only complex, but also fragile, and susceptible to interruption or failure, resulting in the formation of non-healing chronic wounds (one example includes diabetic wounds or ulcers, and in particular diabetic foot ulcers). Factors contributing to non-healing chronic wounds include diabetes, venous or arterial disease, infection, and metabolic disorders in old age.

The terms fracture healing or fracture healing refer to the proliferative physiological process in which the body promotes the repair of a broken bone. During the healing process of fractures, several stages of repair promote proliferation and protection of the areas surrounding the fractures and disorders. The length of the process depends on the extent of the injury, and the usual supply of two to three weeks is given to compensate for most upper body fractures; Somewhere over four weeks is given for a lower body injury. The healing process is mainly determined by the periosteum (the connective tissue membrane covering the bone). The periosteum is one of the sources of progenitor cells that develop into chondroblasts and osteoblasts, which are essential for bone healing. Bone marrow (if present), endosteum, small blood vessels, and fibroblasts are other sources of progenitor cells.

In another embodiment, the polymorphs and pharmaceutically acceptable salts of Compound I described herein are accordingly useful in the treatment of the following types of diseases, disorders or conditions in which stimulation of wound or bone healing processes is desired:

healing of wounds or ulcers in diabetics; improving microvascular perfusion; improving microvascular perfusion after injury or to counteract the inflammatory response in perioperative care; anal fissures; diabetic ulcers; diabetic foot ulcers); fracture healing;

osteoclastic resorption and bone remodeling; and formation of new bone.

The term connective tissue (CT) refers to a type of tissue in a living organism that supports, connects, or separates different types of tissues and organs of the body. It is one of four major classes of animal tissues, the others being epithelial, muscle, and neural tissues. Connective tissue is found everywhere, including in the central nervous system. It is located between other tissues. All CT consists of three main components - crushed substances, fibers and cells - and all of these components are immersed in body fluids.

The term connective tissue disorder or condition refers to any condition that involves abnormalities in the connective tissue in one or more parts of the body. Some disorders are characterized by overactivity of the immune system, followed by inflammation and systemic tissue damage, usually with connective tissue replacing normal tissue (eg, normal tissue in a particular organ). Other disorders include biochemical abnormalities or structural defects in the connective tissue itself. Some of these disorders are hereditary and some are of unknown etiology.

When connective tissue diseases are of autoimmune origin, they are classified as rheumatic diseases, autoimmune rheumatic diseases, or autoimmune collagen-vascular diseases.

In an autoimmune disorder, antibodies or other cells produced by the body attack the body's own tissues. Many autoimmune disorders affect connective tissue in various organs. In autoimmune disorders, inflammation and the immune response can cause damage to the connective tissue around joints, as well as in other tissues, including vital organs such as the kidneys or gastrointestinal tract. The sac that surrounds the heart (pericardium), the membrane that covers the lungs (pleura), the mediastinum (an undefined group of structures in the chest, surrounded by loose connective tissue, containing the heart, great vessels of the heart, esophagus, trachea, phrenal nerve, cardiac nerve, thoracic duct, thymus and lymph nodes of the central chest) and even the brain.

The term fibrosis, as used herein, refers to the accumulation of connective tissue

- 24 045683 nodular tissue or fibrous tissue (scar tissue, collagen) in a specific organ or part of the body. If the fibrosis arises from a single cell line, it is called a fibroma. Fibrosis occurs when the body attempts to repair and replace damaged cells, and thus can be a reactive, benign, or pathological condition. Physiological fibrosis is similar to the process of scarring. The pathological condition develops when the tissue in question is repeatedly and persistently damaged. A single episode of injury, even severe, does not usually cause fibrosis. If the damage recurs or continues (such as in chronic hepatitis), the body tries to repair the damage, but instead it results in an excessive accumulation of scar tissue. Scar tissue begins to replace normal organ tissue, which performs certain functions that scar tissue is unable to perform; it can also affect blood flow and limit blood supply to other cells. As a result, these other functional cells begin to die and more scar tissue forms. When this happens in the liver, blood pressure rises in the vein that carries blood from the intestines to the liver (the portal vein), causing a condition known as portal hypertension.

The term sclerosis refers to the hardening or hardening of tissue or a structure or organ that is normally elastic, usually by replacing tissue specific to a normal organ with connective tissue.

There are many types of fibrosis or fibrotic diseases, including, but not limited to, pulmonary fibrosis (idiopathic pulmonary fibrosis, cystic fibrosis), liver fibrosis (or cirrhosis), endomyocardial fibrosis, old myocardial infarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis (affecting the bone marrow). ), retroperitoneal fibrosis, progressive massive fibrosis (affecting the lungs), nephrogenic fibrosis (affecting the skin), Crohn's disease, arthrofibrosis, Peyronie's disease (affecting the penis), Dupuytren's contracture (affecting the hands and fingers), some forms of adhesive capsulitis (affecting the shoulders) .

There are many types of sclerosis or sclerotic diseases, including, but not limited to, amyotrophic lateral sclerosis (ALS); atherosclerosis; focal segmental glomerulosclerosis and nephrotic syndrome; hippocampal sclerosis (affecting the brain); lichen sclerosus (a disease in which the connective tissue of the vagina and penis thickens); liver sclerosis (liver cirrhosis); multiple sclerosis or focal sclerosis (diseases affecting coordination); osteosclerosis (a disease in which bone density is significantly reduced); otosclerosis (a disease affecting the ears); tuberous sclerosis (a rare genetic disease that affects several systems); primary sclerosing cholangitis (hardening of the bile duct); primary lateral sclerosis (progressive muscle weakness in voluntary muscles); and keloids.

The term scleroderma or systemic sclerosis or progressive systemic sclerosis refers to a condition that involves scarring of joints, skin and internal organs, as well as blood vessel abnormalities. Systemic sclerosis can sometimes occur in limited forms, such as sometimes affecting only the skin or mainly only certain areas of the skin, or as CREST syndrome (where peripheral areas of the skin are involved rather than the trunk). The usual initial symptom of systemic sclerosis is swelling, then thickening and hardening of the skin at the end of the fingers. Raynaud's phenomenon, in which the fingers suddenly and temporarily become very pale and tingly, or numb, painful, or both.

The term polymyositis refers to muscle inflammation. The term dermatomyositis refers to muscle inflammation that is accompanied by skin inflammation. The term polychondritis refers to inflammation of the cartilage.

The term eosinophilic fasciitis refers to a rare condition in which eosinophilic immune cells are released, leading to inflammation and hardening of the fascia, which is the layer of elastic fibrous tissue under the skin, on top and between muscles. The fascia becomes painfully inflamed and swollen and gradually hardens in the arms and legs. As the skin on your hands and feet gradually hardens, it becomes more difficult to move. They end up in unusual positions. Sometimes, if the hands are affected, a person may develop carpal tunnel syndrome.

In another embodiment, specific disease disorders that can be treated and/or prevented by administration of polymorphs and pharmaceutically acceptable salts of Compound I described herein include, but are not limited to, the following type of diseases, including inflammation, autoimmunity, or fibrosis (i.e., fibrotic diseases):

diseases of the genitourinary system and kidneys: diabetic nephropathy; renal fibrosis and renal failure resulting from chronic kidney disease or chronic renal failure; renal fibrosis and renal failure due to accumulation/deposition and tissue damage; kidney sclerosis; progressive sclerosis; glomerulonephritis; focal segmental glomerulosclerosis; nephrotic syndrome; prostate hypertrophy; kidney fibrosis; interstitial renal fibrosis;

respiratory system disorders: pulmonary fibrosis;

idiopathic pulmonary fibrosis; cystic fibrosis; progressive massive fibrosis; progressive massive fibrosis that affects the lungs);

disorders affecting the heart: endomyocardial fibrosis; chronic myocardial infarction; atrial fibrosis; interstitial fibrosis of the heart; cardiac remodeling and fibrosis; cardiac hypertrophy;

diseases of the liver and related organs: sclerosis or cirrhosis of the liver; liver cirrhosis associated with chronic liver disease; liver fibrosis; activation of hepatic stellate cells; NASH; liver collagen fibrousness and general collagen accumulation; liver disease of necroinflammatory and/or immunological origin; biliary primary cirrhosis of the liver; primary sclerosing cholangitis; other cholestatic liver diseases: associated with granulomatous liver disease, liver malignancy, intrahepatic cholestasis of pregnancy, hepatitis, sepsis, drugs or toxins, graft-versus-host disease, liver transplantation, choledocholithiasis, bile duct tumor, pancreatic cancer, Mirizzi syndrome, cholangiopathy or parasites AIDS; schistosomiasis; hepatocellular carcinoma;

diseases or disorders of the digestive tract: Crohn's disease; Ulcerative colitis; sclerosis of the gastrointestinal tract; achalasia;

skin or eye diseases: nephrogenic fibrosis;

proliferative vitroretinopathy; diabetic retinopathy; fibrosis of the eye;

fibrotic local or cutaneous disorders or conditions; dermal fibrosis; scleroderma, skin fibrosis; focal scleroderma; hypertrophic scars; nevus; keloids; sarcoids; granulomas;

diseases affecting the nervous system: amyotrophic lateral sclerosis (ALS); hippocampal sclerosis, multiple sclerosis (MS); focal sclerosis; primary lateral sclerosis;

bone diseases; osteosclerosis;

otosclerosis; other diseases or hearing impairments; hearing impairment, partial or complete hearing loss; partial or complete deafness; noise in ears; noise-induced hearing loss;

other diseases including autoimmune disease, inflammation or fibrosis: scleroderma; localized scleroderma or limited scleroderma; mediastinal fibrosis; fibrous mediastinitis; myelofibrosis; retroperitoneal fibrosis; arthrofibrosis; Peyronie's disease; Dupuytren's contracture; lichen sclerosis; some forms of adhesive capsulitis; atherosclerosis; tuberous sclerosis; systemic sclerosis; polymyositis; dermatomyositis; polychondritis; esinophilic fasciitis; systemic lupus erythematosus or lupus erythematosus;

bone marrow fibrosis, myelofibrosis or osteomyelofibrosis; sarcoidosis; uterine fibroids; endometriosis.

In another embodiment, specific disease disorders that can be treated and/or prevented by administration of polymorphs or pharmaceutically acceptable salts of Compound I described herein include, but are not limited to: certain types of cancer; sickle cell diseases; sickle cell anemia; cancer metastasis; osteoporosis; gastroparesis; functional dyspepsia; complications of diabetes; alopecia or hair loss; diseases associated with endothelial dysfunction; neurological disorders associated with decreased production of nitric oxide; argininosuccinate aciduria; neuromuscular diseases; Duchenne muscular dystrophy (DMD); Becker muscular dystrophy (BMD); pelvic-brachial muscular dystrophy; distal myopathy; myotonic dystrophy type I and type II; Facioscapuloperoneal muscular dystrophy; autosomal and X-linked Emery-Dreyfus muscular dystrophy; oculopharyngeal muscular dystrophy; amyotrophic lateral sclerosis; and spinal muscular atrophy (SMA).

In some embodiments, the invention provides a method of treating a disease, health condition, or disorder in a subject, comprising administering a therapeutically effective amount of a polymorph or pharmaceutically acceptable salt of Compound I described herein to a subject in need of treatment, wherein the disease, health condition, or disorder selected from one of the diseases listed above.

In another embodiment, solid forms of the invention may be delivered in the form of implanted devices such as stents. A stent is a mesh tube inserted into a natural passage/channel in the body to prevent or counteract disease-induced localized narrowing of flow. The term may also refer to a tube used to temporarily hold such a natural canal open to allow access for surgery.

A drug-eluting stent (DES) is a peripheral or coronary stent (scaffold) placed in narrowed, diseased peripheral or coronary arteries that slowly releases a drug to block cell proliferation, usually smooth muscle cell proliferation. This prevents fibrosis, which along with clots (thrombi) can block the stented artery, a process called restenosis. Stent

- 26 045683 is usually placed in a peripheral or coronary artery by an interventional cardiologist or interventional radiologist during an angioplasty procedure. Drugs commonly used in DES to block cell proliferation include analogues of paclitaxel or rapamycin.

In some embodiments, a polymorph or pharmaceutically acceptable salt of Compound I of the invention, or a pharmaceutical composition thereof, can be delivered via a solid form coated drug-eluting stent or pharmaceutical composition. A drug-eluting stent coated with a solid form of Compound I of the invention (or a pharmaceutical composition) may be useful in preventing in-stent restenosis and thrombosis during percutaneous coronary interventions. A drug-eluting stent coated with a solid form of Compound I of the invention (or a pharmaceutical composition) may be capable of preventing smooth cell proliferation as well as promoting revascularization and regeneration of endothelial tissue of the artery into which the stent is inserted.

An alternative to percutaneous coronary intervention to treat intractable angina caused by occlusive coronary artery disease is a procedure called coronary artery bypass grafting (CABG). CABG provides only mitigation of the ongoing process, which is further complicated by the rapid development of graft atherosclerosis. The saphenous vein graft is the most commonly used vascular graft in CABG surgery. Long-term clinical success of vein CABG is difficult for three main reasons: accelerated graft atherosclerosis, incomplete endothelialization, and thrombosis.

In some embodiments, the solid form of Compound I of the invention can be used to prevent subcutaneous graft failure during CABG. The solid forms of the invention can promote the process of endothelialization and help prevent thrombosis. In this indication, the solid form of Compound I is delivered locally in gel form.

The terms disease, disorder, and condition may be used interchangeably herein to refer to an sGC, cGMP, and/or NO-mediated medical or pathological condition.

As used herein, the terms subject and patient are used interchangeably. The terms subject and patient refer to animals (eg, birds such as chicken, quail or turkey, or mammals), particularly mammals, including non-primates (eg, cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats , dogs and mice) and primates (such as monkeys, chimpanzees and humans), more specifically humans. In some embodiments, the subject is a non-human animal, such as farm animals (eg, horses, cows, pigs, and sheep) or pets (eg, dog, cat, guinea pig, or rabbit). In some embodiments, the subject is a human.

The present invention also provides a method of treating one of these diseases, conditions and disorders in a patient, comprising administering a therapeutically effective amount of a polymorph or pharmaceutically acceptable salt of Compound I to a subject in need of treatment. The invention further relates to the use of a polymorph or pharmaceutically acceptable salt of Compound I in the treatment of one of these diseases, conditions and disorders in a subject in need of treatment. The invention further provides a method for preparing or producing a medicament useful in the treatment of one of these diseases, conditions and disorders, comprising the use of a polymorph or pharmaceutically acceptable salt of Compound I.

The term biological sample, as used herein, refers to an in vitro or ex vivo sample and includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal, or extracts thereof; blood, saliva, urine, feces, semen, tears, lymph fluid, eye fluids, vitreous fluid or other body fluids, or extracts thereof.

As used herein, the terms treatment or treatment are used interchangeably. These terms refer to an approach to obtain useful or desired results, including, but not limited to, therapeutic benefit. Therapeutic benefit includes elimination or improvement of the underlying disease being treated; it also includes the elimination or improvement of one or more symptoms associated with the underlying disease, such that the patient experiences improvement although the patient may still be affected by the underlying disease.

As used herein, the terms treat, treat and treat refer to reducing or alleviating the progression, severity and/or duration of a sGC, cGMP and/or NO mediated condition or improving one or more symptoms (preferably one or more different symptoms) of said condition (ie, management of the condition without treatment) as a result of one or more therapies (eg, one or more therapeutic agents, such as a polymorph or pharmaceutically acceptable salt of Compound I or a composition thereof of the invention). In specific embodiments, the terms treat, treatment, and treatment

- 27 045683 relate to improvement of at least one measurable physical parameter sGC, cGMP and/or

NO mediated state. In other embodiments, the terms treat, treat, and treat refer to inhibiting the progression of a sGC, cGMP, and/or NO mediated condition, either physically, such as by stabilizing noticeable symptoms, or physiologically, such as by stabilizing a physical parameter, or both.

The term prevention, as used herein, refers to the administration of a drug in advance for the purpose of preventing or preventing the occurrence of one or more symptoms of a disease or disorder. One skilled in the medical field will recognize that the term prevention is not absolute in perspective. In the medical field, this should be understood to refer to the prophylactic administration of a drug to substantially reduce the likelihood or severity of a condition, or a symptom of a condition, in the context of this invention. In the Physician's Desk Reference, the term prevention is used repeatedly in standard medical contexts. As used herein, the terms prevent, prevent and prevent in relation to a disorder or disease refer to preventing the causes, effects, symptoms or progression of a disease or disorder before the full manifestation of the disease or disorder.

In one embodiment, In one embodiment, the methods of the invention are a preventive or proactive measure for a patient, particularly a person who has a predisposition (e.g., genetic predisposition) to developing a disease, disorder, or symptom associated with sGC, cGMP, and/or NO.

In other embodiments, the methods of the invention are a preventive or proactive measure for a patient, particularly a person suffering from a disease, disorder or condition that puts them at risk of developing a disease, disorder or symptom associated with sGC, cGMP or NO.

The solid forms and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of a disease or disorder mediated, regulated or influenced by sGC, cGMP and/or NO.

The solid forms and compositions described herein are also useful in veterinary medicine for the treatment of pets, exotic animals and farm animals, including, but not limited to, dogs, cats, mice, rats, hamsters, gerbils, guinea pigs, rabbits, horses , pigs and cattle.

In other embodiments, the invention relates to a method of stimulating sGC activity in a biological sample, comprising contacting said biological sample with a solid form or composition of the invention. The use of an sGC stimulator in a biological sample is useful for a variety of purposes known to one of ordinary skill in the art. Examples of such purposes include, but are not limited to, biological assays and storage of biological samples.

Combination therapies.

The solid forms and pharmaceutical compositions described herein can be used in combination therapy with one or more additional therapeutic agents. For combination treatment with more than one active agent, where the active agents are in separate dosage forms, the active agents can be administered separately or in combination. In addition, the administration of one element can be carried out before, simultaneously with, or after the administration of another agent.

When coadministered with other agents, for example, when coadministered with another drug, the effective amount of the second agent will depend on the type of drug used. Suitable dosages are known for the approved agents and may be adjusted by one skilled in the art depending on the condition of the subject, the type of condition(s) being treated, and the amount of compound described and used in the present invention. In cases where the amount is not explicitly stated, the effective amount shall be assumed. For example, the solid forms described herein can be administered to a subject in a dosage range of about 0.01 to about 10,000 mg/kg body weight/day, about 0.01 to about 5,000 mg/kg body weight/day, about from 0.01 to about 3000 mg/kg body weight/day, from about 0.01 to about 1000 mg/kg body weight/day, from about 0.01 to about 500 mg/kg body weight/day, from about 0 .01 to about 300 mg/kg body weight/day, from about 0.01 to about 100 mg/kg body weight/day.

When using combination therapy, an effective amount can be achieved using a first amount of a polymorph or pharmaceutically acceptable salt of Compound I and a second amount of an additional suitable therapeutic agent.

In one embodiment of the present invention, the polymorph or pharmaceutically acceptable salt of Compound I and the additional therapeutic agent are administered in an effective amount (ie, each in an amount that would be therapeutically effective if administered separately). In another embodiment, the polymorph or pharmaceutically acceptable salt of Compound I and the additional therapeutic agent are administered in an amount that does not, by itself, provide a therapeutic effect (subtherapeutic dose). In yet another embodiment, a polymorph or pharmaceutically acceptable salt of Compound I can be administered in an effective amount while the additional therapeutic agent is administered at a subtherapeutic dose. In yet another embodiment, a polymorph or pharmaceutically acceptable salt of Compound I may be administered at a subtherapeutic dose while an additional therapeutic agent, such as a suitable anticancer therapeutic agent, is administered in an effective amount.

As used herein, the terms combination or coadministration may be used interchangeably to indicate the use of more than one therapy (eg, one or more prophylactic and/or therapeutic agents). The use of the terms does not limit the order in which therapies (eg, prophylactic and/or therapeutic agents) are administered to a subject.

Co-administration involves administering a first and a second amount of compounds substantially simultaneously, for example, in a single pharmaceutical composition, such as a capsule or tablet having a fixed ratio of the first and second amounts, or in several separate capsules or tablets for each. Moreover, such co-administration also includes administering each compound sequentially in any order. Coadministration involves separately administering a first amount of a polymorph or pharmaceutically acceptable salt of Compound I and a second amount of the additional therapeutic agent, the compounds being administered close enough in time to have the desired therapeutic effect. For example, the amount of time between each administration to obtain the desired therapeutic effect may vary from several minutes to an hour and may be determined based on the properties of each of the compounds, such as activity, solubility, bioavailability, plasma half-life and kinetic profile. For example, the polymorph or pharmaceutically acceptable salt of Compound I and the second therapeutic agent can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 h apart, within about 1 hour apart, or within about 30 min apart.

More specifically, the first therapy (e.g., a prophylactic or therapeutic amount of a polymorph or pharmaceutically acceptable salt of Compound I described herein) may be administered before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours , 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks earlier), simultaneously with or after (for example, after 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks , 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of a second therapy (eg, a prophylactic or therapeutic agent, such as an anticancer agent) to the subject.

Examples of other therapeutic agents that may be combined with a polymorph or pharmaceutically acceptable salt of Compound I, or administered separately, or in the same pharmaceutical composition include, but are not limited to.

(1) Endothelial releasing factor (EDRF);

(2) NO donors such as nitrosothiols, nitrites, sydnonimine, NONOaT, N-nitrosoamine, N-hydroxyl nitrosamines, nitrozymine, nitrotyrosine, diazetin dioxide, oxatriazole 5-imine, oxime, hydroxylamine, N-hydroxyguanidine, hydroxyurea or furoxan. Some examples of these types of compounds include: glyceryl trinitrate (also known as GTN, nitroglycerin, nitroglycerin and trinitroglycerin), a glycerol nitrate ester; sodium nitroprusside (SNP), in which a nitric oxide molecule is coordinated with metallic iron to form a bipyramidal complex area; 3-morpholinosydnonimine (SIN-1), a zwitterionic compound obtained by combining morpholine and sydnonimine, S-nitroso-N-acetylpenicillamine (SNAP), an N-acetylated amino acid derivative with a nitrosothiol functionality; diethylenetriamine/NO (DETA/NO), a nitric oxide compound covalently bound to diethylenetriamine; and NCX4016, m-nitroxymethyl phenyl ester of acetylsalicylic acid. More specific examples of some of these classes of NO donors include: classical nitrovasodilators such as organic nitrates and nitrites, esters including nitroglycerin, amyl nitrite, isosorbide dinitrate, isosorbide-5-mononitrate and nicorandil; isosorbide (Dilatrate®-SR, Imdur®, Ismo®, Isordil®, Isordil®, Titradose®, Monoket®), FK 409 (NOR-3); FR 144420 (NOR-4); 3-morpholinosidnonimine; linsidomine hydrochloride (SIN-1), S-nitrosoN-acetylpenicillamine (SNAP); AZD3582 (CINOD lead compound), NCX 4016, NCX 701, NCX 1022, HCT 1026, NCX 1015, NCX 950, NCX 1000, NCX 1020, AZD 4717, NCX 1510/NCX 1512, NCX 2216, and NCX 4040 (all available from NicOx S.A.), S-nitrosoglutathione (GSNO), sodium nitroprusside, V-pyrroNO, S-nitrosoglutathione monoethyl ether (GSNO-ester), 6-(2-hydroxy-1-methyl-nitrosohydrazino)N-methyl-1-hexanamine ( NOC-9) or diethylamine NONOate. Nitric oxide donors as disclosed in US Patent Nos. 5155137, 5366997, 5405919, 5650442, 5700830, 5632981, 6290981, 5691423 5721365, 5714511, 6511911 and 5814666, Chry Selis et al. (2002) J Med Chem. 45:5406-9 (such as NO donors 14 and 17), and Nitric Oxide Donors for Pharmaceutical and Biological Research, Eds: Peng George Wang, Tingwei Bill Cai, Naoyuki

- 29 045683

Taniguchi, Wiley, 2005.

(3) Other substances that increase cGMP concentrations, such as protoporphyrin IX, arachidonic acid and phenyl hydrazine derivatives.

(4) Nitric oxide synthase substrates: e.g. n-hydroxyguanidine analogues such as N[G]-hydroxy-L-arginine (NOHA), 1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine and PR5 (1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine); L-arginine derivatives (such as homo-Arg, homo-NOHA, N-tert-butyloxy- and N-(3-methyl-2-butenyl)oxy-L-arginine, canavanine, epsilon guanidine-caproic acid, agmatine, hydroxylagmatine and L-tyrosyl-L-arginine), N-alkyl-N'-hydroxyguanidines (such as N-cyclopropyl-N'-hydroxyguanidine and N-butyl-N'-hydroxyguanidine), N-aryl-N'-hydroxyguanidines (such as N-phenyl-N'-hydroxyguanidine and para-substituted derivatives, which carry substituents -F, -Cl, -methyl, -OH, respectively); guanidine derivatives such as 3-(trifluoromethyl)propylguanidine; and others described in Cali et al. (2005, Current Topics in Medicinal Chemistry 5: 721-736) and disclosed in the references provided herein.

(5) Compounds that increase eNOS transcription: for example, those described in WO 02/064146, WO 02/064545, WO 02/064546 and WO 02/064565, and related patent documents such as US2003/0008915, US2003/0022935, US2003/ 0022939 and US2003/0055093. Other eNOS transcriptional enhancers including those described in US20050101599 (e.g., 2,2difluorobenzo[1,3]dioxole-5-carboxylic acid indan-2-ylamide and 4-fluoro-N-(indan-2-yl)benzamide) and SanofiAventis compounds AVE3085 and AVE9488 (CA Registry NO. 916514-70-0; Schafer et al., Journal of Thrombosis and Homeostasis 2005; Volume 3, Supplement 1: abstract number P14 87).

(6) NO independent heme independent sGC activators, including but not limited to: BAY 582667 (see patent publication DE19943635)

HMR-1766 (sodium ataciguat, see patent publication WO2000002851)

S3448 (2-(4-chlorophenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)phenyl)benzamide (see patent publication DE19830430 and WO2000002851)

HMR-1069 (Sanofi-Aventis).

(7) Heme-dependent sGC stimulators, including but not limited to: YC-1 (see patent publication EP667345 and DE19744026)

Riociguat (BAY 63-2521, Adempas, commercial product described in DE19834044)

Neliciguat (BAY 60-4552, described in WO 2003095451)

- 30 045683

Vericiguat (BAY 1021189, clinical DE19834047 and DE19942809)

copy for riociguat), BAY 41-2272 (described in

BAY 41-8543 (described in DE19834044)

Etriciguat (described in WO 2003086407)

CFM-1571 (see patent publication WO2000027394)

A-344905, its acrylamide analogue A-350619 and its aminopyrimidine analogue A-778935.

A350-619;

A-344905;

A-778935;

Compounds, (WO2009032249), US20100216764, disclosed in one of the publications: US20100292192, US20110201621,

US20090209556, US8455638, US20110118282

US7947664, US8053455 (WO2009094242),

US8507512, (WO2010099054) US20110218202 (WO2010065275), US20130012511 (WO2011119518), US20130072492 (WO2011149921), US20130210798 (WO20120581 32) and other compounds - 31 045683 described in Tetrahedron Letters (2003), 44(48): 8661-8663.

(8) Compounds that inhibit cGMP degradation, such as:

PDE5 inhibitors such as, for example, sildenafil (Viagra®) and other relevant drugs such as avanafil, lodenafil, mirodenafil, sildenafil citrate (Revatio®), tadalafil (Cialis® or

Adcirca®), vardenafil (Levitra®) and udenafil; alprostadil, and dipyridamole; PF-00489791 PDE9 inhibitors such as PF-04447943.

(9) Calcium channel blockers such as: dihydropyridine calcium channel blockers: amlodipine (Norvasc), aranidipine (Sapresta), azelnidipine (Calblock), barnidipine (NuroCa), benidipine (Coniel), kilnidipine (Atelec, Cinalong, Siscard), clevidipine (Cleviprex), diltiazem, efonidipine (Landel), felodipine (Plendil), lacidipine (Motens, Lacipil), lercanidipine (Zanidip), manidipine (Calslot, Madipine), nicardipine (Cardene, Carden SR), nifedipine (Procardia, Adalat), nilvadipine (Nivadil), nimodipine (Nimotop), nisoldipine (Baymycard, Sular, Syscor), nitrendipine (Cardif, Nitrepin, Baylotensin), pranidipine (Acalas), isradipine (Lomir);

phenylalkylamine calcium channel blockers: verapamil (Calan, Isoptin) N.

II gallopamil (Procorum, D600); benzothiazepines: diltiazem (Cardizem);

non-selective calcium channel inhibitors such as mibefradil, bepridil and fluspirilene, fendilin.

(10) Endothelin receptor antagonists (ERAs): for example, the dual (ETA and ETB) endothelin receptor antagonist bosentan (marketed as Tracleer®); sitaxentan, sold under the name Thelin®; ambrisentan is sold as Letairis® in the US; the dual/non-selective endothelin antagonist actelion-1, which entered clinical trials in 2008.

(11) Prostacyclin derivatives or analogues: for example, prostacyclin (prostaglandin I ₂ ), epoprostenol (synthetic prostacyclin, which is sold as Flolan®); treprostinil (Remodulin®), iloprost (Ilomedin®), iloprost (sold as Ventavis®); oral and inhaled forms of Remodulin®, which are under development; beraprost, an oral prostanoid, is available in Japan and South Korea.

(12) Antihyperlipidemic agents such as: bile acid sequestrants (eg cholestyramine, colestipol, colestilan and colesevelam); statins such as atorvastatin, simvastatin, lovastatin, fluvastatin, pitavastatin, rosuvastatin and pravastatin; cholesterol absorption inhibitors such as ezetimibe; other lipid-lowering agents, such as icosapent ethyl ester, omega-3 acid ethyl esters, reducol; fibric acid derivatives such as clofibrate, bezafibrate, clinofibrate, gemfibrozil, ronifibrate, binifibrate, fenofirate, ciprofibrate, choline fenofibrate; niacin derivatives such as acipimox and niacin; also combinations of statins, niacin, supplements that inhibit intestinal absorption of cholesterol (ezetimibe, etc.) and fibrates; antiplatelet therapy such as clopidogrel bisulfate.

(13) Anticoagulants, such as the following types:

Coumarins (vitamin K antagonists): Warfarin® (Coumadin) mainly used in the US and UK; Acenocoumarol® and Phenprocoumon®, mainly used in other countries;

Phenindione®;

heparin and derivatives such as: heparin; low molecular weight heparin, fondaparinux and idraparinux;

direct thrombin inhibitors such as: argatroban, lepirudin, bivalirudin and dabigatran; ximelagatran (Exanta®), not approved in the United States;

tissue plasminogen activators, used to dissolve blood clots and unblock arteries, such as alteplace.

(14) Antiplatelet drugs: for example, thienopyridines such as lopidogrel and ticlopidine; dipyridamole; aspirin.

(15) ACE inhibitors, for example, the following types: sulfhydryl-containing agents such as captopril (trade name Capoten®), the first ACE inhibitor and zofenopril;

dicarboxylate-containing agents such as enalapril (Vasotec/Renitec®); ramipril (Altace/Tritace/Ramace/Ramiwin®); quinapril (Accupril®), perindopril (Coversyl/Aceon®); lisinopril (Lisodur/Lopril/Novatec/Prinivil/Zestril®) and benazepril (Lotensin®);

- 32 045683 phosphonate-containing substances, such as fosinopril; Natural ACE inhibitors, such as: casokinins and lactokinins, which are breakdown products of casein and whey that occur naturally after ingestion of dairy products, especially fermented milk; lactotripeptides ValPro-Pro and Ile-Pro-Pro produced by the probiotic Lactobacillus helveticus or derived from casein, and also having ACE-inhibiting and antihypertensive functions;

other ACE inhibitors such as alacepril, delapril, cilazapril, imidapril, trandolapril, temocapril, moexipril, spirapril.

(16) Supplemental oxygen therapy.

(17) beta blockers, for example the following types: non-selective agents: Alprenolol®, Bucindolol®, Carteolol®, Carvedilol® (has additional α-blocking activity), Labetalol® (has additional α-blocking activity), Nadolol®, Penbutolol ® (has intrinsic sympathomimetic activity), Pindolol® (has intrinsic sympathomimetic activity), Oxprenonol, Acebutolol, Sotalol, Mepindolol, Celiprolol, Arotinolol, Tertatolol, Amosulalol, Nipradilol, Propranolol® and Timolol®;

b1-selective agents: Acebutolol® (has intrinsic sympathomimetic activity), Atenolol®, Betaxolol®, Bisoprolol®, Celiprolol®, Dobutamine hydrochloride, Irsogladine maleate, Carvedilol, Talinolol, Esmolol®, Metoprolol® and Nebivolol®;

b2-selective agents: Butaxamine® (weak α-adrenergic agonist activity).

(18) Antiarrhythmics such as the following types: type I (sodium channel blockers): quinidine, lidocaine, phenytoin, propafenone type III (potassium channel blockers): amiodarone, dofetilide, sotalol type V: adenosine, digoxin.

(19) Diuretics such as: thiazide diuretics, for example, chlorothiazide, chlorthalidone and hydrochlorothiazide, bendroflumethiazide, cyclopenthiazide, methylclothiazide, polythiazide, quinetasone, xipamide, metolazone, indapamide, cycletanine; loop diuretics such as furosemide and toresamide; potassium-sparing diuretics such as amiloride, spironolactone, potassium canrenoate, eplerenone and triamterene; combinations of these agents; other diuretics such as acetazolamide and carperitide.

(20a) Direct acting vasodilators such as hydralazine hydrochloride, diazoxide, sodium nitroprusside, cadralazine; other vasodilators such as isosorbide dinitrate and isosorbide 5 mononitrate.

(20b) Exogenous vasodilators such as:

Adenocard®, an adenosine agonist, is primarily used as an antiarrhythmic agent;

alpha blockers (which block the vasoconstrictor effect of epinephrine): Alpha-1 adrenergic receptor antagonists such as prazosin, indoramin, urapidil, bunazosin, terazosin, doxazosin atrial natriuretic peptide (ANP);

ethanol;

histamine inducers, which complement the proteins C3a, C4a and C5a, work by causing the release of histamine from mast cells and basophilic granulocytes;

tetrahydrocannabinol (THC), the main active chemical in marijuana, which has minor vasodilatory effects;

papaverine, an alkaloid found in the opium poppy papaver somniferum.

(21) Bronchodilators: There are two main types of bronchodilators, β ₂ agonists and anticholinergics, examples of which are given below:

β ₂ agonists: Salbutamol® or albuterol (generic brand name: Ventolin) and Terbutaline® are short-acting β ₂ agonists for rapid relief of COPD symptoms. Long-acting β ₂ agonists (LABA), such as Salmeterol® and Formoterol®;

Anticholinergics: Ipratropium® is the most widely prescribed short-acting anticholinergic drug. Tiotropium® is the most commonly prescribed long-acting anticholinergic drug for COPD;

Theophylline®, a bronchodilator and phosphodiesterase inhibitor.

(22) Corticosteroids: such as beclomethasone, methylprednisolone, betamethasone, prednisone, prednisolone, triamcinolone, dexamethasone, fluticasone, flunisolide and hydrocortisone, and corticosteroid analogues such as budesonide.

(23) Nutritional supplements such as omega-3 oils; folic acid, niacin, zinc, copper, Korean red ginseng root, ginkgo, pine bark, Tribulus terrestris, arginine, Avena sativa, horny weed, maca root, Muira Puama, saw palmetto and Swedish pollen; vitamin C, vitamin E, vitamin K2; testosterone supplements, transdermal testosterone patch; Zoraxel, naltrexone, bremelanotide (formerly RT-141), melanotan II, hMaxi-K; Prelox: A proprietary blend/combination of natural ingredients, L-Arginine Aspartate and Pycnogenol.

(24) PGD2 receptor antagonists, including, but not limited to, compounds described as having PGD2 antagonistic activity in US Published Applications US20020022218, US20010051624 and US20030055077, PCT Published Applications WO9700853, WO9825919, WO030660 46,

- 33 045683

WO03066047, WO03101961, WO03101981, WO04007451, WO0178697, WO04032848, WO03097042,

WO03097598, WO03022814, WO03022813, and WO04058164, published European patents

EP945450 and EP944614, and listed in: Torisu et al. 2004 Bioorg Med Chem Lett 14:4557, Torisu et al.

2004 Bioorg Med Chem Lett 2004 14:4891, and Torisu et al. 2004 Bioorg & Med Chem 2004 12:4685.

(25) Immunosuppressants such as cyclosporine (Ciclosporin A, Sandimmune® Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (sirolimus, Rapamune®) and other immunosuppressants such as FK506, and mycophenolate, such as mycophenolate mofetil (CellCept ®).

(26) Non-steroidal antiasthmatics such as β _-2 -agonists (eg, terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, salmeterol, bitolterol, and pirbuterol) and β- ₂ -agonist-corticosteroid combinations (eg, salmeterol-fluticasone (Advair®) , formoterol budesonide (Symbicort®), theophylline, cromolyn, cromolyn sodium, nedocromil, atropine, ipratropium, ipratropium bromide, leukotriene biosynthesis inhibitors (zileuton BAY 1005).

(27) Nonsteroidal anti-inflammatory drugs (NSAIDs), such as propionic acid derivatives (eg, alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen , suprofen, tiaprofenic acid and thioxaprofen), acetic acid derivatives (for example, indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclosic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidomethacin and zomepirac) , fenamic acid derivatives (for example, flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (for example, diflunisal and flufenisal), oxicams (for example, isoxicam, piroxicam, sudoxicam and tenoxicam), salicylates (for example , acetylsalicylic acid and sulfasalazine) and pyrazolones (eg apazone, benzpiperylone, feprazone, mofebutazone, oxyphenbutazone and phenylbutazone).

(28) Cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®), rofecoxib (Vioxx®), valdecoxib, etoricoxib, parecoxib, and lumiracoxib; (opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine and pentazocine.

(29) Antidiabetic agents such as insulin and insulin mimetics, sulfonylureas (e.g. glyburide, glibenclamide, glipizide, gliclazide, gliquidone, glimepiride, meglinatide, tolbutamide, chlorpropamide, acetohexamide, tolazamide), biguanides such as metformin (Glucophage®), α-glucosidase inhibitors (such as acarbose, epalrestat, voglibose, miglitol), thiazolidinone compounds, such as rosiglitazone (Avandia®), troglitazone (Rezulin®), ciglitazone, pioglitazone (Actos®) and englitazone; insulin sensitizers such as pioglitazone and rosiglitazone; insulin secretagogues such as repaglinide, nateglinide and mitiglinide; incretin mimetics such as exanatide and liraglutide; amylin analogs such as pramlintide; hypoglycemic agents such as chromium picolinate (possibly in combination with biotin); dipeptidyl peptidase IV inhibitors such as sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin; vaccines currently being developed to treat diabetes; AVE-0277, Alum-GAD, BHT-3021, IBC-VS01; cytokine targeted therapy in development for diabetes such as anakinra, canakinumab, diacerein, gevokizumab, LY-2189102, MABP-1, GIT-027.

(30) HDL cholesterol increasing drugs such as Anacetrapib, MK-524A, CER001, DRL-17822, dalcetrapib, JTT-302, RVX-000222, TA-8995.

(31) Antiobesity drugs such as methamphetamine hydrochloride, amfepramone hydrochloride (Tenuate®), phentermine (Ionamin®), benzphetamine hydrochloride (Didrex®), phendimetrazine tartrate (Bontril®, Prelu-2®, Plegine®), mazindol ( Sanorex®), Orlistat (Xenical®), sibutramine hydrochloride monohydrate (Meridia®, Reductil®), Rimonabant (Acomplia®), Amfepramone, Chromium Picolinate, RM-493, TZP-301; combinations such as phentermine/topiramate, bupropion/naltrexone, sibutramine/metformin, bupropion SR/zonisamide SR, salmeterol, xinafoate/fluticasone propionate; lorcaserin hydrochloride, phentermine/topiramate, bupropion/naltrexone, cetilistat, exenatide, KI-0803, liraglutide, metformin hydrochloride, sibutramine/metformin, 876167, ALS-L1023, bupropion SR/zonisamide SR, cOrT-108297, canagliflozin, peak Chromium Olinate, GSK -1521498, LY-377604, metreleptin, obinepitide, P-57AS3, PSN-821, salmeterol xinafoate/fluticasone propionate, sodium tungstate, somatropin (recombinant), TM-30339, TTP-435, tesamorelin, tesofensine, wellneperit, zonisamide, BMS -830216, ALB-127158, AR-1030, ATHX-105, AZD-2820, AZD-8329, beloranib hemioxalate, CP-404, HPP404, ISIS-FGFR4RX, insulinotropin, KD-3010PF, 05212389, PP-1420, PSN- 842, peptide YY3-36, resveratrol, S234462; S-234462, sobetir, TM-38837, tetrahydrocannabivarin, ZYO-1, beta-lapachone.

(32) Angiotensin receptor blockers such as losartan, valsartan, candesartan cilexetil, eprosaran, irbesartan, telmisartan, olmesartran medoxomil, azilsartan medoxomil.

(33) Renin inhibitors such as aliskiren hemifumirate.

(34) Centrally acting alpha-2 adrenergic agonists such as methyldopa, clonidine, guanfacine.

- 34 045683 (35) Adrenergic neuron blockers, such as guanethidine, guanadrel.

(36) I-1-imidazoline receptor agonists such as rilmenidine dihydrogen phosphate and moxonidine hydrochloride hydrate.

(37) Aldosterone antagonists such as spironolactone and eplerenone.

(38) Potassium channel activators such as pinacidil.

(39) Dopamine D1 agonists such as fenoldopam mesylate; other dopamine agonists such as ibopamine, dopexamine and docarpamine.

(40) 5-HT2 antagonists such as ketanserin.

(42) Vasopressin antagonists such as tolvaptan.

(43) Calcium channel sensitizers such as levosimendan or activators such as nicorandil.

(44) PDE-3 inhibitors such as amrinone, milrinone, enoxymone, vesnarinone, pimobendan, olprinone.

(45) Adenylate cyclase activators such as colforsine dapropate hydrochloride.

(46) Positive inotropes such as digoxin and methyldigoxin; metabolic cardiotonic agents such as ubidecarenone; brain natriuretic peptides such as nesiritide.

(47) Drugs used to treat erectile dysfunction, such as alprostadil, aviptadil, phentolamine mesylate, Weige, alprostadil.

(48) Anti-obesity drugs.

Medicines available on the market for the treatment of obesity Methamphetamine hydrochloride (Desoxyn) Abbott Noradrenergic, alpha- and beta-adrenergic receptor agonists 1943 (U.S.) amfepramone hydrochloride (Tenuate) Sanofi Norepinephrine release stimulator 1959 (U.S.) phentermine (lonamine) UCB Celltech Norepinephrine release stimulator 1959 (U.S.) benzphetamine hydrochloride (Didrex) Pfizer Norepinephrine release stimulator 1960 (U.S.) phendimetrazine tartrate (Bontril, Prelu- 2, Plegine) Pfizer Norepinephrine release stimulator 1961 (U.S.) mazindol (Sanorex) Novartis reverse inhibitor capture norepinephrine 1973 (U.S.) Orlistat (Xenical) Roche Pancreatic lipase inhibitor 1998 (New Zealand)

(49) Medicines used to treat Alzheimer's disease: for example, cholinesterase inhibitors prescribed for the treatment of mild to moderate Alzheimer's disease, including Razadyne® (galantamine), Exelon® (rivastigmine) and Aricept® (donepezil), Cognex® (tacrine); Namenda® (memantine), an N-methyl D-aspartate (NMDA) antagonist and Aricept®, indicated for the treatment of moderate to severe Alzheimer's disease; vitamin E (antioxidant).

(50) Antidepressants: tricyclic antidepressants such as amitriptyline (Elavil®), desipramine (Norpramin®), imipramine (Tofranil®), amoxapine (Asendin®), nortriptyline; selective serotonin reuptake inhibitors (SSRIs), such as paroxetine (Paxil®), fluoxetine (Prozac®), sertraline (Zoloft®), and citralopram (Celexa®); and others such as doxepin (Sinequan®) and trazodone (Desyrel®); SNRIs (eg, venlafaxine and reboxetine); dopaminergic antidepressants (eg, bupropion and amineptine).

(51) Neuroprotective agents: for example, memantine, L-dopa, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, neuroprotective agents currently under investigation, including anti-apoptotic drugs (CEP 1347 and CTCT346), lazaroids, bioenergetics, anti-gluta-

- 35 045683 matergic agents and dopamine receptors. Other clinically evaluated neuroprotective agents include, for example, monoamine oxidase B inhibitors, selegiline and rasagiline, dopamine agonists, and complex I mitochondrial enrichment coenzyme Q10.

(52) Antipsychotics: for example, ziprasidone (Geodon™), risperidone (Risperdal™), and olanzapine (Zyprexa™).

(53) NEP inhibitors such as sacubitril, omapatrilat.

(54) Methylene blue (MB).

Sets.

The solid forms and pharmaceutical compositions described herein may be included in the kit. A kit may include one or more doses of two or more agents, each individually packaged or formulated, or one or more doses of two or more agents, each packaged or formulated in combination. Thus, one or more agents may be present in the first container, and the kit may further include one or more agents in the second container. The container or containers are placed in a package, and the package may further include instructions for use or dosage. The kit may include additional components such as syringes or other means for administering agents, as well as diluents or other preparation means. Thus, the kits may include: a) a pharmaceutical composition containing a compound described herein and a pharmaceutically acceptable carrier, excipient or diluent; and b) container or package. The kits may optionally contain instructions describing the method of using the pharmaceutical compositions in one or more of the methods described herein (eg, to prevent or treat one or more of the diseases and disorders described herein). The kit may optionally contain a second pharmaceutical composition containing one or more additional agents described herein for use in cotherapy, a pharmaceutically acceptable carrier, excipient or diluent. A pharmaceutical composition containing a compound described herein and a second pharmaceutical composition contained in the kit may optionally be combined in one pharmaceutical composition.

The kit includes a container or package for containing pharmaceutical compositions, and may also include divided containers, such as a divided vial or a divided foil pouch. The container may be, for example, a paper or cardboard box, a glass or plastic bottle or jar, a resealable pouch (for example, to store tablet fill for placement in another container), or a blister pack of individual doses for extrusion from the package according to the therapeutic regimen. Provision is made for the inclusion of more than one container in a single package for the sale of a single dosage form. For example, the tablets may be contained in a bottle, which in turn is contained in a box.

An example of a set is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules and the like). Blister packs typically consist of a sheet of relatively rigid material covered with a film of preferably clear plastic material. During the packaging process, indentations are formed in the plastic foil. The recesses are sized and shaped to accommodate individual tablets or capsules to be packaged or may be sized and shaped to accommodate multiple tablets and/or capsules to be packaged. The tablets or capsules are then placed into the recesses accordingly and a sheet of relatively rigid material is sealed onto the plastic foil on the side opposite the recesses. As a result, the tablets or capsules are individually sealed or collectively sealed, as desired, in recesses between the plastic film and the sheet. Preferably, the strength of the sheet is such that tablets or capsules can be removed from the blister pack by hand by applying pressure to the indentations, thereby creating a hole in the sheet at the indentation. Tablets or capsules can be removed through the specified opening.

It may be advisable to provide a written notice containing information and/or instructions to the physician, pharmacist, or subject regarding when to use the drug. The daily dose may be in one tablet or capsule, or in several tablets or capsules to be taken on a given day. If the kit contains separate compositions, the daily dose of one or more compositions of the kit may consist of a single tablet or capsule, while the daily dose of another or more compositions of the kit may consist of several tablets or capsules. The kit may take the form of a dispenser designed to dispense daily doses one at a time in the order of their intended use. The dispenser can be equipped with a reminder to further facilitate compliance with the regimen. An example of such a reminder is a mechanical counter that indicates the number of daily doses that have been dispensed. Another example of such a reminder is a battery-powered memory chip coupled to a liquid crystal readout or a reminder tone that, for example, reads the date of the last daily dose that was taken and/or reminds when the next dose is due.

Examples

Example 1. Preparation of crude compound I.

i) Coupling of compound (1') and N,O-dimethylhydroxylamine to give N-methoxy-Nmethylisoxazole-3-carboxamide (2')

(12')

Isooxazole-3-carboxylic acid ((1'), 241.6 g, 2137 mmol, 1.0 eq.), toluene (1450 ml) and DMF (7.8 g, 107 mmol, 0.05 eq.) were loaded into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The resulting suspension was heated to 45-50°C. Oxalyl chloride (325 g, 2559 mmol, 1.2 eq.) was then charged through the addition funnel over 2 hours, maintaining the reaction temperature at 45 to 50° C., and vigorous evolution of gas was observed. After addition, a brown mixture was obtained. The brown mixture was heated to 87-92°C for 1 hour and stirred at 8792°C for 1 hour. The reaction was complete by HPLC. During heating, the brown mixture turned into a dark solution. The reaction was monitored by quenching a portion of the reaction mixture in piperidine and monitoring piperidine amide using HPLC. The dark mixture was cooled to 20-25°C and then filtered through a sintered glass funnel to remove any insoluble matter. The dark filtrate was concentrated under reduced pressure to a volume of 400 ml dark oil.

Potassium carbonate (413 g, 2988 mmol, 1.4 eq.) and water (1000 ml) were charged into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The reaction solution was cooled to -10 - -5°C. N,Ο-dimethylhydroxyamine hydrochloride (229 g, 2348 mmol, 1.1 eq.) was charged into a suitable reaction vessel and dissolved in water (1000 ml). A solution of N,Odimethylhydroxyamine and dichloromethane (2500 ml) was then charged into the potassium carbonate solution.

The above dark oil (400 ml) was then slowly charged through the dropping funnel, maintaining the reaction temperature between -10 and 0°C. The addition was slightly exothermic and a brown mixture was obtained after the addition. The mixture was stirred at 0-5°C for 20 minutes and then heated to 20-25°C. The lower organic layer was collected, and the upper aq. the layer was extracted with dichloromethane (400 ml). The combined organic layers were washed with 15% sodium chloride solution (1200 ml). The organic layer was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give intermediate (2') as a dark oil (261.9 g, 97 wt% yield 76%, 3 wt% toluene by 1H-NMR, water content 0.04 wt% according to KF). 1H-NMR (500 MHz, CDCI3) δ ppm 8.48 (s, 1H); 6.71(s, 1H); 3.78 (s, 3H); 3.38 (s, 3H).

ii) Alkylation of compound (2') and ethyl propiolate to give (E)-ethyl 4-(isoxazol-3-yl)-2(methoxy(methyl)amino)-4-oxobut-2-enoate (3')

(2') (3')

Intermediate (2') (72.2 g, 96 wt% 444 mmol, 1.0 eq), ethyl propiolate (65.7 g, 670 mmol, 1.5 eq) and anhydrous THF (650 ml) were loaded into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The solution was cooled to -65--55°C. Sodium bis(trimethylsilyl)amide in THF (1 M, 650 mL, 650 mmol, 1.46 eq.) was then slowly charged through the addition funnel, maintaining the reaction temperature at -65 to -55°C. The mixture was stirred at a temperature below -55°C for 10 minutes after completion of addition. Then they loaded 1N. HCl (650 ml, 650 mmol, 1.46 eq.) to quench the reaction, the reaction temperature was maintained below -20°C, followed by the immediate addition of ethyl acetate (1500 ml) and water (650 ml). The upper ethyl acetate layer was collected and the lower aqueous layer was extracted with ethyl acetate (800 ml). The combined organic layers were washed with 10% citric acid (1000 ml) and saturated sodium chloride solution (650 ml). The organic layer was concentrated under reduced pressure to give a dark oil.

The dark oil was dissolved in dichloromethane/ethyl acetate/heptane solution (150 ml/100 ml/100 ml). The solution was applied to a layer of silica gel (410 g) and the silica gel layer was eluted with ethyl acetate/heptane (1/1 v/v). The filtrate (~3000 ml) was collected and then concentrated under reduced pressure to a volume of 150 ml to obtain a suspension on standing. Heptane (200 ml) was then added to the suspension and the suspension was concentrated under reduced pressure to a volume of 150 ml. The resulting suspension was filtered and the filter cake was washed with heptane (150 ml). The filter cake was then air dried overnight to give intermediate (3') as a brown solid (63.4 g, 56% yield, >99% HPLC purity). 1H-NMR (500 MHz, CDCl ₃ ) δ ppm 8.42 (d, J=1.53 Hz, 1H);

- 37 045683

6.76 (d, J=1.53 Hz, 1H); 6.18 (s, 1H); 4.47 (kv, J=7.07 Hz, 2H); 3.75 (s, 3H); 3.21 (s, 3H); 1.41 (t, J=7.17 Hz,

3H).

iii) Cyclization of compound 3' and 2-fluorobenzylhydrazine to give ethyl 1-(2-fluorobenzyl)-5(isoxazol-3-yl)-1H-pyrazol-3-carboxylate (4')

Intermediate (3') (72.9 g, 287 mmol, 1.0 eq) and absolute ethanol (730 ml) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer.

The mixture was cooled to 0-5°C. 2-fluorobenzylhydrazine (48.2 g, 344 mmol, 1.2 eq.) was then charged into the mixture. The mixture was stirred at 0-10°C for 1 hour and then heated to 20-25°C and stirred at 2025°C for 16 hours. The reaction was complete by HPLC. Concentrated HCl (33.9 g, 37 wt%, 34 4 mmol, 1.2 eq.) was charged into the reaction mixture for 1 min and the temperature of the mixture was exothermed from 20°C to 38°C. A suspension was obtained. The mixture was cooled to 0-10°C for 1 hour and stirred at 0-10°C for 1 hour. The resulting suspension was filtered and the filter cake was washed with ethanol (200 ml). The filter cake was dried under vacuum at 30-40°C for 16 hours to give intermediate (4') as an off-white solid (81.3 g, 90% yield, >99% HPLC purity). 1H-NMR (500 MHz, CDCl ₃ ) δ ppm 8.47 (d, J=1.68 Hz, 1H); 7.15-7.26 (m, 2H); 6.94-7.08 (m, 2H); 6.77-6.87 (m, 1H); 6.55 (d, J=1.68 Hz, 1H); 5.95 (s, 2H); 4.43 (kV, J=7.02 Hz, 2H); 1.41 (t, J=7.17 Hz, 3H).

iv) Amination of compound (4') to give 1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3carboximidamide hydrochloride (5'B)

(4') (SB)

Anhydrous ammonium chloride (267 g, 4991 mmol, 5.0 eq.) and toluene (5400 ml) were charged into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. Trimethylaluminum in toluene (2 M, 2400 ml, 4800 mmol, 4.8 eq.) was added slowly through the addition funnel, maintaining the reaction temperature at 20-40°C (note: methane gas was observed to evolve during addition). The mixture was then heated to 75-80°C for 30 minutes to obtain a clear white solution. Intermediate (4') (315 g, 999 mmol, 1.0 eq) was added to the reaction mixture in four equal portions over 1 hour at 75-90°C. The reaction mixture was stirred at 80-90°C for 30 minutes and then heated to 100-110°C and stirred at 100-110°C for 3 hours. The reaction was completed by HPLC. The reaction mixture was cooled to 10-20°C and methanol (461 g, 14.4 mol, 14.4 eq.) was slowly added through the addition funnel, maintaining the reaction temperature at 10-40°C. Note: The quenching was very exothermic and large amounts of gas were released. A thick suspension was obtained. 3n. HCl (6400 ml, 3N, 19.2 mol, 19.2 eq.) was then slowly charged through the addition funnel, maintaining the reaction temperature at 20-45°C. The mixture was heated to 80-85°C and stirred at 80-85°C for 10 minutes to obtain a pure two-phase mixture. The mixture was cooled to 0-5°C for 3 hours and stirred at 0-5°C for 1 hour. The resulting suspension was filtered and the filter cake was washed with water (3000 ml). The filter cake was dried under vacuum at 40-50°C for 24 hours to give intermediate (5'B) as an off-white solid (292 g, 91% yield, >99% HPLC purity). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.52 (s, 2H); 9.33 (s, 2H); 9.18 (d, J=1.53 Hz, 1H); 7.88 (s, 1H); 7.29-7.38 (m, 1H); 7.19-7.25 (m, 1H); 7.10-7.16 (m, 1H); 7.03 (d, J=1.53 Hz, 1H); 6.92-6.98 (m, 1 N); 5.91 (s, 2H). M.R. 180-185°C.

v) Cyclization of compound (5'B) and diethyl fluoromalonate to give 5-fluoro-2-(1-(2-fluorobenzyl)5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4, 6-diol (6')

(5'B) (6·)

- 38 045683

Intermediate (5'B) (224.6 g, 698 mmol, 1.0 eq), methanol (2250 ml) and diethyl fluoromalonate (187 g, 1050 mmol, 1.5 eq) were charged to a suitable reaction vessel, equipped with a mechanical stirrer and digital thermometer. Sodium methoxide in methanol solution (567 g, 30 wt.% 3149 mmol, 4.5 eq.) was then charged through a dropping funnel, maintaining the reaction temperature at 20-35°C. The mixture was stirred at 20-35°C for 30 minutes and a light suspension was obtained. The reaction was complete according to HPLC. Solution 1.5 N. HCl (2300 ml, 3450 mmol, 4.9 eq.) was charged through the addition funnel over 1 hour while maintaining the reaction temperature at 20-30°C. A white suspension was obtained. The pH of the reaction mixture should be ~1 according to the pH of the paper. The suspension was stirred at 20-3 0°C for 30 minutes. The resulting suspension was filtered, and the filter cake was washed with a premixed solution of methanol and water (500 ml/500 ml), and then with water (1000 ml). The filter cake was dried under vacuum at 50-60°C for 16 hours to give intermediate (6') as an off-white solid (264 g, 97% yield, >99% HPLC purity). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.82 (brs, 1H); 12.31 (br.s, 1H); 9.14 (d, J=1.53 Hz, 1 N); 7.55 (s, 1H); 7.31-7.37 (m, 1H); 7.18-7.25 (m, 1H); 7.10-7.15 (m, 2H); 6.97-7.02 (t, J=7.55 Hz, 1H); 5.88 (s, 2H).

vi) Chlorination of compound (6') to obtain 3-(3-(4,6-dichloro-5-fluoropyrimidin-2-yl)-1-(2fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (7')

(6') (7')

Intermediate (6') (264 g, 711 mmol, 1.0 eq), acetonitrile (4000 ml) and N,Ndimethylaniline (138 g, 1137 mmol, 1.6 eq) were charged to a suitable reaction vessel equipped with mechanical stirrer and digital thermometer. The suspension mixture was heated to 70-80°C. Phosphorus oxychloride (655 g, 4270 mmol, 6.0 eq.) was then charged through the addition funnel over 1 hour while maintaining the reaction temperature at 70-80°C. The mixture was stirred at 75-80°C for 22 hours and a brown solution was obtained. The reaction was complete according to HPLC. The mixture was then cooled to 0 to

5°C and cotton-like solids precipitated at 25°C. Water (3000 ml) was slowly added through a dropping funnel, maintaining the reaction temperature at 0-10°C. The suspension was stirred at 0-10°C for 30 minutes. The resulting suspension was filtered, and the filter cake was washed with a pre-mixed solution of acetonitrile and water (500 ml/500 ml). The filter cake was dried under vacuum at 35-45°C for 16 hours to give intermediate (7') as an off-white solid (283 g, 98% yield, >99% HPLC purity). 1I-NMR (500 MHz, CDCl ₃ ) δ ppm 8.48 (d, J=1.68 Hz, 1H); 7.44 (s, 1H); 7.19-7.25 (m, 1H); 6.96-7.08 (m, 2H); 6.81-6.88 (m, 1H); 6.60 (d, J=1.68 Hz, 1H); 6.03 (s, 2H).

vii) Substitution of compound (7') with methoxide to give 3-(3-(4-chloro-5-fluoro-6methoxypyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole ( 8')

Methanol (3400 ml) and sodium methoxide in methanol (154 ml, 5.4 M, 832 mmol, 1.2 eq.) were charged into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The reaction mixture was heated to 23-27°C. Intermediate (7') (283 g, 693 mmol, 1.0 eq.) was added to the mixture in small portions (5-10 g each portion) over 40 min, maintaining the reaction temperature at 23-27°C. The suspension was stirred at 23-27°C for 30 minutes. The reaction was complete according to HPLC. The resulting suspension was filtered and the filter cake was washed with methanol (850 ml) and then water (850 ml). The filter cake was dried under vacuum at 35-45°C for 16 hours to give intermediate (8') as an off-white solid (277 g, 99% yield, 97% HPLC purity). ¹ H-NMR (500 MHz, CDCl ₃ ) δ ppm 8.47 (d, J=1.83 Hz, 1H); 7.38 (s, 1H); 7.18-7.25 (m, 1H); 7.01-7.08 (m, 1H); 6.94-7.00 (m, 1H); 6.81-6.88 (m, 1H); 6.60 (d, J=1.68 Hz, 1H); 6.00 (s, 2H); 4.21 (s, 3H).

viii) Hydrogenation of compound (8') to obtain 3-(3-(5-fluoro-4-methoxypyrimidin-2-yl)-1-(2-39 045683 fluorobenzyl)-1H-pyrazol-5-yl) isoxazole (9 ')

Intermediate (8') (226 g, 560 mmol, 1.0 eq), palladium (10% on activated carbon, nominally 50% water wet, 22.6 g, 0.01 mol, 0.018 eq), tetrahydrofuran (3400 ml) and triethylamine (91 g, 897 mmol, 1.6 eq.) were charged into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. Nitrogen was bubbled into the reaction mixture through Teflon tubes for 10 min at 20–30°C. The mixture was then heated to 40-50°C and hydrogen gas was bubbled into the reaction mixture through Teflon tubes for 6 hours, maintaining the reaction temperature at 40-50°C. The reaction was complete according to HPLC. Nitrogen was then bubbled into the reaction mixture through Teflon tubes for 10 min at 40-50°C. The reaction mixture was hot filtered through Hypo Supercel™ and the filter cake was washed with tetrahydrofuran (2000 ml). The filtrate was concentrated under reduced pressure to a volume of ~1300 ml to obtain a suspension. Tetrahydrofuran was then replaced by methanol under reduced pressure by continuously feeding methanol (3000 ml). The final volume after replacing the solvent was 1300 ml. The resulting suspension was filtered and the filter cake was washed with methanol (500 ml). The filter cake was dried under vacuum at 20-25°C for 16 hours to give intermediate (9') as a white solid (192 g, 93% yield, 98% HPLC purity). 1I-NMR (500 MHz, CDCl ₃ ) δ ppm 8.47 (d, J=1.68 Hz, 1H); 8.41 (d, J=2.59 Hz, 1H); 7.36 (s, 1H); 7.17-7.24 (m, 1H); 6.95-7.07 (m, 2H); 6.83-6.90 (m, 1H); 6.60 (d, J=1.68

Hz, 1H); 5.99 (s, 2H); 4.19 (s, 3H).

ix) Demethylation of compound (9') to give 5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)1H-pyrazol-3-yl)pyrimidin-4-ol (10 ')

Intermediate (9') (230 g, 623 mmol, 1.0 eq), MeOH (3450 ml) and conc. HCl (307 g, 37 wt.% 3117 mmol, 5.0 eq.) was charged into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The mixture was heated to 62-65°C and a solution was obtained. Then the mixture was stirred at 60-65°C for 17 hours and a suspension was obtained. The reaction was completed according to data

HPLC. The suspension was cooled to 20-25°C for 2 hours and stirred at 20-25°C for 30 minutes. The resulting suspension was filtered and the filter cake was washed with methanol (1000 ml). The filter cake was dried under vacuum at 35-45°C for 16 hours to give intermediate (10') as a white solid (214 g, 97% yield, >99% HPLC purity). ^1H -NMR (500 MHz, DMSO d6) δ ppm 12.90-13.61 (brs, 1H); 9.11 (d, J=1.68 Hz, 1H); 8.16 (s, 1H); 7.64 (s, 1H); 7.29-7.42 (m, 1H); 7.17

7.28 (m, 2H); 7.08-7.15 (m, 1H); 6, 97 (s, 1H); 5, 91 (s, 3H).

x) Chlorination of compound (10') to obtain 3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2 fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (formula IV)

Intermediate (10') (214 g, 602 mmol, 1.0 eq), acetonitrile (3000 ml) and N,Ndimethylaniline (109 g, 8-99 mmol, 1.5 eq) were charged to a suitable reaction vessel equipped with mechanical stirrer and digital thermometer. The suspension mixture was heated to 70-80°C. Phosphorus oxychloride (276 g, 1802 mmol, 3.0 eq.) was then charged through the dropping funnel over 30 min.

- 40 045683 maintaining the reaction temperature of 70-80°C. The mixture was stirred at 75-80°C for 2 hours and a green solution was obtained. The reaction was complete according to HPLC. Then the mixture was cooled to 0-5°C. Water (1500 ml) was slowly added through a dropping funnel, maintaining the reaction temperature at 0-10°C. The suspension was stirred at 0-10°C for 30 minutes. The resulting suspension was filtered and the filter cake was washed with a pre-mixed solution of acetonitrile and water (500 ml/500 ml) and water (500 ml). The filter cake was dried in vacuo at 30-40°C for 16 hours to obtain intermediate of formula IV as a white to pink solid (214 g, 95% yield, >99% HPLC purity). 1H NMR (500 MHz, CDCl ₃ ) δ ppm 8.65 (s, 1H); 8.48 (d, J=1.68 Hz, 1H); 7.44 (s, 1H); 7.21-7.25 (m, 1H); 6.97-7.06 (m, 2H); 6.83-6.87 (m, 1H); 6.61 (d, J=1.68 Hz, 1H); 6.03 (s, 2H).

a) Cyanation of intermediate (15) to give 2-(bromomethyl)-3,3,3-trifluoro-2((trimethylsilyl)oxy)propanenitrile (16) o si _Br II _F Me ₃ SiCN q _CN

Π '%<

(15) (16)

Trimethylsilanecarbonitrile (153 g, 1.54 mol, 0.97 eq.) and triethylamine (4.44 ml, 3.22 g, 0.032 mol, 0.02 eq.) were charged into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer . The mixture was cooled to 5°C. 3-Bromo-1,1,1-trifluoropropan-2-one ((15), 304 g, 1.59 mol, 1.0 eq.) was charged through a dropping funnel over 35 min, maintaining the reaction temperature between 10 and 20 °C. The mixture was stirred at 20-30°C for 3 hours after addition to obtain intermediate (16) as a thick oil, which was used directly in the next step. 1H-NMR (500 MHz, CDCl ₃ ) δ ppm 3.68 (d, J=11.14 Hz, 1H); 3.57 (d, J=11.14 Hz, 1H), 0.34-0.37 (m, 9H).

b) Conversion of the nitrile of compound (16) to the amide to give 2-(bromomethyl)-3,3,3-trifluoro-2hydroxypropanamide (17)

Concentrated sulfuric acid (339 mL, 6.37 mol, 4.0 eq.) was stirred in a suitable reaction vessel equipped with a mechanical stirrer, digital thermometer and addition funnel. Sulfuric acid was heated to 45°C. The above intermediate (16) was added through a dropping funnel over 50 minutes, keeping the temperature below 75°C. The reaction mixture was stirred at 75 °C for 2 h and then allowed to cool to room temperature. ¹ H-NMR showed that the reaction was complete.

The reaction mixture was cooled to -15°C and diluted with ethyl acetate (1824 ml) through a dropping funnel over 45 minutes (very exoteric), maintaining the temperature between -15 and 5°C. Water (1520 ml) was added slowly through a dropping funnel over 1 hour 20 minutes (very exoteric) from -10 to 0°C. The layers were separated and the organic layer was washed with 15% aqueous sodium chloride (1520 ml), 25% aqueous sodium carbonate (911 ml), and then 15% aqueous sodium chloride (911 ml). The organic layer was filtered and concentrated under reduced pressure to obtain 348 g of intermediate (17) as a light yellow oil. This oil was dissolved in methanol (1200 ml) and concentrated to give 380 g of intermediate (17). (296 g adjusted weight, 79% yield). 1H-NMR (500 MHz, CDCl ₃ ) δ 6.61-6.94 (m, 1H); 5.92-6.26 (m, 1H); 3.93-4.00 (m, 1H); 3.68 (d, J=11.14 Hz, 1H).

c) N-Alkylation of compound (17) to obtain 2-(aminomethyl)-3,3,3-trifluoro-2hydroxypropanamide (14)

BUT _CH CONH ₂ mu but conh ₂

Br^X^F ^NH3 _r H^X^F

Pf MeOH P ^F (17) (14)

7n. a solution of ammonia in methanol (600 ml, 4.28 mol, 10 eq.) was charged into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The solution was cooled to 0-5°C. Intermediate (17) (102 g, 0.432 mol, 1 eq) was then added via addition funnel over 30 min at 0-5°C. The reaction mixture was heated to 20-25°C for 1 hour and kept for 72 hours. The reaction was completed according to HPLC. The reaction mixture was cooled to 0-5°C and sodium methoxide (78 ml, 5.4 M, 0.421 mol, 0.97 eq.) was added over 2 minutes. The reaction mixture was then concentrated under reduced pressure to a volume of 300 ml. Added 2 l of ethyl acetate and concentrate

- 41 045683 the reaction was continued under reduced pressure to a volume of up to 700 ml to obtain a suspension. 700 ml of ethyl acetate was added to the suspension to bring the final volume to 1400 ml. 102 ml of water was added and stirred for 2 minutes to obtain a two-phase solution. The layers were separated. The ethyl acetate layer was concentrated under reduced pressure to a volume of 600 ml. The ethyl acetate layer was concentrated under reduced pressure to a volume of 600 ml. The ethyl acetate layer was then heated to >60°C and heptane (600 ml) was added slowly from 55 to 60°C. The mixture was cooled to 15-20°C to obtain a suspension. The suspension was stirred at 15-20°C for 2 hours and filtered. The solids were dried in vacuo at 25°C for 16 hours to give amine (14) as a white solid (48 g, 64% yield). 'H-NMR (500 MHz, MeOH-d4) δ ppm 2.94 (d, J= 13.73 Hz, 1H); 3.24 (d, J=13.58 Hz, 1H).

d) Chiral resolution of amine (14) as a 1:1 salt of (R)-2,2-dimethyl-5-(trifluoromethyl)oxazolidine5-carboxamide (18A) and (D)-malic acid.

o o ₀ ^ΗΟ γ^ΟΗ HN^NH ₂ (ISA) and ιι _ \ -Yr

Ji O OH λ-ο ^CF 3 nh ₂ ---------------------------► I o ^{H0 CF} 3 acetone Ηθ^γΛ _οΗ o he (14)

Amine (14) (105 g, 0.608 mol, 1.0 eq.), (D)-malic acid (82 g, 0.608 mol, 1.0 eq.) and acetone (1571 ml) were charged into a suitable reaction vessel equipped with mechanical stirrer and digital thermometer. The reaction mixture was stirred at 20-25°C for 16 hours. The resulting suspension was filtered and the wet precipitate was washed with acetone (300 ml). The wet precipitate was returned to the reaction vessel and acetone (625 ml) was charged. The suspension was heated to 53°C and kept for 6 hours. The suspension was cooled to 20-25°C and kept at this temperature for 16 hours. The suspension was filtered and the wet precipitate was washed with acetone (200 ml). The wet residue was dried in vacuo at 40°C for 4 hours to obtain 82.4 g of salt (18A) and (D)-malic acid 1:1 as a white solid (82.4 g, 39% yield, 97 % e.i.). 1I-NMR (500 MHz, D ₂ O) δ ppm 4.33 (br.s, 1H); 3.61 (lat, J=13.58 Hz, 1H); 3.40-3.47 (m, 1H); 2.76 (lat, J=15.87 Hz, 1H); 2.53-2.63 (m, 1H); 2.16 (br.s, 4H).

e) 1:1 coupling of (D)-malic acid salt of intermediate (18A) and formula IV to give (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-( 2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)-2-hydroxypropanamide (compound I)

A 1:1 salt of intermediate (18A) and (D)-malic acid (74.1 g, 0.214 mol, 2.5 eq.) and water (44.8 ml) were charged into a suitable reaction vessel equipped with a mechanical stirrer and digital thermometer. The reaction mixture was heated to 70°C and stirred for 20 minutes. The acetone formed during the reaction was removed by purging with nitrogen. The reaction mixture was cooled to 3040°C and the compound of formula IV (32 g, 0.086 mol, 1.0 eq.), DMSO (448 ml) and Hunig's base (44.7 ml, 0.257 mol, 3.0 eq.) was charged. The reaction mixture was heated to 90°C and stirred at 90°C for 17 hours. The reaction was completed by HPLC. The mixture was then cooled to 60°C. The mixture was then cooled to 60°C. Another portion of Hunig's base (104 ml, 0.599 mol, 7.0 eq.) was charged, then water (224 ml) at 55-62°C. The reaction mixture was stirred for 15 minutes at 55-60°C to form a seed layer. Water (320 ml) was added through a dropping funnel at 55-62°C over 30 minutes, and the resulting suspension was stirred for 1 hour at 55-60°C. The resulting suspension was filtered and the filter cake was washed with a pre-mixed solution of methanol and water (320 ml/320 ml), then with water (640 ml). The filter cake was then dried in vacuo at 40°C for 16 hours to give Compound I as an off-white solid (40 g, 92% yield, 99% HPLC purity, 98% ee). 1I-NMR (500 MHz, DMSO4) δ ppm 9.10 (s, 1H); 8.33 (d, J=2.90 Hz, 1H); 7.93 (s, shir, 1H); 7.90 (s, 1H); 7.78 (s, shir, 1H); 7.69 (s, shir, 1H); 7.52 (s, 1H); 7.33 (kV, J=7.02 Hz, 1H); 7.17-7.25 (m, 1H); 7.17-7.25 (m, 1H); 7.10 (t, J=7.48 Hz, 1H); 6.98 (t, J=7.55 Hz, 1H); 5.90 (s, 2H); 3.92-4.05 (m, 2H).

The relationship between crude compound I and its polymorphs, Form A, Form B, Form D, Form E, Form F, Form G and Form H, is illustrated in FIG. 12.

- 42 045683

Example 2 Recrystallization of crude (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5(isoxazol-3-yl)-1 H-pyrazole -3-yl)pyrimidin-4-yl)amino)methyl)-2-hydroxypropanamide (crude compound I) into polymorph form B.

Crude compound I (0.68 kg, 1.33 mol) and acetonitrile (20.4 L) were charged into a 30 L jacketed reaction vessel. The reaction mixture was stirred at low speed and heated to 70-75°C until most of the solids dissolved. The solution in a 30 L jacketed reaction vessel was flow-filtered through a gas dispersion tube (large frit) into a 100 L jacketed reaction vessel. The reaction mixture was then heated to 70-75°C and water (20.4 L) was charged, maintaining the batch temperature >65°C for 1 hour. The reaction mixture was cooled to 52-62°C and stirred for a minimum of 1 hour at 52 -62°C to form the seed layer. The resulting suspension was cooled to 0-5°C for at least 4 hours and kept at 0-5°C for at least 1 hour. The suspension was filtered and the filter cake was washed with a pre-mixed solution of acetonitrile and water (3.4 l/3.4 l). The filter cake was then dried in vacuo at 90-100°C for a minimum of 30 hours to obtain compound I as polymorph B as a white solid (0.58 kg, 85% yield). ¹ H-NMR (500 MHz, DMSO-d6) δ ppm 9.10 (s, 1H); 8.33 (d, J=2.90 Hz, 1H); 7.93 (s, shir, 1H); 7.90 (s, 1H); 7.78 (s, shir, 1H); 7.69 (s, shir, 1H); 7.52 (s, 1H); 7.33 (kV, J=7.02 Hz, 1H); 7.17-7.25 (m, 1H); 7.17-7.25 (m, 1H); 7.10 (t, J=7.48 Hz, 1H); 6.98 (t, J=7.55 Hz, 1H); 5.90 (s, 2H); 3.92-4.05 (m, 2H).

Example 3. Recrystallization of crude (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5(isoxazol-3-yl)-1H-pyrazol- 3-yl)pyrimidin-4-yl)amino)methyl)-2-hydroxypropanamide (compound I) into polymorphic form E.

A 5 L four-neck round bottom flask equipped with a mechanical stirrer, condenser, dropping funnel, nitrogen inlet/outlet, thermocouple and heat-cooler was charged with crude compound I (67.4 g, 132 mmol) and methanol (2500 mL). The mixture was heated to >60°C (eg, above 70°C) to obtain a solution. The solution was filtered and the filtrate was heated to >60°C. Water (1500 ml) was added to the mixture while maintaining the temperature >60°C. The mixture was allowed to cool to room temperature over 1 hour and kept at this temperature for 1 hour. The suspension was filtered and the filter cake was washed with methanol/water (600 ml, 1/1 v/v). The filter cake was collected and dried in vacuo at 80°C for 72 hours to obtain compound I as polymorph E as a white solid (59.5 g, 88% yield).

Example 4A. Recrystallization of polymorphic form E (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3- yl)pyrimidin-4-yl)amino)methyl)-2-hydroxypropanamide into polymorphic form A.

Compound I as polymorph E (19.3 g, 38 mmol) was charged into a 1 L, 4-round bottom flask equipped with a mechanical stirrer, condenser, addition funnel, nitrogen inlet/outlet, thermocouple, and heat/cool tank. ethyl acetate (600 ml). The mixture was heated to >70°C to obtain a solution. The solution was filtered and the filtrate was stirred at 20-25°C for 16 hours to obtain a suspension. The suspension was concentrated in vacuo to a final volume of ~150 ml. Heptane (300 ml) was added to the suspension over 20 min and the mixture was concentrated in vacuo to a final volume of ~350 ml. The suspension was filtered and the filter cake was washed with heptane (50 ml). The filter cake was collected and dried in vacuo at 100°C for 3 hours to obtain polymorph A as a white solid (19.1 g, 99% yield).

Example 4B. Recrystallization of crude (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5(isoxazol-3-yl)-1H-pyrazol-3-yl )pyrimidin-4-yl)amino)methyl)-2-hydroxypropanamide (compound I) into polymorphic form A.

Polymorph Form A was also prepared directly from crude compound I by isolation from ethyl acetate in a manner similar to that described in Example 4A, using crude compound I instead of Form E as the starting material.

Polymorph Form A was also obtained directly from crude compound I by isolation from DMSO/water after heating at a temperature higher than 60°C.

Polymorph Form A was also isolated when crude compound I was suspended in any of the solvents heptane, (isopropyl acetate)IPAC, ethanol, ethyl acetate or decane at room temperature and left to stir for 14-30 hours. Samples were filtered and residual solids were analyzed using powder X-ray diffraction.

Example 5A. Recrystallization of polymorphic form E (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3- yl)pyrimidin-4-yl)amino)methyl)-2-hydroxypropanamide to polymorph form D.

Compound I in the form of polymorphic form E (14.0 g, 28 mmol) and n -decan (560 ml). The mixture was heated to 145-155°C and kept at 14 5-155°C for 45 minutes. The resulting suspension was cooled to 20-30°C for 1 hour and then filtered. The filter cake was washed with heptane (280 ml).

- 43 045683

The filter cake was collected and dried in vacuo at 80°C for 72 hours to give Compound I as Form D as a white solid (12.9 g, 92% yield).

Example 5B. Other methods for obtaining polymorphic form D.

Polymorph Form D was also prepared by heating many other polymorphs (pure) at 180°C, as shown in FIG. 12 and described below. In some embodiments, Compound I is heated to produce a Form D polymorph. In some embodiments, a Form F polymorph is heated to produce a Form D polymorph. In some embodiments, a Form B polymorph is heated to produce a Form D polymorph. In some embodiments, the Form B polymorph is heated to produce a Form D polymorph. Form E is heated to produce a Form D polymorph. In some embodiments, a Form G polymorph is heated to produce a Form D polymorph. In some embodiments, a Form H polymorph is heated to produce a Form D polymorph.

Compound I, Form F, Form B, Form E, Form G or Form H (5 g) was charged into a 100 ml round bottom flask. The solid was heated to 18 0°C and kept at 180°C for 5 minutes. All of the solid compound I slowly melts and dissolves to give a solid. The solid was ground using a mortar and pestle to obtain ~4.8 g of powder. HPLC showed 99.8% purity. Powder X-ray diffraction showed it to be form D. DSC showed a sharp peak at 196°C.

Example 6: Obtaining Form F.

A new polymorphic form F was obtained when form A was heated alone at 160°C. This form appears unstable at room temperature and has not been isolated pure.

Example 7 Recrystallization of crude (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5(isoxazol-3-yl)-1H-pyrazole -3-yl)pyrimidin-4-yl)amino)methyl)-2-hydroxypropanamide (compound I) to polymorph form G.

A flask equipped with a stirrer was charged with crude compound I (2.0 g) and acetone (15.0 ml). The mixture was stirred at room temperature (22-25°C) for two hours. The resulting suspension was then filtered. The filter cake was washed with acetone (5 ml). The filter cake was collected and dried under vacuum at 40°C for 15 hours to obtain the form G polymorph as a white solid.

Polymorph Form G was also prepared by stirring polymorph Form H, obtained as described below, in acetone at room temperature, followed by filtration and drying in vacuo at 30-40°C.

Example 8. Recrystallization of crude (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5(isoxazol-3-yl)-1H-pyrazol- 3-yl)pyrimidin-4-yl)amino)methyl)-2-hydroxypropanamide into the polymorphic form H.

A flask equipped with a stirrer was charged with crude compound I (2.0 g) and acetone (15.0 ml). The mixture was heated to 45-50°C and stirred until a solution was formed. The hot solution was then filtered and slowly cooled to room temperature with stirring. Stir for an additional 15 hours and the resulting suspension was then filtered. The filter cake was washed with acetone (5 ml). The filter cake was collected and dried in vacuo at 40°C for 15 hours to obtain polymorphic form H as a white solid.

Example 9. Characteristics of the polymorph.

X-ray powder diffraction (XRPD).

Powder X-ray diffraction traces were obtained using a D8 Advance, Bruker; using one of two methods:

Scan 5-45° 2-theta, step size 0.02°, 1 s per step or scan 3-40° 2-theta, step size 0.037°, 1.5 s per step.

Fourier transform infrared spectroscopy (FTIR).

FTIR traces were acquired using a Nicolet iS10 FTIR device from ThermoFisher Scientific.

Method: analyzed by attenuated total internal reflection with 32 scans and resolution 4 in the wavenumber range 525-4000 cm ^-1 with a background obtained before each measurement.

Example 10. Preparation of HCl salt.

Protocol 1: 50.5 mg of compound I as its polymorph D and 98.2 ml of 1 M HCl were suspended in 2 ml of i-PrOH. The suspension was stirred at a temperature from 20 to 40°C. A heating rate of 40°C/hour and a cooling rate of 5°C/hour were used. After 8 days, the suspension was filtered and the solid was dried under vacuum (approx. 5 mbar, 1 hour).

Protocol 2: 299.9 mg of compound I as its polymorph form D and a few crystals of the hydrochloric acid salt obtained above (from protocol 1) were suspended in 5 ml of i-PrOH. Then 589 ml of 1 M HCl and 5 ml of i-PrOH were added and the suspension was stirred at a temperature ranging from 20 to 40°C. A heating rate of 40°C/h and a cooling rate of 5°C/h were used. After 6 days, the suspension was filtered and the solid was dried under vacuum (approximately 5 mbar, 1 hour).

- 44 045683

Example 11. Characteristics of HCl salt.

The HCl salt of compound I is characterized by the powder X-ray diffraction pattern in FIG. eleven.

The HCl salt of compound I was characterized by elemental analysis giving measured and calculated values for the 1:1 ratio (form D:HCl) shown in the table below.

Element Measured values Calculated values Form D:HC1=1:1 WITH 45.8% wt. 46.2% wt. N 3.3% wt. 3.1% wt. N 18.0% wt. 18.0% wt. 0 8.8% wt. 8.8% wt. C1 6.3% wt. 6.5% wt.

The terminology used herein is intended to describe specific embodiments only and is not intended to limit the invention. As used herein, singular forms are intended to also include plural forms unless the context clearly indicates otherwise. It will further be understood that the terms contain (and any forms thereof, such as contains and containing), have (and any forms thereof, such as has or having), include (and any forms thereof, such as includes and including) and accommodate ( and any of its forms, such as contains and containing) and any other grammatical variants thereof are open linking verbs. As a result, a method or means that contains, has, includes or accommodates one or more steps or elements has the one or more steps or elements, but is not limited to having only the one or more stages or elements. Likewise, a method step or agent element that contains, has, includes or accommodates one or more features has those one or more features, but is not limited to having only one or more features. In addition, a method or structure that is configured in a certain way is configured in at least that way, but may also be configured in ways that are not listed.

As used herein, the terms containing, has, including, containing, and other grammatical variations thereof include the terms consisting of and consisting essentially of.

The phrase consisting primarily of or grammatical variations thereof, when used herein, shall be taken to indicate the claimed features, integers, steps or components, but does not preclude the addition of one or more additional features, integers, steps, components or groups thereof, but only if their additional features, integers, stages, components or groups do not significantly change the basic and new characteristics of the claimed composition, means or method.

All publications cited herein are incorporated herein by reference as if each individual publication were specifically and individually identified for inclusion by reference herein as if fully set forth.

Subject matter incorporated by reference is not intended to be an alternative to any of the limitations of the claims unless otherwise indicated.

Where one or more ranges are mentioned herein, it is intended that each range is intended to provide a concise presentation of information, where the range is intended to cover every discrete point within the range as if it were fully set forth herein.

Although several aspects and embodiments of the present invention have been described and illustrated herein, alternative aspects and embodiments may be contemplated by those skilled in the art to achieve the same objectives. Accordingly, the present disclosure and the accompanying claims are intended to cover all such additional and alternative aspects and embodiments that fall within the true spirit and scope of the invention.

Claims (10)

1. Crystalline free form of Form A of Compound I Compound I, characterized by peaks in the powder X-ray diffraction pattern including 6.0, 18.3, 19.3, 20.2 and 22.0 °2θ. 2. Crystalline free form of Form A of compound I according to claim 1, further characterized by peaks in the powder x-ray diffraction pattern including 6.0, 8.5, 9.5, 12.4-12.9, 13.4, 17.1 , 18.3, 19.3, 20.2, 22.0, 30.1 and 34.1 °2θ. 3. Crystalline free form of Form A of compound I according to claim 1, further characterized by peaks in the powder x-ray diffraction pattern including 6.0, 6.7, 8.5, 9.5, 10.9, 12,412.9, 13.4 , 16.2, 17.1, 18.3, 19.3, 20.2, 22.0, 23.0, 24.1-24.8, 25.8, 30.1 and 34.1 °2θ . 4. Crystalline free form of Form A of compound I according to claim 1, further characterized by peaks in the powder X-ray diffraction pattern including 6.1 (80.81% rel. int.), 9.6 (40.35%), 12.6 (41.26%), 13.6 (43.19%), 18.4 (53.57%), 19.4 (100.00%), 20.3 (57.01%) and 22.0 (56.64) °2θ. 5. Crystalline free form of Form A of compound I according to any one of claims 1 to 4, further characterized by an IR spectrum which shows a band with a maximum at 1730 cm ^-1 . 6. A method for obtaining crystalline free form A of compound I according to any one of claims 1 to 5, including the following steps: a) dissolving crystalline free form E of compound I in ethyl acetate at a temperature above 70°C to obtain a solution wherein form E is characterized by peaks in the powder x-ray diffraction pattern selected from 7.4, 18.8-19.3, 21.1, 24 .8 and 25.5 °2θ; b) filtering the specified solution and stirring the resulting filtrate at 20-25 ° C for 16 hours to form a suspension; c) concentrating, filtering and drying said suspension under vacuum. 7. A method for obtaining crystalline free form A of compound I according to any one of claims 1 to 5, including the following steps: a) dissolving the crude compound I in ethyl acetate at a temperature above 70°C to obtain a solution; b) filtering the said solution and stirring the resulting filtrate at 20-25°C for 16 hours to form a suspension and c) concentrating, filtering and drying said suspension under vacuum. 8. A method for obtaining crystalline free form A of compound I according to any one of claims 1 to 5, including the following steps: a) heating the crude compound I in DMSO at a temperature above 60°C to form a solution; b) adding water to form a slurry and c) filtering said suspension to isolate the crystalline free form of Form A. 9. A method for obtaining crystalline free form A of compound I according to any one of claims 1 to 5, including the following steps: a) suspending the crude compound I in a solvent selected from heptane, isopropyl acetate, ethanol, ethyl acetate or decane or a mixture thereof; b) stirring for 14-30 hours at room temperature and c) filtering to the specified suspension and drying in vacuum. 10. A pharmaceutical composition containing a crystalline free form of compound I according to any one of claims 1 to 5 and at least one pharmaceutically acceptable excipient or carrier.