Solid forms of sgc stimulator

Abstract

To provide novel crystalline solid forms of a specific stimulator of soluble guanylate cyclase (sGC).SOLUTION: A novel crystalline solid form of Compound I, exemplified by Form E, which is a crystalline free form characterized by one or more peaks in the XRPD spectrum selected from 7.4, 18.8-19.3, 21.1, 24.8, and 25.5° 2θ.SELECTED DRAWING: None

Description

[Technical Field]

[0001]

[0001] The present disclosure relates to solid forms of stimulators of soluble guanylate cyclase (sGC). Methods for preparing these solid forms are also provided herein. The present invention also relates to pharmaceutical formulations and dosage forms comprising these solid forms and their use, alone or in combination with one or more additional agents, for treating and / or preventing various diseases or disorders that may benefit from sGC stimulation or increased concentrations of nitric oxide (NO) and / or cyclic guanosine monophosphate (cGMP). [Background technology]

[0002]

[0002] sGC is the primary 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 levels of cGMP in turn regulate the activity of downstream effectors, including protein kinases, phosphodiesterases (PDEs), and ion channels.

[0003]

[0003] In the body, NO is synthesized from arginine and oxygen by various nitric oxide synthases (NOS) and by the sequential reduction of inorganic nitrate. Three distinct isoforms of NOS have been identified: inducible NOS (iNOS or NOS II), found in activated macrophage cells; resident neuronal NOS (nNOS or NOS I), involved in neurotransmission and long-term potentiation; and resident endothelial NOS (eNOS or NOS III), which regulates smooth muscle relaxation and blood pressure. Experimental and clinical evidence indicates that reduced NO concentration or bioavailability and / or decreased responsiveness to endogenously produced NO contribute to the development of disease.

[0004]

[0004] NO-independent, heme-dependent sGC stimulators exhibit several important distinguishing features compared with sGC activators, including a critical dependence of their activity on the presence of the reduced prosthetic heme moiety, strong synergistic enzyme activation upon binding with NO, and NO-independent direct stimulation of sGC to stimulate cGMP synthesis. The benzylindazole compound YC-1 was the first sGC stimulator identified. Additional sGC stimulators with improved potency and sGC specificity have since been developed.

[0005]

[0005] Compounds that stimulate sGC in an NO-independent manner offer significant advantages over other current alternative treatments that target the aberrant NO pathway. There is a need to develop novel, well-characterized sGC stimulators. Compound I is an sGC stimulator with demonstrated efficacy for the treatment of multiple NO-related disorders in preclinical models. Compound I was previously described as a pale orange solid in WO2014144100, Example 1. Compound I may exist in various crystalline forms and may also form several pharmaceutically acceptable salts.

[0006]

[0006] The properties of a solid state related to its effectiveness as a drug may depend on the form of the solid. For example, in a drug substance, variations in solid form may result in differences in properties such as solubility and dissolution rate, surface properties (e.g., wettability), powder properties (flow, adhesion, bulk density, mixing behavior, compressibility, static electricity, etc.), tablet properties (hardness, homogeneity, friability, disintegration, stability to heat and humidity, etc.), oral absorption, bioavailability, storage properties (caking, hygroscopicity), toxicology results, and clinical trial results.

[0007]

[0007] Characterization of polymorphs is useful for preventing certain problems that arise during clinical trials and / or commercialization of a drug, for example, to avoid inconsistencies between drug substance and product (e.g., lot-to-lot inconsistencies), hydration or dehydration of hydrates, chemical degradation, amorphization or polymorphic transformation in the formulation. A polymorph may also be preferred if it improves solubility and / or bioavailability compared to another polymorph of the compound or its amorphous form. A polymorph may also be preferred because it confers increased physical or chemical stability, provides a higher melting point (leading to improved mechanical properties), has a more acceptable taste or odor, or has a more neutral pH, etc. Summary of the Invention [Problem to be solved by the invention]

[0008] In one aspect, the present invention provides a crystalline solid form of Compound I, shown below:

[0009] [ka]

[0010] Regarding. For purposes of this disclosure, "Compound I" refers to the free base or hydrochloride salt of the structure displayed above, unless otherwise specified. Compound I, as its crystalline free base, is known to be highly polymorphic, possessing seven crystalline forms (Forms A, B, D, E, F, G, and H), as well as multiple solvates. Compound I was previously described in WO2014144100, Example 1, as a pale orange solid.

[0011] In one embodiment, the crystalline solid form of Compound I disclosed herein is a polymorph of the free base. In another embodiment, the crystalline solid form of Compound I is the hydrochloride salt. In one embodiment, the polymorphs of Compound I are the crystalline free base form. In another embodiment, they are solvates.

[0012] 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 present invention relates to a pharmaceutical composition comprising one or more polymorphs of Compound I disclosed herein, or the hydrochloride salt of Compound I, and at least one pharmaceutically acceptable excipient or carrier. In another embodiment, the present invention relates to a pharmaceutical dosage form comprising said pharmaceutical composition.

[0013] In another embodiment, the present invention relates to a method of treating a disease, condition, or disorder in a subject in need thereof, comprising administering to the subject, alone or in combination therapy, a therapeutically effective amount of a polymorph of Compound I disclosed herein, or a mixture of polymorphs thereof, or a hydrochloride salt thereof; the disease or disorder resulting from sGC stimulation or NO and / or cGMP stimulation. The disease or disorder may benefit from increased concentrations of [Brief explanation of the drawings]

[0014] [Figure 1] FIG. 1 shows an XRPD pattern of an amorphous form of Compound I. [Figure 2] FIG. 1 shows overlaid XRPD patterns (scaled and offset from bottom to top) of Forms A, B, D and E in the 2-theta scale range of 5-45. [Figure 3A] FIG. 1 shows the XRPD pattern of Form A in the 2-theta-scale range of 5 to 45. [Figure 3B] FIG. 1 shows the XRPD patterns of Form A before and after 14 months of storage. [Figure 3C] FIG. 1 shows the XRPD pattern of Form A in the 2-theta-scale range of 3 to 40. [Figure 4A] FIG. 1 shows the XRPD pattern of Form B in the 2-theta-scale range of 5 to 45. [Figure 4B] FIG. 1 shows the XRPD patterns of Form B before and after 14 months of storage. [Figure 4C] FIG. 1 shows the XRPD pattern of Form B in the 2-theta-scale range of 3-40. [Figure 5A] FIG. 1 shows the XRPD pattern of Form D in the 2-theta-scale range of 5 to 45. [Figure 5B] FIG. 1 shows the XRPD patterns of Form D before and after 14 months of storage. [Figure 5C] FIG. 1 shows the XRPD pattern of Form D in the 2-theta-scale range of 3 to 40. [Figure 6] FIG. 1 shows the XRPD pattern of Form E in the 2-theta-scale range of 5 to 45. [Figure 7] FIG. 1 shows the XRPD pattern of Form F in the 2-theta-scale range of 3 to 40. [Figure 8] FIG. 1 shows the XRPD pattern of Form G in the 2-theta-scale range of 3 to 40. [Figure 9] FIG. 1 shows the XRPD pattern of Form H in the 2-theta-scale range of 3 to 40. [Figure 10] FIG. 1 shows the overlaid FT-Raman spectra (bottom to top, scaled, offset) of Forms A, B, D, and E in the wavenumber range of 1800-200 cm −1 . [Figure 11] FIG. 1 shows the XRPD pattern of the HCl salt of Compound I in the 2-theta-scale range of 0 to 40. [Figure 12] FIG. 1 shows the relationship between crude Compound I, polymorphic Form A, Form B, Form D, Form E, Form F, Form G and Form H.

[0015]

[0014] The figures are provided as examples and are not intended to limit the scope of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0016] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that it is not intended to limit the invention to those embodiments. Rather, the invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present invention as defined by the claims. The present invention is directed to the This includes, but is not limited to, any methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention. In the event that one or more incorporated literature references, patents, or similar materials differ from or conflict with this application, including but not limited to defined terms, terminology usage, described techniques, etc., this application controls.

[0017] Definitions and General Terms For purposes of this disclosure, chemical elements are identified based on the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Edition, 1994. Additionally, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th Edition, Smith, M.B. and March, J., eds. John Wiley & Sons, New York: 2001, which are incorporated herein by reference in their entireties.

[0018]

[0017] The present disclosure also encompasses isotopically labeled compounds, which are identical to those cited herein except that one or more atoms are replaced by an atom having an atomic mass or mass number different from that typically found in nature. All isotopes of any particular atom or element specified are considered within the scope of the compounds of the invention, and their uses. m isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively. 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. Certain isotopically labeled compounds of the invention (e.g., 3 H and 14 C-labeled compounds) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes are useful for their ease of preparation and detectability. Additionally, deuterium (i.e., 2 Substitution with heavier isotopes, such as H), may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances. 15 O. 13 N, 11 C, and 18Positron-emitting isotopes such as F are useful for positron emission tomography (PET) studies to assess substrate receptor occupancy. Isotopically labeled compounds of the invention can generally be prepared by procedures similar to those disclosed in the Schemes and / or Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0019] As used herein, a "solid form" of Compound I is characterized by or describes a particular solid-state lattice structure (at the unit cell scale) of said compound. A compound such as Compound I can exist in its "neat form" or "free base form," which can be either crystalline or amorphous. The free base form of a compound is formed solely by molecules of the compound.

[0020]

[0020] As used herein, "amorphous" or "amorphous form" is a solid form that does not have long-range molecular order and therefore lacks a characteristic X-ray powder diffraction pattern (XRPD).

[0021]

[0021] A "crystal" or "crystalline body" is a homogeneous solid formed by a repeating three-dimensional pattern of atoms, ions, or molecules with constant distances between the elements. The term "crystal" may also be used to refer to the unit cell of such a pattern.

[0022] As used herein, "crystallization" is a process that results in the formation of solid crystals from a solution, melt, vapor, a different solid phase, or, more rarely, direct deposition from a gas. Crystallization can be a natural or artificial process. Crystallization is also a chemical solid-liquid separation technique in which mass transfer of a solute occurs from a liquid solution to a pure solid crystalline phase.

[0023] As used herein, "polymorphism" refers to the ability of a compound (e.g., Compound I) to exist in more than one crystalline form or to crystallize in different crystalline structures. A "polymorph" is each different crystalline structure of a compound (e.g., Compound I). A polymorph is a crystalline structure of the free form of a compound (i.e., a crystalline free form) or a solvate thereof (i.e., a "multicomponent crystalline form") when a compound, such as Compound I, crystallizes with a solvent. In some embodiments, when the crystallization solvent is water, the solvate is a hydrate.

[0024] As used herein, "solvate" refers to an association or complex of one or more solvent molecules (molecules of a substance that is liquid at room temperature) with a compound (e.g., Compound I) in a crystalline form, resulting in a crystalline solid of novel characteristics. This disclosure describes several "ansolvates" of the free base form of Compound I (i.e., solid forms of Compound I that are in crystalline free form and are not solvates).

[0025]

[0025] There are other types of solid forms that can be formed. For example, when both compounds in a multi-component crystal are independently solid when present at room temperature, the resulting solid form is called a "co-crystal."

[0026] When one of the components in the solid form significantly transfers a proton to the other component and the components of the resulting multi-component crystal are ionic, the resulting solid form is called a "salt."

[0027] In a cocrystal, no ion transfer occurs between the different components in solid form, and as a result, the resulting components exist in non-ionic form. In a cocrystal, the two (or more) components of a multicomponent crystal are solid and non-ionic when they exist independently of each other at room temperature.

[0028]

[0028] When two substances are mixed, whether a salt or a co-crystal forms depends on how large the difference between the pKa of the two components is.

[0029] The present disclosure describes one solid form of Compound I, which is a salt (hydrochloride salt).

[0029]

[0030] There are many crystallization techniques available that allow one skilled in the art to obtain crystalline materials. For crystallization to occur from a solution, the solution must be "supersaturated." This means that the solution must contain more dissolved solute entities (molecules or ions) than would be present under thermodynamic equilibrium conditions (a saturated solution). This can be achieved by a variety of methods, including: 1) "cooling crystallization"; 2) the addition of a second solvent to reduce the solubility of the solute (a technique known as "anti-solvent crystallization"); 3) chemical reaction; 4) pH change; and 5) slurry conversion in organic and / or aqueous solvent systems, which are the most common methods used in industrial operations. Other methods, such as "solvent evaporation crystallization," can also be used. As used herein, "supersaturation" is the difference between the concentration of a solution (C) and the concentration at equilibrium (C*) at the same temperature. It is measured in concentration units.

[0030]

[0031] The term "chemically stable" characterizes a solid form (e.g., a polymorph or salt) of Compound I such that it can be maintained at defined conditions, e.g., 40°C / 75% relative humidity, for example, 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, etc. , 12 months, 18 months, 24 months, or longer, does not decompose into one or more new, different chemical compounds. In some embodiments, under the specified conditions, less than 25% of the Compound I polymorph decomposes; in some embodiments, less than 20%, 15%, 10%, 5%, 3%, 1%, or 0.5% of the Compound I polymorph decomposes. In some embodiments, no detectable amount of a given Compound I polymorph decomposes under the specified conditions after a specified period of time (as determined by the lowest detection limit of the analytical technique used).

[0031]

[0032] The term "physically stable" characterizes a crystalline solid form (e.g., a polymorph or salt) of Compound I such that the crystalline solid form does not change to one or more different crystalline solid forms (e.g., a polymorph that changes to a different polymorph of Compound I as measured by analytical techniques such as XRPD) or amorphous forms when exposed to defined conditions, such as, for example, 40°C / 75% relative humidity, for a defined period of time, such as, 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 crystalline solid form of Compound I changes to one or more different solid forms (another crystalline solid form or amorphous form) when exposed to the defined conditions. In some embodiments, when exposed to the specified conditions, 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 forms of Compound I convert to one or more different crystalline solid forms or amorphous forms of Compound I. In some embodiments, no detectable amount of a given solid form of Compound I converts to one or more different solid forms of Compound I under the specified conditions.

[0032]

[0033] The term "substantially pure," when referring to a designated crystalline solid form of Compound I (e.g., a polymorph or salt of Compound I described herein), means that the designated crystalline solid form contains less than 20% (by weight) of residual components (such as alternate polymorph(s) or amorphous forms of Compound I, or additional solvent molecules or impurities). In other embodiments, a substantially pure crystalline solid form of Compound I contains less than 10% (by weight) of alternate polymorph(s) or amorphous forms of Compound I, or additional solvent molecules or impurities. In other embodiments, it contains less than 5% (by weight) of alternate polymorph(s) or amorphous forms of Compound I, or additional solvent molecules or impurities. In yet other embodiments, it contains less than 1% (by weight) of alternate polymorph(s) or amorphous forms of Compound I, or additional solvent molecules or impurities.

[0033]

[0034] The term "substantially similar," as used herein, when describing a spectrum, trace, heat curve, etc., means that the characteristic of the indicated solid form of Compound I (e.g., a polymorph or salt of Compound I described herein) is described as containing less than 10% of peaks that differ from the peaks in the spectrum, trace, or curve assigned to the particular solid form of Compound I for which the spectrum, trace, heat curve, etc. is depicted and discussed herein. In other embodiments, this includes less than 5% of different peaks. In yet other embodiments, this includes less than 1% of different peaks.

[0034]

[0035] In comparing XRPD spectra, when a spectrum is "substantially similar" to those shown in the present disclosure for a particular solid form of Compound I, characteristic peaks in the spectrum are measured at the same °2θ values as those shown in a figure of the present disclosure, or within a range of + or -0.5 units of °2θ from those of the peaks shown in the figure. The XRPD of a solid form of Compound I is considered to be "essentially unchanged" after a particular length of time and under particular conditions if the XRPD of the solid form is "substantially similar" before and after the particular length of time and under the particular conditions.

[0035]

[0036] The present disclosure often refers to the evaluation of chemical, physical, or biological parameters disclosed herein. Those skilled in the art will understand that such parameters may be substituted with other chemical, physical, or biological parameters not disclosed herein that are essentially similar with respect to identifying solid forms.

[0036] Embodiment

[0037] In one aspect, the present invention provides a crystalline solid form of Compound I, shown below:

[0037] [ka]

[0038] Regarding. Compound I is an sGC stimulator with demonstrated efficacy in preclinical models for the treatment of multiple NO-related disorders. Compound I can exist in various crystalline forms, or polymorphs. Some of these polymorphs are crystalline free base forms. Other polymorphs are solvates. In some embodiments, the solvates are hydrates. Compound I also forms several pharmaceutically acceptable salts, including its hydrochloride salt.

[0039] In one embodiment, the solid form of Compound I disclosed herein is a polymorph. In another embodiment, the solid form of Compound I is its hydrochloride 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 pale orange solid.

[0040] In one embodiment, the crystalline solid form of Compound I is polymorphic Form E. Form E is formed when crude Compound I, prepared as described in the Examples section, is dissolved in MeOH at >60° C. (e.g., >70° C.) to obtain a solution, followed by filtration, and the filtrate is heated to >60° C., water is added, cooled to room temperature (rt), followed by filtration and drying under vacuum at 80° C. for 72 hours.

[0041] In another embodiment, the crystalline solid form of Compound I is polymorphic Form A. Form A is formed when Compound I is dissolved in ethyl acetate at >70° C. to obtain a solution, followed by filtration, and the filtrate is further stirred at 20-25° C. for 16 hours to obtain a slurry, which is concentrated under vacuum, heptane is added, and the resulting slurry is further concentrated, filtered, and dried under vacuum at 100° C. for 3 hours.

[0042] In another embodiment, polymorphic form A can be prepared by dissolving polymorphic form E in ethyl acetate at >70°C to obtain a solution, followed by filtration, and further stirring the filtrate at 20-25°C for 16 hours to obtain a slurry, concentrating the slurry under vacuum, adding heptane, and further stirring the resulting slurry. The resulting product is concentrated to 100° C., filtered, and dried under vacuum at 100° C. for 3 hours.

[0043]

[0043] In another embodiment, polymorphic form A can be obtained directly from crude compound I by heating in DMSO at a temperature above 60°C, followed by the addition of water to form a slurry, and filtering the slurry.

[0044] In another embodiment, polymorph Form A is also isolated when crude Compound I is slurried in a solvent at room temperature and allowed to stir for 14 to 30 hours. In some embodiments, the solvent is selected from heptane, isopropyl acetate (IPAC), ethanol, ethyl acetate, or decane, or a mixture thereof. The slurry is then filtered and dried under vacuum.

[0045] In another embodiment, the solid form of Compound I is polymorphic 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 obtain a slurry, followed by cooling the slurry to 20-30° C. over 1 hour, filtering, and drying under vacuum at 80° C. for 72 hours.

[0046]

[0046] In another embodiment, Form D can be formed by heating any of the polymorphic forms Form E, Form B, Form F, Form G or Form H, or a mixture thereof, neat (in the absence of solvent) at 180°C.

[0047] In another embodiment, the solid form of Compound I is polymorphic 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, and cooling to 52-62°C to form a slurry, which is cooled to 0-5°C over 4 hours, filtered, and dried under vacuum at 90-100°C for a minimum of 30 hours.

[0048] In another embodiment, the solid form of Compound I is polymorphic Form F. Form F is obtained when Form A, prepared as described in the Examples section, is heated, neat, to 160°C.

[0049] In another embodiment, the solid form of Compound I is polymorphic Form G. Form G is obtained when crude Compound I, prepared as described in the Examples section, is slurried in acetone at ambient temperature for 2 hours, followed by filtration and drying under vacuum at 30-40° C. In another embodiment, polymorphic Form G is obtained when polymorphic Form H is stirred in acetone at rt (room temperature), followed by filtration and drying under vacuum at 30-40° C.

[0050] In another embodiment, the solid form of Compound I is polymorphic Form H. Form H can be obtained 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 slurry, and then stirring at room temperature for 5 hours, followed by filtration and drying under vacuum at 30-40°C.

[0051] In one embodiment, the solid form of Compound I is polymorphic Form A.

[0052] In some embodiments, Form A is characterized by an FT-Raman spectrum substantially similar to that shown in FIG.

[0052]

[0053] In some embodiments, Form A has an IR spectrum of 1730 cm -1It is characterized by showing a band maximum at

[0054] In some embodiments, Form A is substantially the same as that shown in FIG. 2 or FIG. 3A. It is characterized by a similar XRPD spectrum.

[0053]

[0055] In other embodiments, Form A is characterized by one or more peaks in an XRPD spectrum selected from: 6.0, 18.3, 19.3, 20.2, and 22.0 °2θ.

[0054]

[0056] In other embodiments, Form A is characterized by one or more peaks in an XRPD spectrum 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.

[0055]

[0057] In other embodiments, Form A is characterized by one or more peaks in an XRPD spectrum 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, 24.1-24.8, 25.8, 30.1, and 34.1 °2θ.

[0056]

[0058] In some embodiments, Form A is characterized by an XRPD spectrum substantially similar to that shown in Figure 3C.

[0059] In other embodiments, Form A is characterized by one or more peaks in an XRPD spectrum selected from: 6.1 (80.81% relative intensity or rel int), 18.4 (53.57%), 19.4 (100.00%), 20.3 (57.01%), and 22.0 (56.64) °2θ.

[0057]

[0060] In other embodiments, Form A is characterized by one or more peaks in an XRPD spectrum selected from 6.1 (80.81% relative intensity), 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.

[0058]

[0061] In other embodiments, Form A is characterized by exhibiting an XRPD trace that is essentially unchanged when stored for 14 months under stability conditions of 40° C. and 75% relative humidity. The XRPD traces for Form A before and after storage under these conditions are shown in FIG. 3B.

[0059]

[0062] In one embodiment, the solid form of Compound I is polymorphic Form B.

[0063] In some embodiments, Form B is characterized by an FT-Raman spectrum substantially similar to that shown in FIG.

[0060]

[0064] In some embodiments, Form B has an IR spectrum of 1200 cm -1 It is characterized in that it exhibits a peak maximum at

[0065] In some embodiments, Form B is characterized by an XRPD spectrum substantially similar to that shown in Figure 2 or Figure 4A.

[0061]

[0066] In another embodiment, Form B has a molecular weight of 18.8 to 19.1 o It is characterized by one or more peaks in the XRPD spectrum at 2θ.

[0067] In another embodiment, Form B is characterized by one or more peaks in an XRPD spectrum selected from 8.8, 16.4, 17.2, 18.8-19.1, 20.1, and 21.1-21.6 °2θ.

[0062]

[0068] In another embodiment, Form B is 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.

[0063]

[0069] In some embodiments, Form B is characterized by an XRPD spectrum substantially similar to that shown in Figure 4C.

[0070] In other embodiments, Form B is characterized by one or more peaks in an XRPD spectrum selected from 8.9 (76.55% relative intensity), 17.4 (57.67%), 19.1 (100.00%), and 25.5 (52.26) °2θ.

[0064]

[0071] In other embodiments, Form B is characterized by one or more peaks in an XRPD spectrum selected from: 7.0 (44.44% relative intensity), 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.

[0065]

[0072] In other embodiments, Form B is characterized by exhibiting an XRPD trace that is essentially unchanged when stored for 14 months under stability conditions of 40° C. and 75% relative humidity. The XRPD traces for Form B before and after storage under these conditions are shown in FIG. 4B.

[0066]

[0073] In one embodiment, the solid form of Compound I is polymorphic Form D.

[0074] In some embodiments, Form D is characterized by an FT-Raman spectrum substantially similar to that shown in FIG.

[0067]

[0075] In some embodiments, Form D has an IR spectrum of 1665, 1639 and 968 cm -1 In some embodiments, Form D is characterized in that its IR spectrum exhibits a band maximum at 1665 cm -1 In other embodiments, Form D is characterized in that its IR spectrum exhibits a band maximum at 1639 cm -1 In other embodiments, Form D is characterized in that its IR spectrum exhibits a band maximum at 968 cm -1 It is characterized by a band maximum at

[0068]

[0076] In some embodiments, Form D is characterized by an XRPD spectrum substantially similar to that shown in FIG. 2 or FIG. 5A.

[0077] In other embodiments, Form D is characterized by exhibiting an XRPD trace that is essentially unchanged when stored for 14 months under stability conditions of 40° C. and 75% relative humidity. The XRPD traces for Form D before and after storage under these conditions are shown in FIG. 5B.

[0069]

[0078] In other embodiments, Form D has a pH of 18.8 o It is characterized by peaks in the XRPD spectrum at 2θ.

[0079] In another embodiment, Form D is characterized by one or more peaks in an XRPD spectrum selected from 17.1, 18.1, 18.8, and 25.0 degrees 2θ.

[0070]

[0080] In another embodiment, Form D is characterized by one or more peaks in an XRPD spectrum selected from 8.8, 17.1, 18.1, 18.8, and 25.0 degrees 2θ.

[0071]

[0081] In some embodiments, Form D is characterized by an XRPD spectrum substantially similar to that shown in Figure 5C.

[0082] In other embodiments, Form D is characterized by one or more peaks in an XRPD spectrum selected from 4.7 (97.11% relative intensity), 18.1 (80.97%), 18.6 (100.00%), and 26.8 (65.25) °2θ.

[0072]

[0083] In other embodiments, Form D is characterized by one or more peaks in an XRPD spectrum selected from: 4.7 (97.11% relative intensity), 8.3 (64.04%), 18.1 (80.97%), 18.6 (100.00%), and 26.8 (65.25) °2θ.

[0073]

[0084] In one embodiment, the solid form of Compound I is polymorphic Form E.

[0085] In some embodiments, Form E is characterized by an FT-Raman spectrum substantially similar to that shown in FIG.

[0074]

[0086] In some embodiments, Form E has an IR spectrum of 1690 and 1515 cm -1 In some embodiments, Form E is characterized in that its IR spectrum exhibits a band maximum at 1690 cm -1 In some embodiments, Form E is characterized in that its IR spectrum exhibits a peak maximum at 1515 cm -1 It is characterized in that it exhibits a peak maximum at

[0075]

[0087] In some embodiments, Form E is characterized by an XRPD spectrum substantially similar to that shown in FIG. 2 or FIG.

[0088] In other embodiments, Form E is characterized by one or more peaks in an XRPD spectrum selected from 7.4, 18.8-19.3, 21.1, 24.8, and 25.5 degrees 2θ.

[0076]

[0089] In other embodiments, Form E is characterized by one or more peaks in an XRPD spectrum selected from 7.4, 13.9, 15.1, 16.3, 17.6, 18.8-19.3, 21.1, 22.3-22.5, 24.8, 25.5, and 27.1 °2θ.

[0077]

[0090] In one embodiment, the solid form of Compound I is polymorphic Form F.

[0091] In some embodiments, Form F is characterized by an XRPD spectrum substantially similar to that shown in FIG.

[0078]

[0092] In other embodiments, Form F is characterized by one or more peaks in an XRPD spectrum selected from °2θ of 5.3 (100.00% relative intensity), 8.6 (58.80%), and 16.4 (62.95%).

[0079]

[0093] In another embodiment, Form F is characterized by one or more peaks in an XRPD spectrum selected from the following °2θ: 5.3 (100.00% relative intensity), 8.6 (58.80%), 16.4 (62.95%), and 19.0 (48.51%).

[0080]

[0094] In one embodiment, the solid form of Compound I is polymorphic Form G.

[0095] In some embodiments, Form G is characterized by an XRPD spectrum substantially similar to that shown in FIG.

[0081]

[0096] In other embodiments, Form G is characterized by one or more peaks in an XRPD spectrum selected from °2θ of 10.7 (relative intensity of 55.47%) and 18.33 (100.00%).

[0082]

[0097] In another embodiment, Form G is characterized by one or more peaks in an XRPD spectrum selected from: 10.7 (55.47% relative intensity), 13.9 (42.47%), 18.33 (100.00%), and 21.6 (40.73%) °2θ.

[0083]

[0098] In one embodiment, the solid form of Compound I is polymorphic Form H.

[0099] In some embodiments, Form H is characterized by an XRPD spectrum substantially similar to that shown in FIG.

[0084]

[0100] In other embodiments, Form H has a saturation index of 5.77 (relative intensity of 89.22%), 6.3 It is characterized by one or more peaks in the XRPD spectrum selected from °2θ of 9 (100.00%), 9.1 (84.17%), and 18.5 (67.04%).

[0085]

[0101] In another embodiment, Form H has a saturation index of 5.77 (relative intensity of 89.22%), 6.3 It is characterized by one or more peaks in the XRPD spectrum selected from °2θ of 9 (100.00%), 9.1 (84.17%), 18.5 (67.04%), and 18.83 (67.04%). A pharmaceutically acceptable salt of the present invention.

[0086]

[0102] The phrase "pharmaceutically acceptable salts" as used herein refers to the pharmaceutically acceptable salts of Compound I. The term "compound I" refers to a pharmaceutically acceptable organic or inorganic salt. Pharmaceutically acceptable salts of compound I can be used in medicine. However, non-pharmaceutically acceptable salts can be useful as intermediates in the preparation of other solid forms of compound I.

[0087]

[0103] A pharmaceutically acceptable salt does not include the inclusion of another atom or molecule which acts as a counterion. Counterions include: A counterion can be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt can have more than one charged atom in its structure. If multiple charged atoms are part of the pharmaceutically acceptable salt, it can have multiple counterions. In some cases, the counterions can be the same. In other cases, they can be different for each charged atom. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterions.

[0088]

[0104] The pharmaceutically acceptable salts described herein and other typical pharmaceutically acceptable salts The preparation of such salts is more fully described by Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977:66:1-19, which is incorporated herein by reference in its entirety.

[0089]

[0105] In one embodiment, the pharmaceutically acceptable salt of Compound I is the hydrochloride salt of Compound I. do.

[0106] The hydrochloride salt of Compound I was prepared as described above in its polymorphic form D. I can be prepared by suspending it in 1 M HCl, mixing it with i-PrOH, and stirring it in a temperature cycle between 20 and 40 °C at a heating rate of 40 °C / hr and a cooling rate of 5 °C / hr.

[0090]

[0107] The hydrochloride salt of Compound I is characterized by a melting point of 256°C.

[0108] The hydrochloride salt of Compound I has an aqueous solubility of 0.5 mg / mL at pH 1.4. The aqueous solubility was determined at the pH of the saturated solution. The salt was shaken in water at 25°C for 24 hours. After filtration, the concentration was determined by HPLC to be 0.5 mg / mL at pH 1.4.

[0091]

[0109] The hydrochloride salt of Compound I exhibits an XRPD pattern substantially similar to that shown in FIG. It is characterized by Pharmaceutical Compositions and Methods of Administration

[0110] The crystalline solid forms disclosed herein may be prepared as pharmaceutical compositions or "formulations." It can be formulated into a pharmaceutical preparation.

[0092]

[0111] A typical formulation comprises a crystalline solid form of Compound I and a carrier, diluent, or excipient. The carrier, diluent, and excipient are prepared by mixing the following ingredients. Suitable carriers, diluents, and excipients are well known to those skilled in the art and include carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, and the like. The specific carrier, diluent, or excipient used will vary depending on the means and purpose for which the polymorph or pharmaceutically acceptable salt of Compound I is formulated. Solvents are generally selected by those skilled in the art based on solvents recognized as safe (GRAS - Generally Regarded as Safe) when administered to mammals. Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and the like, and mixtures thereof. The formulation may also include other types of excipients such as one or more buffering agents, stabilizers, anti-adherents, surfactants, wetting agents, lubricants, emulsifiers, binders, suspending agents, disintegrants, fillers, adsorbents, coatings (e.g., enteric or slow release), preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents and other known additives that provide for the elegant appearance of a drug or auxiliary agent in the manufacture of a pharmaceutical product (i.e., a drug).

[0093]

[0112] The formulations may be prepared using conventional dissolution and mixing procedures. The bulk drug substance (i.e., a polymorph or pharmaceutically acceptable salt of Compound I) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compound having the desired degree of purity is optionally mixed with a pharmaceutically acceptable diluent, carrier, excipient, or stabilizer, resulting in a lyophilized formulation, crushed powder, or aqueous solution. Formulation can be carried out by mixing the compound with a physiologically acceptable carrier at ambient temperature, at an appropriate pH, and at the desired degree of purity. The pH of the formulation will depend primarily on the specific use and concentration of the compound, but can range from about 3 to about 8. When the formulations described herein are solid amorphous dispersions formed by a solvent process, additives can be added directly to the spray-drying solution, forming a mixture in which the additives are dissolved or suspended as a slurry in the solution, followed by spray drying. Alternatively, additives can be added subsequent to the spray-drying process to aid in the formation of the final formulated product.

[0094]

[0113] Polymorphs or pharmaceutically acceptable salts of Compound I are typically prepared into pharmaceutical dosage forms. The polymorphic compound I or pharmaceutically acceptable salt of the compound I can be prepared for various routes and types of administration.Since different pathologies justify the use of different administration routes, different dosage forms can exist for the same compound.

[0095]

[0114] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form may vary. These dosages may vary depending on the intended subject and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain approximately 1 to 1,000 mg of active agent, combined with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% of the total composition (weight:weight). Pharmaceutical compositions may be prepared to provide easily measurable dosages. For example, an aqueous solution intended for intravenous infusion may contain about 3 to 500 μg of active material per milliliter of solution, so that infusion of a suitable volume can occur at a rate of about 30 mL / hour. As a general suggestion, the starting pharmaceutically effective amount of the inhibitor to be administered will be in the range of about 0.01 to 100 mg / kg per dose, i.e., about 0.1 to 20 mg / kg of patient body weight per day, with a typical starting range of 0.3 to 15 mg / kg / day for the compound used.

[0096]

[0115] The term "therapeutically effective amount" as used herein refers to the amount of a therapeutically effective dose administered by a researcher, veterinarian, physician, or "Therapeutically effective" or "pharmaceutically effective" means the amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, or human that is being sought by a clinician or other physician. A therapeutically effective or pharmaceutically effective amount of a compound administered is governed by such considerations and is the minimum amount necessary to ameliorate, cure, or treat a disease or disorder or one or more symptoms thereof.

[0097]

[0116] Pharmaceutical compositions of polymorphs or pharmaceutically acceptable salts of Compound I are useful in good medical practice. The drug is formulated, dosed, and administered in a manner consistent with the intended purpose, i.e., in an amount, concentration, schedule, course, vehicle, and route of administration. Factors to consider in this context include the particular disorder being treated, the particular mammal being treated, the condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to medical professionals, such as the age, weight, and response of the individual patient.

[0098]

[0117] The term "prophylactically effective amount" refers to an amount that prevents or reduces the chance of developing a disease or disorder. It refers to an amount effective to substantially reduce or reduce the severity of a disease or disorder before it occurs, or to reduce the severity of one or more of its symptoms before the symptoms develop. Generally, preventative measures are divided into primary prevention (preventing the development of the disease) and secondary prevention (when the disease has already developed, thereby protecting the patient from worsening this process).

[0099]

[0118] Acceptable diluents, carriers, excipients, and stabilizers vary depending on the dosage and buffers such as phosphate, citrate, and other organic acids, which are non-toxic to the recipient at concentrations that are non-toxic to the recipient; antioxidants, including ascorbic acid and methionine; preservatives (such as ammonium octadecyldimethylbenzyl chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); proteins, such as serum albumin, gelatin, or immunoglobulins; polysaccharides, such as PEG-1, PEG-2, PEG-3, PEG-4, PEG-5, PEG-6, PEG-7, PEG-8, PEG-9, PEG-10, PEG-11, PEG-12, PEG-13, PEG-14, PEG-15, PEG-16, PEG-17, PEG-18, PEG-19, PEG-21, PEG-22, PEG-23, PEG-24, PEG-25, PEG-26, PEG-27, PEG-28, PEG-29, PEG-30, PEG-31, PEG-32, PEG-33, PEG-44, PEG-45, PEG-46, PEG-47, PEG-48, PEG-49 ...50, PEG-51, PEG-52, PEG-53, PEG-54, PEG-55, PEG-55, PEG-55 These include 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 dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN®, PLURONICS®, or polyethylene glycol (PEG). Active pharmaceutical ingredients can also be contained in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, such as, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methyl methacrylate) microcapsules, respectively; colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, etc.). Such techniques can be described in Remington's: The Science and Practice of Pharmacy, 21st Edition, University of the Sciences in Philadelphia, Eds., 2005 (hereinafter "Remington's").

[0100]

[0119] The terms "administer," "administering," or "administration" refer to a solid form of the invention, With reference to a composition or formulation, it is meant that the compound is introduced into the system of an animal in need of treatment. When the compound of the present invention is provided in combination with one or more other active agents, "administration" and variations thereof are understood to include simultaneous and / or sequential introduction of the compound and the other active agent(s), respectively.

[0101]

[0120] The compositions described herein can be administered, for example, orally (e.g., in capsules, powders, etc.). The compositions may be administered systemically or locally, depending on the severity and type of condition being treated, for example, by inhalation (e.g., using an aerosol, gas, inhaler, nebulizer, or the like), auricle (e.g., using ear drops), topically (e.g., using a cream, gel, liniment, lotion, ointment, paste, transdermal patch, or the like), ophthalmically (e.g., using eye drops, eye gel, eye ointment), rectally (e.g., using an enema or suppository), nasally, buccally, vaginally (e.g., using a douche, intrauterine device, vaginal suppository, vaginal ring, or tablet, or the like), via an implanted reservoir or the like, or parenterally.

[0102]

[0121] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intravenous, and intravenous administration. The compositions are preferably administered orally, intraperitoneally, or intravenously, including, but not limited to, intranodal, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques.

[0103]

[0122] The pharmaceutical compositions described herein may be in the form of capsules, tablets, aqueous suspensions or liquids. The composition may be orally administered in any orally acceptable dosage form, including, but not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound(s), the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils and fats (especially cottonseed, tuberous root, corn, germ, olive, castor, and sesame oils), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and fragrances.

[0104]

[0123] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is present in at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia; c) humectants, such as glycerin; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retardants, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) soluble solids, such as sorbitol, ... For example, it is mixed with wetting agents such as cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof.The tablets may be uncoated or may be coated by known techniques, including microencapsulation, to mask unpleasant taste or to delay disintegration and absorption in the digestive tract, thereby providing a sustained action over a long period of time.For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used alone or with wax.Water-soluble taste-masking materials such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose may be used.

[0105]

[0124] Polymorphs of Compound I or pharmaceutically acceptable salts of Compound I suitable for oral administration Formulations may be prepared as discrete units such as tablets, pills, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules such as gelatin capsules, syrups or elixirs, etc. Formulations of compounds intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.

[0106]

[0125] Formulations for oral use may contain active ingredients such as calcium carbonate, calcium phosphate, etc. The active ingredient may also be provided as a hard gelatin capsule mixed with an inert solid diluent such as polyethylene glycol or kaolin, or as a soft gelatin capsule mixed with a water-soluble carrier such as polyethylene glycol or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0107]

[0126] The active solid form may also be microencapsulated with one or more of the excipients described above. It may be in a condensed form.

[0127] When aqueous suspensions are required for oral use, the active ingredient may be added to emulsifying and suspending agents. The syrup and elixir may be combined with a sweetener such as glycerin, propylene glycol, sorbitol, or sucrose. Such preparations may also contain a demulcent, a preservative, a flavoring agent, a coloring agent, and an antioxidant.

[0108]

[0128] Sterile injectable forms (e.g., for parenteral administration) of the compositions described herein are The suspension may be an aqueous or oily suspension. These suspensions may be formulated using suitable dispersing or wetting agents and suspending agents based on techniques known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol or PEG 400. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially its polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for injectable formulations.

[0109]

[0129] Oily suspending agents include, for example, arachis oil, olive oil, sesame oil or coconut oil. The polymorph of Compound I or its pharmaceutically acceptable salt can be prepared by suspending it in vegetable oil such as oil or mineral oil such as liquid paraffin.Oily suspensions can contain thickening agents such as beeswax, hard paraffin or cetyl alcohol.Sweeteners such as those specified above and flavoring agents can be added to provide a palatable oral preparation.These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

[0110]

[0130] Aqueous suspensions of polymorphs of Compound I or pharmaceutically acceptable salts of Compound I are prepared by dissolving in water. The active substance is contained in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia, as well as dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensates of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensates of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), and condensates of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides (e.g., 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, such as sucrose or saccharin, and one or more sweetening agents.

[0111]

[0131] Injectable preparations may be sterilized, for example, by filtration through a bacterial-retaining filter. By incorporating the agents, they can be sterilized in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0112]

[0132] Injectable solutions or microemulsions are administered into the patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the compound. To maintain such a constant concentration, a continuous intravenous delivery device may be utilized. One example of such a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

[0113]

[0133] Compositions for rectal or vaginal administration preferably contain the solid forms described herein. Suppositories can be prepared by mixing the body form with suitable non-irritating excipients or carriers, such as cocoa butter, beeswax, polyethylene glycol, or a suppository wax that is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active compound. Other formulations suitable for vaginal administration can be provided as pessaries, tampons, creams, gels, pastes, foams, or sprays.

[0114]

[0134] The pharmaceutical compositions described herein may also be used to treat diseases of the eye, ear, skin, or lower intestinal tract. They may be administered topically, particularly when the target of treatment, including the disease, includes areas or organs easily accessible by topical application. Suitable topical formulations are readily prepared for each of these areas or organs.

[0115]

[0135] Dosage forms for topical or transdermal administration of the compounds described herein include ointments, These formulations include pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, if necessary. Ophthalmic formulations, ear drops, and eye drops are also considered to be within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of compounds to the body. Such Dosage forms can be prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel. Topical application to the lower intestinal tract can be achieved in a rectal suppository (see above) or a suitable enema formulation. Topical transdermal patches can also be used.

[0116]

[0136] For topical application, the pharmaceutical composition may be suspended in one or more carriers. The solid form of the present invention may be formulated into a suitable ointment containing the active ingredient suspended or dissolved therein. Carriers for topical administration include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition may be formulated into a suitable lotion or cream containing the active ingredient 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 ester wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol, and water.

[0117]

[0137] For ophthalmic use, the pharmaceutical composition may be prepared in an isotonic, pH adjusted, sterile saline solution. They may be formulated as micronized suspensions in water or, preferably, as solutions in isotonic, pH-adjusted, sterile saline, with or without preservatives such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated into an ointment such as petrolatum. For treatment of the eye or other external tissues, such as the mouth and skin, the formulation 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 into an ointment, the active ingredient(s) may be utilized with either an oleaginous, paraffinic, or water-miscible ointment base.

[0118]

[0138] Alternatively, the active ingredients can be formulated into a cream with an oil-in-water cream base. The topical formulation may be formulated as follows: If desired, the aqueous phase of the cream base may contain polyhydric alcohols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerin, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may desirably contain compounds that enhance the absorption or permeation of active materials through the skin or other affected areas. Examples of such dermal permeation enhancers include dimethyl sulfoxide and related analogues.

[0119]

[0139] Prepared using a polymorph of Compound I or a pharmaceutically acceptable salt of Compound I The oily phase of the emulsion may be composed of known materials in a known manner. While the phase may contain only one emulsifier (otherwise known as a diuretic), it is desirable to include a mixture of at least one emulsifier with a fat, oil, or both. A hydrophilic emulsifier may be included along with a lipophilic emulsifier, which acts as a stabilizer. In some embodiments, the emulsifier includes both an oil and a fat. Together, the emulsifier(s), with or without stabilizer(s), constitute the so-called emulsifying wax, which, together with the oil and fat, forms the oily dispersed phase of the cream formulation, the so-called emulsifying ointment base. Suitable diuretics and emulsion stabilizers for use in formulating polymorphs of Compound I or pharmaceutically acceptable salts of Compound I include Tween™-60, Span™-80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0120]

[0140] The pharmaceutical compositions may also be administered by nasal aerosol or by inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, utilizing benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents. Formulations suitable for pulmonary or nasal administration have a particle size ranging, for example, from 0.1 to 500 micrometers (micros) (including particles in the range of 0.1 to 500 micrometers in micrometer increments, such as 0.5, 1, 30, 35 micrometers), administered by rapid inhalation through the nostrils or by inhalation through the mouth to reach the alveolar sacs.

[0121]

[0141] The pharmaceutical composition (or formulation) used may be in accordance with the method used to administer the drug. The packaging may be carried out in various ways depending on the intended use. Generally, the article for distribution includes a container containing the pharmaceutical preparation in an appropriate form. Suitable containers are well known to those skilled in the art and include bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-evident combination that prevents unauthorized access to the contents of the package. In addition, the container has a label affixed thereon that indicates the contents of the container. The label may also include appropriate warnings.

[0122]

[0142] The formulations may be presented, for example, in unit dose or sealed containers such as sealed ampoules and vials. It may be packaged in multi-dose containers and 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. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, or an appropriate fraction thereof, of an active ingredient, as hereinbefore described.

[0123]

[0143] In another embodiment, the polymorph of Compound I or a pharmaceutically acceptable salt of Compound I is The active ingredient may be formulated into a veterinary composition containing a veterinary carrier. The veterinary carrier is a substance useful for administering the composition and may be a solid, liquid, or gaseous substance that is otherwise inert or acceptable in the field of veterinary medicine and compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally, or by any other desired route. Treatment method

[0144] In another aspect, the present invention provides a crystalline solid form of Compound I disclosed herein. The present invention relates to the treatment of certain disorders by use of these compounds, either alone or in combination, or in pharmaceutical compositions containing them, in patients in need thereof.

[0124]

[0145] The present disclosure relates to crystalline solid forms of Compound I, and pharmaceutical formulations thereof, as well as compounds that can be used alone. The present invention relates to the use thereof, alone or in combination with one or more further agents, for treating and / or preventing various diseases in which increased levels of NO or increased levels of cGMP are desirable.

[0125]

[0146] Increased NO production or increased cGMP concentrations in tissues may have other effects. Among other things, they provide vasodilation, inhibition of platelet aggregation and adhesion, antihypertensive, antiremodeling, antifibrotic, antiapoptotic, anti-inflammatory and neurosignaling effects.

[0126]

[0147] In other embodiments, the crystalline solid forms of Compound I disclosed herein are oxidized. They are useful in the prevention and / or treatment of diseases and disorders characterized by an undesirable decrease in bioavailability and / or sensitivity to NO in biological systems (e.g., in the human body), such as those associated with conditions of stress or nitrosative stress.

[0127]

[0148] The term "cardiovascular disease" (or "cardiovascular disorder") is used herein to mean a In this case, it refers to a disease based on abnormal conditions of the circulatory system, such as the heart, blood vessels (arteries, capillaries, and veins), or both. The term also includes any disease that generally affects the cardiovascular system, including, inter alia, heart disease, vascular disease of the brain, vascular disease of the kidneys, liver and related organs, or lungs, and peripheral arterial disease.

[0128]

[0149] "sGC-related cardiovascular diseases" are thought to involve the NO / sGC / cGMP system. Cardiovascular diseases that are known or suspected and can be treated or prevented by sGC activation / stimulation, by activation of NO synthase, or by addition of NO or NO-donors or NO precursors such as L-arginine or L-citrulline, or by inhibition of PDE (phosphodiesterase) enzymes responsible for the breakdown of cGMP, or by a combination of any of the above mentioned methods.

[0129]

[0150] The term "vasodilation," as used herein, refers to the widening of blood vessels. This is due to the relaxation of smooth muscle cells within the vessel walls, specifically in the vena cava, aorta, and smaller arterioles. In essence, this process is the reverse of "vasoconstriction," in which blood vessels narrow. When blood vessels dilate, blood flow increases due to a decrease in vascular resistance. Thus, dilation of arterial blood vessels (mainly arterioles) reduces blood pressure. This response can be endogenous (due to local processes in the surrounding tissue) or extrinsic (due to hormones or the nervous system). Additionally, the response can be localized to a specific organ (depending on the metabolic needs of a specific tissue during strenuous exercise) or systemic (seen throughout the systemic circulation).

[0130]

[0151] The term "vasoconstriction," as used herein, refers to the contraction of blood vessels due to muscle contraction. Vasoconstriction is one mechanism by which the body regulates and maintains mean arterial pressure (MAP). Generalized vasoconstriction typically results in an increase in systemic blood pressure, but can also occur in specific tissues, causing a localized decrease in blood flow.

[0131]

[0152] As used herein, the term "bronchoconstriction" refers to the narrowing of the airways in the lungs. It is used to define bronchoconstriction, which is caused by the tightening of the surrounding smooth muscles, resulting in coughing, wheezing, and shortness of breath. The condition has many causes, the most common of which is asthma. Exercise and allergies can cause this symptom in otherwise asymptomatic individuals. Other conditions, such as chronic obstructive pulmonary disease (COPD), can also present with bronchoconstriction.

[0132]

[0153] Throughout this disclosure, the terms "high blood pressure," "arterial hypertension," or "hypertension" are used. "High blood pressure (HBP)" is used interchangeably to describe a very common and highly preventable chronic condition in which arterial blood pressure (BP) is higher than normal or desired. If not properly controlled, it represents a significant risk factor for several serious cardiovascular and renal conditions. Hypertension can be a primary condition called "essential hypertension" or "idiopathic hypertension," or it can 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.

[0133]

[0154] As used herein, the term "resistant hypertension" refers to hypertensive disorders that are resistant to different antihypertensive drug classes. Resistant hypertension refers to hypertension that remains above target blood pressure (typically <140 / 90 mmHg, although a lower target of <130 / 80 mmHg is recommended for patients with comorbid diabetes or renal disease) despite the concurrent use of three antihypertensive drugs. Individuals who require four or more drugs to control their blood pressure are also considered to have resistant hypertension. Hypertension is a very common comorbid condition in 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, hypertension Hypertension often appears as part of the metabolic syndrome of insulin resistance, which also includes central obesity and dyslipidemia. In type 1 diabetes, hypertension can lead to the development of diabetic nephropathy.

[0134]

[0155] "Pulmonary hypertension (PH)" as used herein refers to hypertension in the pulmonary vasculature (pulmonary arteries, pulmonary arteries, PH is a disease characterized by persistently elevated blood pressure in the veins and pulmonary capillaries, which leads to right-sided hypertrophy and ultimately right-sided heart failure and death. Common symptoms of PH include shortness of breath, dizziness, and syncope, all of which worsen with exertion. Without treatment, the median life expectancy after diagnosis is 2.8 years. PH exists in many different forms, which are categorized based on their etiology. Categories include pulmonary arterial hypertension (PAH), PH with left heart disease, PH associated with pulmonary disease and / or hypoxemia, PH due to chronic thrombotic and / or embolic disease, and various forms of PH. While PAH is rare in the general population, its prevalence increases in association with certain common conditions, such as HIV infection, scleroderma, and sickle cell disease. Other forms of PH are generally more common than PAH; for example, the association of PH with chronic obstructive pulmonary disease (COPD) is of particular concern. Current treatments for pulmonary hypertension depend on the stage and mechanism of the disease.

[0135]

[0156] The term "coronary artery disease" refers to a condition in which the blood supply to the heart muscle is partially or completely blocked ( This refers to a condition of myocardial or myocardial ischemia. This reduced blood supply to the myocardium can result in a number of "acute myocardial syndromes": chest pain (stable or unstable, also called "angina" or "angina pectoris") and different 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 arterial walls, which can then progress to narrowing through the formation of atheromatous plaques and ultimately blockage of blood flow through the arteries. This atherosclerotic process can affect not just the arteries of the heart, but other arteries as well. Because arteries are usually already partially blocked by atheromatous plaques (atheromas), blood clots are the most common cause of arterial blockage. Atheromas can rupture or tear, leading to the formation of a blood clot. Occasionally, coronary artery disease is caused by spasm of the coronary arteries, which can occur spontaneously or as a result of the use of certain drugs (e.g., cocaine, nicotine). Rarely, coronary artery disease is caused by a congenital defect, a viral infection (e.g., Kawasaki disease), systemic lupus erythematosus (lupus), inflammation of the arteries (arteritis), a blood clot that has migrated from a heart chamber into one of the coronary arteries, or physical damage (e.g., from an injury or radiation therapy).

[0136]

[0157] "Unstable angina," as used herein, refers to persistent or worsening angina. This represents a changing pattern of angina symptoms, including heart palpitations and initial severe symptoms.

[0158] MI (myocardial infarction) can be classified into two types: "non-ST-segment elevation" MI and and "ST-segment elevation" MI. Complications of acute coronary syndromes depend on how large, how long, and where the coronary artery is blocked. If the blockage affects a large amount of myocardium, the heart does not pump efficiently. If the blockage stops blood flow to the heart's electrical system, heart rhythm can be affected. When a heart attack occurs, part of the myocardium dies. The dead tissue and the scar tissue that replaces it do not contract. The scar tissue sometimes expands or even bulges as the rest of the heart tries to contract. As a result, there is less muscle to pump blood. If enough muscle dies, the heart's pumping ability can be so reduced that it cannot meet the body's demand for oxygen and blood. Heart failure, low blood pressure, or both then occur. If more than half of the myocardium is damaged or dead, the heart generally cannot function, and severe disability or death is possible.

[0137]

[0159] As used herein, "heart failure" (HF) refers to impaired cardiac function and Heart failure is a progressive disorder of left ventricular (LV) myocardial remodeling that ultimately results in a complex clinical syndrome characterized by circulatory congestion and inadequate delivery of blood and nutrients to body tissues. This condition occurs when the heart is damaged or overworked and unable to pump all the blood returning to it from the systemic circulation. Because less blood is pumped, increased blood return to the heart occurs, and fluid buildup occurs in other parts of the body. Heart failure also impairs the kidney's ability to eliminate sodium and water, further complicating fluid retention. Heart failure is characterized by autonomic neuropathy, neurohormonal activation, and cytokine overproduction, contributing to progressive circulatory failure. Symptoms of heart failure include dyspnea (shortness of breath) during exercise or rest and during nighttime awakenings due to sudden shortness of breath, both of which suggest pulmonary edema; generalized fatigue or weakness; edema of the feet, ankles, and legs; short-term weight gain; or a chronic cough, including those that produce mucus or blood. Depending on its clinical symptoms, heart failure is classified as new, transient, acute, post-acute, or chronic. Acute heart failure, i.e., the rapid or gradual onset of symptoms requiring emergency treatment, can occur as a result of decompensation of new or chronic heart failure. The term "heart failure" is often used to mean "chronic heart failure." The terms "congestive heart failure (CHF)" and "congestive cardiac failure (CCF)" are often used interchangeably for chronic heart failure. Common causes of heart failure include previous myocardial infarction (heart attack), hypertension, atrial fibrillation, valvular heart disease, and coronary artery disease, including cardiomyopathies. These cause heart failure by altering either the structure or function of the heart.

[0138]

[0160] There are two main types of heart failure: "heart failure due to left ventricular systolic dysfunction" or "Heart failure with reduced ejection fraction (HFREF)," also known as "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 percentage of blood pumped out of the heart during one contraction. Normally, it is between 50 and 75%.

[0139]

[0161] The term "acute" (as in "acute HF") is used to mean rapid onset. "Chronic" refers to a condition of long duration. Chronic heart failure is a long-term condition, usually accompanied by a stable symptomatology. "Acute decompensated" heart failure refers to an episode of worsening or decompensated heart failure, which may be characterized by the patient having a change in the signs and symptoms of heart failure, resulting in the need for emergency treatment or hospitalization. Heart failure can also occur in high-output situations, where ventricular systolic function is normal but the heart is unable to cope with a significant increase in blood volume (hence the term "high-output heart failure").

[0140]

[0162] In circulatory physiology, the term "ejection fraction (EF)" refers to the amount of blood pumped with each heartbeat or cardiac cycle. EF is defined as the percentage of blood in the left and right ventricles that is pumped out through the pulmonary valve. In the finite mathematics made possible by medical imaging, EF applies to both the right ventricle, which ejects blood into the pulmonary circulation through the pulmonary valve, or the left ventricle, which ejects blood into the cerebral and systemic circulation through the aortic valve.

[0141]

[0163] The term "heart failure with preserved ejection fraction (HFPEF)" generally refers to a heart failure with an ejection fraction greater than 55%. It is understood to represent the onset of signs and symptoms of heart failure with a high ejection fraction. It is characterized by decreased left ventricular compliance, leading to increased pressure in the left ventricle. Increased left atrial size, as a result of poor left ventricular function, increases the risk for congestive heart failure, atrial fibrillation, and pulmonary hypertension, which are often seen in HFPEF. Risk factors include hypertension, hyperlipidemia, diabetes, smoking, and obstructive sleep apnea. In this type of heart failure, the myocardium contracts well during diastole, but the ventricles do not fill well with blood.

[0142]

[0164] The term "heart failure with reduced ejection fraction (HFREF)" refers to a condition in which the ejection fraction is less than 40%. Indicates a certain heart failure.

[0165] Diabetes is a common comorbidity in patients with heart failure and is associated with poorer outcomes. Similarly, these conditions are associated with potentially compromising the effectiveness of treatment. Other important comorbidities include systemic hypertension, chronic airflow obstruction, sleep apnea, cognitive impairment, anemia, chronic kidney disease, and arthritis. Chronic left heart failure is frequently associated with the development of pulmonary hypertension. The frequency of certain comorbidities differs between men and women: hypertension and thyroid disease are more common among women, while men typically suffer from chronic obstructive pulmonary disease (COPD), peripheral vascular disease, coronary artery disease, and renal insufficiency. Depression is a frequent comorbidity of heart failure, and the two conditions can and often do coexist with each other. Cachexia has long been recognized as a severe and frequent complication of heart failure, affecting up to 15% of all heart failure patients and associated with poor prognosis. Cardiac cachexia is defined as the non-edematous, involuntary loss of at least 6% of body weight over a 6-month period.

[0143]

[0166] The term "arrhythmia" as used herein refers to the 90% of people who experience a heart attack. This refers to an abnormal heart rhythm that occurs in over 50% of people. Sometimes the problem is with the part of the heart that is beating and causing the heart to beat too slowly; other times, the problem is with the part of the heart that can cause the heart to beat too quickly or irregularly. Sometimes the signal to beat doesn't get transmitted from one part of the heart to another, causing the heart to beat slowly or stop. In addition, areas of the myocardium that aren't dying but have poor blood flow can become irritable. This causes heart rhythm problems such as ventricular tachycardia or ventricular fibrillation. If the heart stops pumping completely, this can lead to cardiac arrest.

[0144]

[0167] The "pericardium" is the sac or membrane that surrounds the heart. "Pericarditis" or inflammation of this membrane Heart attack can develop as a result of a heart attack and can result in fever, pericardial effusion, inflammation of the membranes that cover the lungs (pleura), pleural effusion, and joint pain. Other complications after a heart attack can include mitral valve malfunction, rupture of the heart muscle, a bulge in the ventricular wall (aneurysm), blood clots, and low blood pressure.

[0145]

[0168] The term "cardiomyopathy" refers to a progressive impairment of the structure and function of the muscular walls of the heart chambers. Types of cardiomyopathy are dilated, hypertrophic, and restrictive. Cardiomyopathy often leads to symptoms of heart failure and can also cause chest pain, fainting, and sudden death.

[0146]

[0169] The term "mitral valve regurgitation" "Mitral regurgitation," "mitral insufficiency," or "mitral incompetence" describes a condition in which the heart's mitral valve does not close tightly, allowing blood to flow backward into the heart. As a result, blood cannot travel efficiently through the heart or to the rest of the body, resulting in fatigue or shortness of breath.

[0147]

[0170] The term "sleep apnea" refers to the most common sleep-disordered breathing disorder. It occurs when air enters the upper airway. It is a condition characterized by intermittent, periodic reductions or complete cessation of airflow, which may or may not involve obstruction of the airways. There are three types of sleep apnea: obstructive sleep apnea, the most common form; central sleep apnea; and mixed sleep apnea.

[0148]

[0171] Central sleep apnea (CSA) is a condition that occurs when breathing is interrupted rather than a physical blockage of the airway. It is caused by a malfunction in the brain's normal signals for breathing. The lack of respiratory effort leads to an increase in carbon dioxide in the blood, which can wake the patient. CSA is rare in the general population but occurs relatively frequently in patients with systolic heart failure.

[0149]

[0172] As used herein, the terms "metabolic syndrome," "insulin-dependent "Glucose resistance syndrome" or "Syndrome X" describes a group or cluster of metabolic conditions (abdominal obesity, elevated fasting blood glucose, "dyslipidemia" (i.e., elevated lipid levels), and elevated blood pressure (HBP)) that occur together more frequently than by chance alone and together are associated with type 2 diabetes. Metabolic syndrome promotes the development of cardiovascular disease and metabolic syndrome. Metabolic syndrome is characterized by a specific lipid profile of elevated triglycerides, decreased high-density lipoprotein cholesterol (HDL-cholesterol), and sometimes moderately elevated low-density lipoprotein cholesterol (LDL-cholesterol) levels, as well as the accelerated progression of "atherosclerotic disease" due to the pressure of component risk factors. There are several types of dyslipidemia: "hypercholesterolemia" refers to elevated cholesterol levels. Familial hypercholesterolemia is a specific form of hypercholesterolemia caused by a defect in chromosome 19 (19p13.1-13.3). "Hyperglyceridemia" refers to elevated glyceride levels (e.g., "hypertriglyceridemia" includes elevated triglyceride levels). "Hyperlipoproteinemia" refers to elevated lipoprotein levels (usually LDL, unless otherwise indicated).

[0150]

[0173] The term "steatosis" refers to the abnormal retention of lipids within cells. It reflects the disturbance of the normal process of glyceride synthesis and removal. Excess fat accumulates in vesicles that replace the cytoplasm of cells. In severe cases, cells may rupture. Because the liver is the organ primarily involved in fat metabolism, fatty degeneration is usually observed in the liver. It is also observed in the heart, kidney, and muscle tissue.

[0151]

[0174] As used herein, the term "peripheral vascular disease (PVD)" generally refers to " Peripheral arterial disease (PAD), also referred to as peripheral arterial occlusive disease (PAOD), refers to blockage of the large arteries, but not of the coronary vessels, the aortic arch vasculature, or the brain. PVD can result from atherosclerosis, stenosis, embolism, platelet thrombosis, or other types of inflammatory processes leading to blockage. This can result in acute or chronic ischemia (lack of blood supply). PVD is a term often used to describe atherosclerotic blockages found in the lower extremities. PVD also includes a subset of diseases classified as microvascular diseases resulting from episodic narrowing of arteries (e.g., Raynaud's phenomenon) or their widening (erythromelalgia), i.e., vasospasm. Peripheral arterial disease includes occlusive thromboangiitis, peripheral arterial occlusive disease, Raynaud's disease, and Raynaud's syndrome. Common symptoms include cold legs or feet, intermittent claudication, leg pain, and severe limb ischemia (ulcers and necrosis of the legs). Diagnostic and treatment guidelines for peripheral arterial disease can be found in Eur. J. Vasco Endovasc. Surg, 2007, 33(1), S1.

[0152]

[0175] The term "stenosis" as used herein refers to a narrowing of a blood vessel or other tubular organ. It refers to an abnormal narrowing in a structure or stenosis. It is also sometimes called "stricture" (such as in urethral stricture). The term "coarctation" is synonymous but is generally used only in the context of aortic coarctation. The term "restenosis" refers to the recurrence of stenosis after treatment.

[0153]

[0176] The term "thrombosis" refers to the formation of a blood clot ("platelet") within a blood vessel that blocks blood flow through the circulatory system. "Thromboembolism" refers to the formation of a blood clot (an "embolus"). When a blood vessel is injured, the body uses platelets (thrombocytes) and fibrin to form a blood clot to prevent blood loss. Alternatively, if the right conditions exist, blood clots can form in the body even when a blood vessel is not injured. If clotting is too vigorous and the clot detaches, the traveling clot is known herein as an "embolus." The term "thromboembolism" refers to the combination of thrombosis and its major complication, "embolism." When platelet emboli occupy more than 75% of the surface area of an arterial lumen, blood flow to the supplied tissues is reduced sufficiently to cause symptoms caused by reduced oxygen (hypoxia) and the accumulation of metabolic products such as lactic acid ("gout"). Blockages of greater than 90% can result in anoxia, a complete lack of oxygen, and "infarction," a condition of cell death.

[0154]

[0177] "Embolism" (multiple embolisms) refers to a blockage (vascular occlusion) in a distant part of the body. An event that results in an embolism (a discrete intravascular mass that can clog an arterial capillary bed at a site far from its origin) within the narrow capillaries of an arterial bed. This should not be confused with a platelet embolus, which blocks at its site of origin. The material that forms the embolism can have many different origins: if the material is blood, the "embolus" is termed a "platelet embolus"; solid material can also include fat, bacterial remnants, infected tissue, etc.

[0155]

[0178] "Ischemia" is a restriction in blood supply to a tissue that affects cellular metabolism (the tissue's survival). Ischemia is a condition that causes a lack of oxygen and glucose necessary for the circulation of blood (to keep the body functioning). Ischemia is generally caused by problems with blood vessels, resulting in damage or dysfunction of tissue. It also sometimes refers to local anemia in a given part of the body due to blood congestion (vasoconstriction, thrombosis, or embolism, etc.). When "ischemia" occurs in the heart muscle (or "myocardium"), the ischemia is termed myocardial ischemia. Other types of ischemia are, for example, cerebral ischemia, critical limb ischemia, etc.

[0156]

[0179] "Reperfusion" occurs when blood supply returns to tissue after a period of ischemia. During ring healing, processes of inflammation and oxidative stress can occur. One example of this sequence of events is the ischemia-reperfusion associated with organ transplantation.

[0157]

[0180] "Reperfusion injury" refers to the return of blood supply to tissues after a period of ischemia and the recovery of normal function. Rather, it is the tissue damage that occurs when inflammation and oxidative damage result. Reperfusion of ischemic problems is often associated with microvascular injury, specifically due to increased permeability of capillaries and arterioles, which leads to increased diffusion and fluid filtration across tissues. Activated endothelial cells produce more reactive oxygen species but less NO following reperfusion, an imbalance that triggers an inflammatory response. In response to tissue injury, leukocytes are carried to the area by newly restored blood flow and release numerous inflammatory factors and free radicals. The restored blood flow carries with it oxygen, which damages cellular proteins, DNA, and cell membranes. This ischemia-reperfusion process is also thought to contribute to the formation and failure of healing chronic wounds (e.g., pressure sores or diabetic ulcers).

[0158]

[0181] The term "vasculopathy," as used herein, refers to a condition that affects blood vessels (arteries, veins, and Cerebral amyloidosis (CAA) is a general term for diseases of the blood vessels (capillaries). The most common and most widespread vasculopathy is "diabetic vasculopathy," a common complication of chronic diabetes. Another common type of vasculopathy is "cerebral amyloid angiopathy" (CAA), also known as congophilic vasculopathy, in which amyloid deposits form in the walls of blood vessels in the central nervous system. The term congophilic vasculopathy is used because the presence of abnormal amyloid aggregates can be demonstrated by microscopic examination of brain tissue after application of a special stain called Congo Red. The amyloid material is found only in the brain, and therefore the disease is not related to other forms of amyloidosis.

[0159]

[0182] A "stroke" or cerebrovascular accident (CVA) is caused by a blockage in the blood supply to the brain. Stroke is the rapid loss of brain function(s) due to a blockage (thrombosis, arterial embolism, fatty deposits, or spasms), or "ischemia" (with lack of blood flow and resulting in inadequate oxygen and glucose supply to tissues) caused by hemorrhage (blood leakage). As a result, the affected area of the brain cannot function, and the person may be unable to move one or more limbs on one side of the body, unable to understand or comprehend speech, or unable to see on one side of the field of vision. Risk factors for stroke include older age, high blood pressure, previous stroke or transient ischemic attack (TIA), diabetes, high cholesterol, smoking, and atrial fibrillation. High blood pressure is the most important modifiable risk factor for stroke. "Ischemic stroke" can sometimes be treated in the hospital with thrombolysis (also known as "clot-dissolving drugs"). Some hemorrhagic strokes are treated and benefit from neurological surgery. Prevention of recurrence may include the administration of antiplatelet drugs such as aspirin and dipyridamole, control and reduction of high blood pressure, and the use of statins. Selected patients may benefit from carotid endarterectomy and the use of anticoagulants.

[0160]

[0183] "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 occurs more frequently in people with vascular risk factors (e.g., high blood pressure, diabetes, hyperlipidemia, smoking) and in people who have had several strokes. Many people have both vascular dementia and Alzheimer's disease. Vascular dementia typically occurs when multiple small cerebral infarctions (or occasional hemorrhages) cause enough neuronal or axonal loss to impair brain function. Vascular dementia includes the following types: multiple lacunar infarcts (small blood vessels are affected, with infarcts deep within the hemisphere in white and gray matter); multi-infarct dementia (medium-sized blood vessels are affected); strategic single-infarct dementia (a single infarct occurs in a critical area of the brain, such as the angular gyrus or thalamus); Binswanger dementia or subcortical arteriosclerotic encephalopathy (small vessel dementia is associated with severe, poorly controlled hypertension and systemic vascular disease, resulting in diffuse and irregular loss of axons and myelin along with widespread gliosis and tissue death due to infarction or loss of blood supply to the brain's white matter).

[0161]

[0184] The term "glioma" refers to a type of tumor that begins in the brain or spine. They are called gliomas because they arise from the brain. The most common site for gliomas is the brain. Gliomas comprise approximately 30% of all brain and central nervous system tumors and 80% of all malignant brain tumors.

[0162]

[0185] American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders Based on the DSM-IV, the term "sexual dysfunction" encompasses a range of conditions "characterized by disturbances in sexual desire and psychophysiological changes associated with the sexual response cycle"; although problems of this nature are common, sexual dysfunction is considered to exist only when the problem causes distress to the patient. This can be either physical or psychological in origin. Sexual dysfunction can exist as a primary condition, generally hormonal in nature, but most often is secondary to other medical conditions or drug treatments for said conditions. All types of sexual dysfunction can be further classified as lifelong, acquired, situational, or generalized (or a combination of these).

[0163]

[0186] The DSM-IV-TR defines five major categories of "female sexual dysfunction": It defines desire / sexual interest disorder; "sexual arousal disorder (including genital, subjective, and mixed)"; orgasmic disorder; dyspareunia and vaginismus; and persistent sexual arousal disorder.

[0164]

[0187] Female sexual arousal disorder (FSAD) is the inability to achieve a sufficient level of sexual arousal. FSAD is defined as the persistent or cyclical inability to achieve or maintain arousal, resulting in personal distress. FSAD encompasses both a lack of subjective sensation of arousal (i.e., subjective sexual arousal disorder) and a lack of physical responses such as lubrication and swelling (i.e., genital / physical sexual arousal disorder). FSAD is generally caused by or complicated by medical or physiological factors, but can be strictly psychological in origin. Hypoestrogenism is the most common physiological condition associated with FSAD, leading to urogenital atrophy and decreased vaginal lubrication.

[0165]

[0188] As used herein, "erectile dysfunction (ED)" refers to the loss of function of the penis during sexual activity. A male sexual dysfunction characterized by the inability to develop or maintain an erection Penile erection is the hydraulic effect of blood entering and being held in the spongy tissue within the penis. This process begins when a signal is transmitted from the brain to the nerves within the penis, often as a result of sexual arousal. Difficulty in achieving an erection indicates erectile dysfunction. The most important organic causes are cardiovascular disease and diabetes, neurological problems (e.g., trauma from prostatectomy surgery), hormone deficiency (hypogonadism), and drug side effects.

[0166]

[0189] In one embodiment, the polymorphs and pharmaceutically acceptable salts of Compound I described herein are The salts are therefore useful in the prevention and / or treatment of the following types of cardiac, pulmonary, peripheral, hepatic, renal, or cerebrovascular / endothelial circulation-related disorders, conditions, and diseases: hypertension and disorders associated with reduced 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; diabetic hypertension; essential hypertension; secondary hypertension; gestational hypertension; preeclampsia; portal hypertension; myocardial infarction; Heart failure, HFPEF, HFREF; acute and chronic HF; more specific forms of HF: acute decompensated HF, right ventricular failure, left ventricular failure, total HF, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, HF with heart valve anomalies, mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, tricuspid stenosis, tricuspid regurgitation, pulmonary stenosis, pulmonary regurgitation, complex heart valve anomalies; diabetic heart failure; alcoholic or stored hypertrophic cardiomyopathy; diastolic HF, systolic HF; acute pre-existing chronic HF (worsening HF); diastolic or systolic dysfunction; coronary dysfunction; arrhythmias; reduced ventricular preload; cardiac hypertrophy; heart failure / cardiorenal syndrome; portal hypertension; endothelial dysfunction or injury; atrial and ventricular rhythm disturbances and conduction disturbances: stages I to III (AVB) Atrioventricular block (classes I-III), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, polymorphic ventricular tachycardia, atrial and ventricular premature beats, AV junction premature beats, sick sinus syndrome, syncope, AV nodal reentrant tachycardia; Wolff-Parkinson-White syndrome or acute coronary syndrome; boxer cardiomyopathy; premature ventricular beats; cardiomyopathy; cancer-induced cardiomyopathy; chemotherapy-induced cardiotoxicity; Thromboembolic disorders and ischemia; myocardial ischemia; infarction; myocardial infarction; heart attack; myocardial dysfunction; endothelial dysfunction; stroke; transient ischemic attack (TIA); thromboangiitis obliterans; stable or unstable angina; coronary or peripheral arterial spasm; variant angina; Prinzmetal angina; cardiac hypertrophy; preeclampsia; thrombogenic disorders; ischemia-reperfusion injury; ischemia-reperfusion associated with organ transplantation; lung transplant, pulmonary transplant, heart transplant, and vein graft failure; ischemia-reperfusion associated with conservative blood replacement in trauma patients; Peripheral vascular disease; peripheral arterial disease; peripheral arterial occlusive disease; muscle hypertonia; Raynaud's syndrome or phenomenon (primary and secondary); Raynaud's disease; critical limb ischemia; peripheral embolism; intermittent claudication; vaso-occlusive crisis; muscular dystrophy, Duchenne muscular dystrophy, Becker muscular dystrophy; microcirculatory abnormalities; vascular leakage or permeability control; lumbar spinal stenosis; thromboangiitis obliterans; thromboangiitis; peripheral perfusion disturbances; arterial and venous thrombosis; microalbuminuria; peripheral and autonomic neuropathies; diabetic neuropathic pain; diabetic microangiopathy; hepatic vaso-occlusive disorder; vaso-occlusive crisis in sickle cell disease; hypertensive crisis; · Edema; renal edema due to heart failure; Improvement of perception, concentration, learning or memory performance following cognitive impairment such as that occurring in Alzheimer's disease; Parkinson's disease; vascular dementia; vascular cognitive impairment; cerebral vasospasm; congenital myasthenic syndromes; subarachnoid hemorrhage; traumatic brain injury; mild cognitive impairment, age-related learning and memory impairment, age-related memory loss, vascular dementia, head injury, stroke, post-stroke dementia, traumatic head injury, generalized disturbances of concentration, and disturbances of concentration in children with learning and memory problems; dementia with Lewy bodies; dementia with frontal lobe degeneration including Pick's syndrome; progressive supranuclear palsy; dementia with corticobasal degeneration; amyotrophic lateral sclerosis (ALS); Huntington's disease; demyelination; multiple sclerosis; thalamic degeneration; Creutzfeldt-Jakob dementia; HIV dementia Schizophrenia; Schizophrenia with dementia or Korsakoff psychosis; Multiple system atrophy and other forms of Parkinsonism Plus; Movement disorders; Neuroprotection; Anxiety, tension and depression or post-traumatic stress disorder (PTSD); Bipolar disorder; Schizophrenia; CNS-related sexual dysfunction and sleep disorders; Pathological eating disorders and the use of luxury foods and addictive drugs; Controlling cerebral perfusion; Migraine; Prevention and control of the consequences of cerebral infarction (apoplexy cerebri); Prevention and control of the consequences of stroke, cerebral ischemia and head injury; Neuropathies associated with CNS diseases; Neuropathic pain associated with MS; Chemotherapy-induced neuropathic pain; Neuropathic pain associated with shingles; Neuropathic pain associated with spinal surgery; Shock; cardiogenic shock; sepsis; septic shock; anaphylactic shock; aneurysms; control of leukocyte activation; inhibition or regulation of platelet aggregation; multiple organ dysfunction syndrome (MODS); multiple organ failure (MOF); Pulmonary / Respiratory Conditions: Pulmonary hypertension (PH); pulmonary arterial hypertension (PAH) and associated pulmonary vascular remodeling; vascular remodeling in the form of focal thrombosis and right ventricular hypertrophy; pulmonary hypertonia; primary pulmonary hypertension; secondary pulmonary hypertension; familial pulmonary hypertension; isolated pulmonary hypertension; precapillary pulmonary hypertension; idiopathic pulmonary hypertension; other forms of PH; PH associated with left ventricular disease, HIV, SCD, thromboembolism (CTEPH), sarcoidosis, COPD, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), acute lung injury, alpha-1 antitrypsin deficiency (AATD), emphysema, smoking-induced emphysema, and cystic fibrosis (CF); thrombotic pulmonary arteriopathy; multifactorial pulmonary arteriopathy; cystic fibrosis; bronchoconstriction or pulmonary bronchoconstriction; acute respiratory syndromes; pulmonary fibrosis, lung transplantation; asthma; Left ventricular dysfunction, hypoxemia, WHO group I, II, III, IV, and V hypertension, mitral valve disease, constrictive pericarditis, aortic valve stenosis, cardiomyopathy, mediastinal fibrosis, pulmonary fibrosis, anomalous pulmonary venous return, pulmonary venous obstruction, pulmonary vasculitis, collagen vascular disease, congenital heart disease, elevated pulmonary venous pressure, interstitial lung disease, sleep-disordered breathing, sleep apnea, impaired alveolar hypoventilation, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease, other blood coagulation disorders, chronic thromboembolism, pulmonary hypertension associated with or related to pulmonary embolism; pulmonary embolism caused by tumors, parasites, or foreign bodies; connective tissue diseases, lupus, lupus nephritis, schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease, asthma, emphysema, chronic bronchitis, pulmonary capillary hemangiomatosis, histiocytosis X, lymphangiomatosis, compressed pulmonary vessels compressed pulmonary vessels due to adenopathy, tumor, or fibrosing mediastinitis; Arteriosclerotic diseases or conditions: atherosclerosis, atherosclerosis associated with endothelial injury, platelet and monocyte adhesion and aggregation, smooth muscle proliferation or migration; restenosis, which develops after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), transluminal coronary angioplasty (PTCA), heart transplantation, bypass surgery or inflammatory processes; Damage to micro- and macrovascular vessels (vasculitis); increased levels of fibrinogen and low density DLD; increased concentrations of plasminogen activator inhibitor 1 (PA-1); Metabolic syndrome; metabolic disorders or disorders related to metabolic syndrome: obesity; excess subcutaneous fat; excess body fat accumulation; diabetes; hypertension; lipid-related disorders, hyperlipidemia, dyslipidemia, hypercholesterolemia, decreased high-density lipoprotein cholesterol (HDL-cholesterol), moderately elevated low-density lipoprotein cholesterol (LDL-cholesterol) levels, hypertriglyceridemia, hyperglyceridemia, hypolipoproteinemia, sitosterolemia, fatty liver disease, alcoholic fatty liver disease (AFLD), non-alcoholic fatty liver disease (NAFLD), hepatitis; preeclampsia; multiple kidney disease progression; hepatic steatosis or abnormal lipid accumulation in the liver, non-alcoholic steatohepatitis (NASH); fatty degeneration of the heart, kidneys, or muscles; alpha-betalipoproteinemia; sitosterolemia; xanthomatosis; Tangier disease; hyperammonemia and related disorders; hepatic encephalopathy; other toxic encephalopathies; Reye's syndrome; Disorders of sexual, gynecological and urological conditions: erectile dysfunction; impotence; premature ejaculation; Sexual dysfunction; female sexual arousal dysfunction; hypofunctional sexual arousal disorder; vaginal atrophy; dyspareunia (dyspareunia); atrophic vaginitis; benign prostatic hyperplasia (BPH), prostatic hyperplasia, prostatic enlargement; bladder outlet obstruction; bladder pain syndrome (BPS); interstitial cystitis (IC); overactive bladder; neurogenic bladder and incontinence; diabetic nephropathy; primary and secondary dysmenorrhea; lower urinary tract syndrome (LUTS); endometriosis; pelvic pain; benign and malignant diseases of the male and female genitourinary system; chronic kidney disease; acute and chronic renal insufficiency; acute and chronic renal failure; lupus nephritis; underlying or associated renal diseases: hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial damage, nephropathic diseases, primary and congenital kidney diseases, nephritis; diseases characterized by abnormally decreased creatinine and / or water excretion; diseases characterized by abnormally increased blood concentrations of urea, nitrogen, potassium and / or creatinine; diseases characterized by altered activity of renal enzymes, diseases characterized by altered activity of glutamyl synthetase; diseases characterized by altered urine osmolality or urine volume; diseases characterized by increased microalbuminuria, diseases characterized by macroalbuminuria; diseases characterized by glomerular and arteriolar lesions, tubular dilatation, hyperphosphatemia and / or the need for dialysis; sequelae of renal insufficiency; pulmonary edema enema-related renal dysfunction; HF-related renal dysfunction; uremia- or anemia-related renal dysfunction; electrolyte abnormalities (herkalemia, hyponatremia); disturbances in bone and carbohydrate metabolism; acute kidney injury; · Eye diseases or disorders such as glaucoma, retinopathy and diabetic retinopathy.

[0167]

[0190] The term "inflammation" refers to the reaction of the body to harmful stimuli such as pathogens, damaged cells, or irritants. It represents a complex biological response of vascular tissues. Classic signs of acute inflammation are pain, fever, redness, swelling, and loss of function. Inflammation is a protective attempt by the organism to remove injurious stimuli and initiate the healing process. Although inflammation and infection are often correlated, inflammation is not synonymous with infection (inflammation is often the result of infection). Inflammation can also occur in the absence of infection, but this type of inflammation is typically nonadaptive (such as in atherosclerosis). Inflammation is a stereotyped response and is therefore considered a mechanism of innate immunity, as opposed to adaptive immunity, which is specific to each pathogen. Progressive destruction of tissue in the absence of inflammation jeopardizes the survival of the organism. On the other hand, chronic inflammation can lead to host diseases such as hay fever, periodontitis, atherosclerosis, rheumatoid arthritis, and even cancer (e.g., gallbladder cancer). This is because inflammation is normally tightly regulated by the body. Inflammation can be classified as either acute or chronic. Acute inflammation is the body's initial response to harmful stimuli and is accompanied by increased migration of plasma and leukocytes (especially granulocytes) from the blood to the injured tissue. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vasculature, immune system, and various cells within the injured tissue. Long-term inflammation, known as chronic inflammation, results in a progressive transition in the types of cells present at the site of inflammation and is characterized by the simultaneous destruction and healing of tissue from the inflammatory process.

[0168]

[0191] In another embodiment, the polymorphs and pharmaceutically acceptable salts of Compound I described herein are The acceptable salts are therefore useful in the prevention and / or treatment of the following types of cardiac, pulmonary, peripheral, hepatic, renal, digestive or central nervous system disorders, conditions and diseases which may involve inflammation or inflammatory processes: Inflammation of the heart muscle (myocarditis); chronic myocarditis; acute myocarditis; viral myocarditis; Vasculitis; pancreatitis; peritonitis; rheumatoid diseases; Inflammatory diseases of the kidney; immunological kidney diseases: kidney transplant rejection, immune complex-induced kidney disease, toxin-induced nephropathy, contrast-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 diseases of the eye, blepharitis, dry eye syndrome, and Sjogren's syndrome; ocular fibrosis.

[0169]

[0192] The term "wound healing" refers to the process by which the skin (or another organ or tissue) heals itself after injury. It represents the intricate process by which the body repairs itself. For example, in normal skin, the epidermis (outermost layer) and dermis (inner or deeper layer) exist in steady-state equilibrium, forming a protective barrier against the external environment. Once this protective barrier is breached, the normal (physiological) process of wound healing is immediately initiated. The classical model of wound healing is divided into three or four sequential and overlapping phases: (1) hemostasis (not considered a phase by some authors), (2) inflammation, (3) proliferation, and (4) remodeling. Upon injury to the skin, a complex series of biochemical events occurs in a tightly orchestrated cascade to repair the injury. Within the first minutes after injury, platelets adhere to the injury site, become activated, and aggregate (associate with each other), followed by activation of the coagulation cascade, which forms a clot of aggregated platelets in a network of cross-linked fibrin proteins. This clot stops active bleeding ("hemostasis"). During the inflammatory phase, bacteria and cellular debris are phagocytosed by leukocytes and removed from the wound. Platelet-derived growth factors (stored in platelet alpha granules) are released into the wound, which triggers cell migration and division during the proliferative phase. The proliferative phase is characterized by angiogenesis, collagen deposition, granulation tissue formation, epithelialization, and wound contraction. In "angiogenesis," vascular endothelial cells form new blood vessels. In "fibroplasia" and granulation tissue formation, fibroblasts grow and form a new, temporary extracellular matrix (ECM) by excreting collagen and fibronectin. Simultaneously, "re-epithelialization" of the epidermis occurs, as epithelial cells proliferate and "move" over the wound bed, providing new tissue coverage. During wound contraction, myofibroblasts reduce the size of the wound by gripping and contracting the wound edges using mechanisms similar to those in smooth muscle cells. As their roles near completion, unnecessary cells undergo apoptosis. During maturation and remodeling, collagen is remodeled and reorganized along lines of tension, and cells that are no longer needed are removed by apoptosis. However, this process is not only complex but also fragile and prone to interruption or failure, leading to the formation of non-healing chronic wounds (one example includes diabetic wounds or ulcers, and in particular diabetic foot ulcers).Factors that contribute to non-healing chronic wounds are diabetes, venous or arterial disease, infection, and metabolic deficiencies in the elderly.

[0170]

[0193] The term "bone healing mechanism," or "fracture healing mechanism," refers to the process by which the body promotes the repair of bone fractures. Fracture healing represents a proliferative physiological process that promotes healing. During fracture healing, several recovery phases promote proliferation and protection of the area surrounding the fracture and dislocation. The length of the process depends on the extent of the injury, with a typical margin of 2-3 weeks for repair of most upper body fractures; lower body injuries can last anywhere from 4 weeks to more. The healing process is primarily determined by the "periosteum," the connective tissue membrane that covers the bone. The periosteum is one source of precursor cells that develop into "chondroblasts" and osteoblasts, which are essential for bone healing. Bone marrow (when present), endosteum, microvasculature, and fibroblasts are other sources of precursor cells.

[0171]

[0194] In another embodiment, the polymorphs and pharmaceutically acceptable salts of Compound I described herein are The acceptable salts are therefore useful in the treatment of the following types of diseases, disorders or conditions in which stimulation of the wound or bone healing process is desirable: Diabetic wound or ulcer healing; improved microvascular perfusion; improved microvascular perfusion following injury or to counteract the inflammatory response in perioperative care; anal fissures; diabetic ulcers; diabetic foot ulcers; bone healing mechanisms; osteoclastic bone resorption and remodeling; and new bone formation.

[0172]

[0195] The term "connective tissue" (CT) refers to tissues that support, connect, or connect different types of tissue in the body. It refers to a type of animal tissue that separates the tissues and organs of the body. It is one of four general classes of animal tissue, the others being epithelial, muscular, and nervous tissue. Connective tissue is the tissue that connects the central nervous system. They are found throughout the body, including the nervous system. They are located between other tissues. All CTs have three main components: matrix, fibers, and cells, and all of these components are bathed in fluid.

[0173]

[0196] The term "connective tissue disorder or condition" refers to a condition that causes a connective tissue disorder or condition in one or more parts of the body. Connective tissue disorders refer to any condition involving an abnormality in connective tissue. Certain disorders are typically characterized by immune system hyperactivity, with replacement of normal tissue (e.g., normal tissue of a particular organ) with connective tissue, resulting in inflammation and systemic damage to the tissue. Other disorders involve biochemical abnormalities or structural defects in the connective tissue itself. Some of these disorders are hereditary, and some are of unknown etiology.

[0174]

[0197] When connective tissue disorders are of autoimmune origin, they are called "rheumatic disorders," "autoimmune disorders," It is classified as an "autoimmune rheumatic disorder" or an "autoimmune collagen-vascular disorder."

[0198] In "autoimmune disorders," antibodies or other cells produced by the body attack the body's immune system. Attacking its own tissues. Many autoimmune disorders affect connective tissue in various organs. In autoimmune disorders, inflammation and the immune response can also lead to connective tissue damage around joints and in other tissues, including vital organs such as the kidneys or gastrointestinal organs. The sac surrounding the heart (pericardium), the membrane covering the lungs (pleura), the mediastinum (an ill-defined group of structures in the thorax, surrounded by loose connective tissue, including the heart, the cardiac great vessels, the esophagus, the trachea, the phrenic nerve, the cardiac nerves, the thoracic duct, the thymus, and the lymph nodes of the central chest), and even the brain can be affected.

[0175]

[0199] The term "fibrosis" as used herein refers to the development of fibrosis in a particular organ or part of the body. Fibrosis refers to the accumulation of connective tissue or fibrous tissue (scar tissue, collagen) in the body. When fibrosis arises from a single cell lineage, it is called a "fibroma." Fibrosis occurs because the body attempts to repair and replace damaged cells and can therefore be a reactive, benign, or pathological condition. Physiological fibrosis is similar to the scarring process. Pathological conditions develop when the target tissue is repeatedly and continuously injured. A single episode of injury, even if severe, does not usually result in fibrosis. When injury is repeated or continuous (such as occurs in chronic hepatitis), the body attempts to repair the injury, but this attempt instead results in the excessive accumulation of scar tissue. Scar tissue begins to replace normal tissue in organs that perform specific functions that the scar tissue cannot perform; it can also obstruct 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, the blood pressure in the vein that carries blood from the intestines to the liver (the portal vein) increases, causing a condition known as "portal hypertension."

[0176]

[0200] The term "sclerosis" usually refers to the replacement of normal organ-specific tissue with connective tissue. refers to a hardening or stiffening of tissues or structures or organs that are normally flexible.

[0201] Pulmonary fibrosis (idiopathic pulmonary fibrosis, cystic fibrosis), liver fibrosis (or "cirrhosis") There are many types of fibrosis or fibrotic diseases, including, but not limited to, idiopathic myocardial fibrosis, endomyocardial fibrosis, previous 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 hand and fingers), and some forms of adhesive capsulitis (affecting the shoulder).

[0177]

[0202] Amyotrophic lateral sclerosis (ALS); atherosclerosis; focal segmental glomeruli Sclerosis and nephrotic syndrome; hippocampal sclerosis (affects the brain); lichen sclerosus (a disease that hardens the connective tissue of the vagina and penis); hepatic sclerosis (cirrhosis of the liver); multiple sclerosis or focal sclerosis There are many types of sclerosis or "sclerotic diseases," including, but not limited to, sclerosis (a disease that affects coordination); osteosclerosis (a disease in which bone density is significantly reduced); otosclerosis (a disease that affects the ears); tuberous sclerosis (a rare genetic disease that affects multiple systems); primary sclerosing cholangitis (hardening of the bile ducts); primary lateral sclerosis (progressive weakness in voluntary muscles); and keloids.

[0178]

[0203] The terms "scleroderma" or "systemic sclerosis" or "progressive systemic sclerosis" are used interchangeably. It describes a condition involving scarring of the joints, skin, and internal organs, as well as vascular abnormalities. Systemic sclerosis can sometimes occur in a limited form, for example, sometimes affecting only the skin or primarily certain areas of the skin, or as CREST syndrome (involving peripheral skin but not the trunk). The usual initial symptom of systemic sclerosis is swelling, followed by thickening and hardening of the skin on the fingertips. "Raynaud's phenomenon" is common, in which the fingers suddenly and temporarily become very pale and tingly or numb, painful, or both.

[0179]

[0204] The term "polymyositis" refers to inflammation of the muscles. The term "dermatomyositis" refers to inflammation of the skin. The term "polychondritis" refers to inflammation of the cartilage.

[0205] The term "eosinophilic fasciitis" describes a rare disorder in which eosinophilic immune cells are released, resulting in inflammation and hardening of the "fascia," a layer of tough fibrous tissue just below the skin and over and between the muscles. The fascia becomes painful, inflamed, swollen, and gradually hardens in the arms and legs. As the skin on the arms and legs progressively hardens, the arms and legs become difficult to move. Eventually, they become immobile in their normal position. Sometimes, when the arms are involved, patients can develop carpal tunnel syndrome.

[0180]

[0206] In another embodiment, a polymorph or pharmaceutically acceptable salt of Compound I described herein is Specific diseases of disorders that can be treated and / or prevented by administering acceptable salts include, but are not limited to, the following types of diseases, including inflammatory, autoimmune, or fibrotic diseases (i.e., fibrotic diseases): Genitourinary system or kidney disorders: diabetic nephropathy; renal fibrosis and failure due to chronic kidney disease or renal insufficiency; renal fibrosis and failure due to accumulation / deposition and tissue injury; nephrosclerosis; progressive sclerosis; glomerulonephritis; focal segmental glomerulosclerosis; nephrotic syndrome; prostatic hyperplasia; renal fibrosis; interstitial renal fibrosis; Pulmonary system disorders: pulmonary fibrosis; idiopathic pulmonary fibrosis; cystic fibrosis; progressive massive fibrosis; progressive massive fibrosis affecting the lungs; Disorders affecting the heart: endomyocardial fibrosis; previous myocardial infarction; atrial fibrosis; cardiac interstitial fibrosis; cardiac remodeling and fibrosis; cardiac hypertrophy; Liver and related organ disorders: liver sclerosis or cirrhosis; cirrhosis associated with chronic liver disease; liver fibrosis; hepatic stellate cell activation; NASH; hepatic fibrocollagen and total collagen accumulation; liver diseases of necrotizing inflammatory and / or immunological origin; primary biliary cirrhosis; primary sclerosing cholangitis; other cholestatic liver diseases: those associated with granulomatous liver disease, hepatic malignancies, intrahepatic cholestasis of pregnancy, hepatitis, sepsis, drugs or toxins, graft-versus-host disease, post-liver transplant, common bile duct stones, bile duct tumors, pancreatic cancer, Mirizzi syndrome, AIDS cholangiopathy or parasites; schistosomiasis; hepatocellular carcinoma; Digestive system diseases or disorders: Crohn's disease; ulcerative colitis; gastrointestinal sclerosis; achalasia; Skin or eye diseases: renal fibrosis; proliferative vitroretinopathy; diabetic retinopathy; ocular fibrosis; fibrotic localized or skin disorders or conditions; dermal fibrosis; scleroderma, dermal fibrosis; morphea; hypertrophic scars; nevi; 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 hearing diseases or disorders; hearing loss, partial or total hearing loss; partial or total hearing loss; tinnitus; noise-induced hearing loss; Other diseases involving autoimmune, inflammatory or fibrotic diseases: scleroderma; localized scleroderma or morphea; mediastinal fibrosis; fibrotic mediastinitis; myelofibrosis; retroperitoneal fibrosis; arthrofibrosis; Peyronie's disease; Dupuytren's contracture; lichen sclerosus; some forms of adhesive capsulitis; atherosclerosis; tuberous sclerosis; systemic sclerosis; polymyositis; dermatomyositis; polychondritis; eosinophilic fasciitis; systemic lupus erythematosus or lupus; bone marrow fibrosis, myelofibrosis or osteomyelofibrosis; sarcoidosis; uterine fibroids; endometriosis.

[0181]

[0207] In another embodiment, a polymorph or pharmaceutically acceptable salt of Compound I described herein is Specific diseases of disorders that can be treated and / or prevented by administering an acceptable salt include, but are not limited to: certain types of cancer; sickle cell disease; sickle cell anemia; cancer metastasis; osteoporosis; gastroparesis; functional dyspepsia; diabetic complications; alopecia or hair loss; diseases associated with endothelial dysfunction; neuropathies associated with decreased nitric oxide production; argininosuccinic aciduria; neuromuscular diseases, including, but not limited to, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), limb-girdle muscular dystrophy, distal myopathy, myotonic dystrophy types I and II, facioscapuloperoneal muscular dystrophy, autosomal and X-linked Emery-Dreifuss muscular dystrophy, oculopharyngeal muscular dystrophy, amyotrophic lateral sclerosis, and spinal muscular atrophy (SMA).

[0182]

[0208] In some embodiments, the present invention provides a method for treating a disease, condition, or disorder in a subject. The present invention relates to a method for treating a disease, condition, or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a polymorph or pharmaceutically acceptable salt of Compound I described herein, wherein the disease, condition, or disorder is selected from one of the diseases listed above.

[0183]

[0209] In another embodiment, the solid form of the present invention is in the form of an implantable device, such as a stent. Stents are mesh "tubes" inserted into natural passageways / conduits in the body to prevent or counteract disease-induced, localized flow constrictions. The term can also refer to tubes used to temporarily hold such natural conduits open to allow access for surgery.

[0184]

[0210] Drug-eluting stents (DES) are used to treat narrowed, diseased peripheral or coronary arteries. A DES is a peripheral or coronary stent (scaffold) that is placed inside a peripheral or coronary artery and slowly releases a drug to block cell proliferation, usually smooth muscle cell proliferation. This prevents blood clots (platelet emboli) as well as fibrosis that could otherwise block the stented artery (a process called restenosis). Stents are typically placed into peripheral or coronary arteries during an angioplasty procedure by an interventional cardiologist or interventional radiologist. Drugs commonly used in DES to block cell proliferation include paclitaxel or rapamycin analogs.

[0185]

[0211] In some embodiments of the present invention, polymorphs or pharmaceutical forms of Compound I of the present invention are The therapeutically acceptable salt, or pharmaceutical composition thereof, can be delivered by a drug-eluting stent coated with a solid form or pharmaceutical composition. A drug-eluting stent coated with a solid form (or pharmaceutical composition) of Compound I of the present invention may be useful for preventing stent restenosis and thrombosis during percutaneous transluminal coronary angioplasty. A drug-eluting stent coated with a solid form (or pharmaceutical composition) of Compound I of the present invention may prevent smooth cell growth, as well as aid in the revascularization and regeneration of the endothelial tissue of the artery into which the stent is inserted. It is possible.

[0186]

[0212] Percutaneous coronary intervention for the treatment of refractory angina caused by coronary artery obstructive disease The alternative is a procedure termed coronary artery bypass grafting (CABG). CABG only provides palliation of an ongoing process, which is further complicated by the rapid development of graft atherosclerosis. Saphenous vein grafts are the most commonly used conduits in CABG surgery. The long-term clinical success of venous CABG is hindered by three major reasons: accelerated graft atherosclerosis, incomplete endothelialization, and thrombosis.

[0187]

[0213] In some embodiments, the solid forms of Compound I of the present invention are administered as saphenous grafts during CABG. It can be used to prevent graft failure. The solid form of the present invention can assist the endothelialization process and help prevent thrombosis. In this capacity, the solid form of Compound I is delivered locally in the form of a gel.

[0188]

[0214] The terms "disease," "disorder," and "condition" refer to disorders that involve the development of sGC, cGMP, and / or may be used interchangeably herein to refer to NO-mediated medical or pathological conditions.

[0189]

[0215] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds such as chickens, quails, or turkeys, or mammals), particularly "mammals," including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice), and primates (e.g., monkeys, chimpanzees, and humans), and more particularly humans. In some embodiments, the subject is a non-human animal, such as a farm animal (e.g., a horse, cow, pig, or sheep), or a pet (e.g., a dog, cat, guinea pig, or rabbit). In some embodiments, the subject is a human.

[0190]

[0216] The present invention also provides a method for treating one of the aforementioned diseases, conditions and disorders in a subject. Also provided is a method for treating one of these diseases, conditions, and disorders, comprising administering a therapeutically effective amount of a polymorph or a pharmaceutically acceptable salt of Compound I to a subject in need of treatment. Alternatively, the present invention provides the use of a polymorph or a 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 present invention further provides a method for making or manufacturing a medicament useful for treating one of these diseases, conditions, and disorders, comprising using a polymorph or a pharmaceutically acceptable salt of Compound I.

[0191]

[0217] The term "biological sample" as used herein refers to a sample, whether in vitro or ex vivo. It refers to a biological sample, including, but not limited to, a cell culture or extract thereof; a biopsy or extract thereof obtained from a mammal; blood, saliva, urine, feces, semen, tears, lymphatic fluid, ocular fluid, vitreous humor, or other bodily fluid or extract thereof.

[0192]

[0218] As used herein, the terms "treatment" or "treating" are used interchangeably. These terms refer to an approach for obtaining a beneficial or desired result, including, but not limited to, therapeutic benefit. Therapeutic benefit includes eradication or amelioration of the underlying disorder being treated, as well as eradication or amelioration of one or more symptoms associated with the underlying disorder, such that the patient experiences improvement, even though the patient may still be suffering from the underlying disorder.

[0193]

[0219] As used herein, the terms "treat," "treatment," and "treating" " refers to the progression of a disease resulting from the administration of one or more therapeutic agents (e.g., one or more therapeutic agents such as a polymorph or pharmaceutically acceptable salt of Compound I of the present invention, or a composition thereof). "Treat" refers to a reduction or improvement in the severity and / or duration of an sGC-, cGMP-, and / or NO-mediated condition, or an improvement in one or more symptoms (preferably one or more discernible symptoms) of said condition (i.e., "managing" without "curing" the condition). In certain embodiments, the terms "treat," "treatment," and "treating" refer to an improvement in at least one measurable physical parameter of an sGC-, cGMP-, and / or NO-mediated condition. In other embodiments, the terms "treat," "treatment," and "treating" refer to an inhibition of progression of an sGC-, cGMP-, and / or NO-mediated condition, either physically, e.g., by stabilization of a discernible symptom, or physiologically, e.g., by stabilization of a physical parameter, or both.

[0194]

[0220] The term "preventing" as used herein refers to preventing one or more of a disease or disorder. "Prevent" refers to the administration of a medication to forestall or prevent the onset of a symptom or symptoms. Those of ordinary skill in the medical field will recognize that the term "prevent" is not an absolute term. In the medical field, it is 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, and this is the intent intended in this disclosure. The Physician's Desk Reference, a standard document in the field, uses the term "prevent" hundreds of times. When used therein, the terms "prevent," "preventing," and "prevention," in reference to a disorder or disease, refer to preventing the cause, effects, symptoms, or progression of a disease or disorder before the disease or disorder itself becomes fully manifest.

[0195]

[0221] In one embodiment, the methods of the present invention provide sGC-, cGMP- and / or NO-related The present invention is a preventative or "preemptive" measure for patients, particularly humans, who have a predisposition (eg, a genetic predisposition) to developing the disease, disorder or condition.

[0196]

[0222] In another embodiment, the methods of the present invention provide a method for administering to a patient sGC, cGMP, or NO-related The present invention is a preventative or "pre-emptive" measure for patients, particularly humans, suffering from a disease, disorder or condition that is at risk of developing into the disease, disorder or condition.

[0197]

[0223] The solid forms and pharmaceutical compositions described herein contain sGC, cGMP, and and / or may be used alone or in combination therapy for the treatment or prevention of diseases or disorders mediated, controlled or affected by NO.

[0198]

[0224] The solid forms and compositions disclosed herein also have the potential to be used in dogs, cats, mice, and rats. The present invention is also useful for veterinary treatment of companion animals, exotic animals and farm animals, including, but not limited to, rats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs and cattle.

[0199]

[0225] In another embodiment, the present invention provides a method for stimulating sGC activity in a biological sample. The present invention also provides a method for the treatment of sGC stimulating agents, which comprises contacting said biological sample with the solid form or composition of the present invention. The use of sGC stimulating agents in biological samples is useful for various purposes known in the art. Examples of such purposes include, but are not limited to, biological assays and biological specimen storage.

[0200] Combination therapy

[0226] The solid forms and pharmaceutical compositions described herein may comprise one or more further It can be used in combination therapy with other therapeutic agents. For combination treatment with more than one active agent, if the active agents are in separate dosage formulations, the active agents can be administered separately or together. In addition, the administration of one element can be before, simultaneously with, or after the administration of the other agent.

[0201]

[0227] When co-administered with other agents, e.g., when co-administered with another therapeutic drug, The "effective amount" of the two drugs depends on the type of drug used. Suitable dosages are known for approved drugs and can be adjusted by those skilled in the art based on the subject's condition, the type of condition(s) being treated, and the amount of the compound described herein used. If no amount is specified, an effective amount is assumed. For example, the solid forms described herein can be administered to a subject at dosage ranges of about 0.01 to about 10,000 mg / kg body weight / day, about 0.01 to about 5000 mg / kg body weight / day, about 0.01 to about 3000 mg / kg body weight / day, about 0.01 to about 1000 mg / kg body weight / day, about 0.01 to about 500 mg / kg body weight / day, about 0.01 to about 300 mg / kg body weight / day, or about 0.01 to about 100 mg / kg body weight / day.

[0202]

[0228] When "combination therapy" is utilized, an effective amount includes a first amount of a polymorph of Compound I or This may be achieved using a pharmaceutically acceptable salt and a second amount of an additional suitable therapeutic agent.

[0229] In one embodiment of the present invention, a polymorph or a pharmaceutically acceptable salt of Compound I, and the additional therapeutic agent are each administered in an effective amount (i.e., an amount that is therapeutically effective when each is administered alone). In another embodiment, the polymorph or pharmaceutically acceptable salt of Compound I and the additional therapeutic agent are each administered in an amount that does not provide a therapeutic effect alone (a subtherapeutic dose). In yet another embodiment, the polymorph or pharmaceutically acceptable salt of Compound I may be administered in an effective amount, while the additional therapeutic agent is administered in a subtherapeutic dose. In yet another embodiment, the polymorph or pharmaceutically acceptable salt of Compound I may be administered in a subtherapeutic dose, while the additional therapeutic agent, such as, for example, a suitable cancer therapeutic agent, is administered in an effective amount.

[0203]

[0230] As used herein, the terms "in combination with" or "co-administration" refer to one or more The terms may be used interchangeably to refer to the use of more therapeutic agents (e.g., one or more prophylactic and / or therapeutic agents). The use of the terms does not restrict the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject.

[0204]

[0231] Simultaneous administration may be achieved, for example, by a capsule or other container having a fixed ratio of first and second amounts. The simultaneous administration of the first and second amounts of compounds includes administration in an essentially simultaneous manner, such as in a single pharmaceutical composition such as a tablet, or in multiple separate capsules or tablets. In addition, such simultaneous administration also includes the use of each compound in a sequential manner, in any order. When simultaneous administration involves separate administration of a first amount of a polymorph or a pharmaceutically acceptable salt of Compound I and a second amount of an additional therapeutic agent, the compounds are administered sufficiently closely in time to have the desired therapeutic effect. For example, the period between each administration that can produce the desired therapeutic effect can range from minutes to hours and can be determined taking into account the properties of each compound, such as potency, solubility, bioavailability, plasma half-life, and kinetic characteristics. For example, the polymorph or a 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 hours of each other, within about 1 hour of each other, or within about 30 minutes of each other.

[0205]

[0232] More particularly, a first therapeutic agent (e.g., a prophylactic or therapeutic amount as defined herein) is administered. The described polymorph or pharmaceutically acceptable salt of Compound I) can be administered to a subject concomitantly prior to (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 before) or after (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 after) the administration of a second therapeutic agent (e.g., a prophylactic or therapeutic agent such as an anti-cancer agent).

[0206]

[0233] In combination with a polymorph or pharmaceutically acceptable salt of Compound I, either separately or Examples of other therapeutic agents that may be administered in the same pharmaceutical composition include: (1) Endothelium-derived releasing factor (EDRF); (2) NO donors, such as nitrosothiols, nitriles, sydnonimines, NONOates, N-nitrosamines, N-hydroxylnitrosamines, nitrosoimines, nitrotyrosines, diazetine dioxide, oxatriazole 5-imines, oximes, hydroxylamines, N-hydroxyguanidines, hydroxyureas, or antifuroxans. Some examples of these types of compounds include: glyceryl trinitrate (GTN, also known as nitroglycerin, nitroglycerine, and trinitrogylcerin), the nitrate ester of glycerol; sodium nitroprusside (SNP), in which one molecule of nitric oxide coordinates to iron metal to form a square bipyramidal complex; 3-morpholinosydnonimine (SIN-1), a zwitterionic compound formed by the combination of morpholine and sydnonimine; S-nitroso-N-acetylpenicillamine (SNAP), an N-acetylamino acid derivative with a nitrosothiol functionality; diethylenetriamine / NO (DETA / NO), a compound of nitric oxide covalently linked to diethylenetriamine; and NCX4016, the m-nitroxymethylphenyl ester of acetylsalicylic acid.Some more specific examples of these classes of NO donors are: classical nitrovasodilators such as organic nitrates and nitrites, including nitroglycerin, amyl nitrite, isosorbide dinitrate, 5-isosorbide mononitrate, and nicorandil; isosorbide (Dilatrate®-SR, Imdur®, Ismo®, Isordil®, Isordil®, Titradose®, Monoket®), FK409 (NOR-3); FR144420 (NOR-4); 3-morpholinosydnonimine; linsidomine chlorohydrate ("SIN-1"); S-nitroso-N-acetylpenicillamine ("SNAP"); AZD3582 (CINOD) Lead compound), NCX4016, NCX701, NCX1022, HCT1026, NCX1015, NCX950, NCX1000, NCX1020, AZD4717, NCX1510 / NCX1512, NCX2216, and NCX4040 (all available from NicOx SA), S-nitrosoglutathione (GSNO), sodium nitroprusside, S-nitrosoglutathione mono-ethyl-ester (GSNO-ester), 6-(2-hydroxy-1-methyl-nitrosohydrazino)-N-methyl-1-hexanamine (NOC-9) or diethylamine NONOate. Nitric oxide donors are also described in U.S. Patent Nos. 5,155,137, 5,366,997, 5,405,919, 5,650,442, 5,700,830, 5,632,981, 6,290,981, 5,691,423, 5,721,365, 5,714,511, 6,511,911, and 5,814,666, Chrysselis et al. (2002) J Med Chem. 45:5406-9 (e.g., NO donors 14-17), and Nitric Oxide Donors for Pharmaceutical and Biological Research, Eds: Peng George Wang, Tingwei Bill Cai, Naoyuki Also disclosed in Taniguchi, Wiley, 2005;. (3) other substances that increase cGMP concentrations, such as protoporphyrin IX, arachidonic acid, and phenylhydrazine derivatives; (4) Nitric oxide synthase substrates: for example, n-hydroxyguanidine-based analogs 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 (homo-Arg, homo-NOHA, N-tert-butyloxal, such as si- and N-(3-methyl-2-butenyl)oxy-L-arginine, canavanine, epsilon guanidine-carboxylic acid, agmatine, hydroxyl-agmatine, 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 its para-substituted derivatives with -F, -Cl, -methyl, and -OH substituents, respectively); guanidine derivatives such as 3-(trifluoromethyl)propylguanidine; and others reviewed in Cali et al. (2005, Current Topics in Medicinal Chemistry 5:721-736) and others disclosed in the references cited therein; (5) Compounds that enhance eNOS transcription: for example, those described in WO 02 / 064146, WO 02 / 064545, WO 02 / 064546 and WO 02 / 064565, and corresponding patent documents such as US2003 / 0008915, US2003 / 0022935, US2003 / 0022939 and US2003 / 0055093. Other eNOS transactivators, including those described in US20050101599 (e.g., 2,2-difluorobenzo[1,3]dioxole-5-carboxylic acid indan-2-ylamide, and 4-fluoro-N-(indan-2-yl)-benzamide), and the Sanofi-Aventis compounds AVE3085 and AVE9488 (CA Registry NO. 916514-70-0; Schafer et al., Journal of Thrombosis and Homeostasis 2005; Volume 3, Supplement 1: Abstract No. P1487); (6) NO-independent, heme-dependent sGC activator: BAY 58-2667 (see patent publication DE19943635)

[0207] [ka]

[0208] HMR-1766 (ataciguat sodium, see patent publication WO2000002851)

[0209] [ka]

[0210] S3448 (2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide (see patent publications DE19830430 and WO2000002851)

[0211] [ka]

[0212] and HMR-1069 (Sanofi-Aventis) Including, but not limited to:

[0213] (7) Heme-dependent sGC stimulators: YC-1 (see patent publications EP667345 and DE19744026)

[0214] [ka]

[0215] Riociguat (BAY 63-2521, Adempas, commercial product, described in DE19834044)

[0216] [ka]

[0217] Neliciguat (BAY 60-4552, described in WO 2003095451)

[0218] [ka]

[0219] Vericiguat (BAY 1021189, clinical backup to riociguat), BAY 41-2272 (described in DE19834047 and DE19942809)

[0220] [ka]

[0221] BAY 41-8543 (described in DE19834044)

[0222] [ka]

[0223] Etriciguat (described in WO 2003086407)

[0224] [ka]

[0225] CFM-1571 (see patent publication WO2000027394)

[0226] [ka]

[0227] A-344905, its acrylamide analog A-350619 and aminopyrimidine analog A-778935.

[0228] [ka]

[0229] [ka]

[0230] Compounds disclosed in one of the publications: US20090209556, US8455638, US20110118282 (WO2009032249), US20100292192, US20110201621, US7947664, US8053455 (WO2009094242), US20100216764, US8 507512, (WO2010099054), US20110218202 (WO2010065275), US20130012511 (WO2011119518), US20130072492 (WO2011149921), US20130210798 (WO2012058132) and other compounds disclosed in Tetrahedron Letters (2003), 44(48):8661-8663 Including, but not limited to:

[0231] (8) Compounds that inhibit the degradation of cGMP: PDE5 inhibitors, such as sildenafil (Viagra®) and other related drugs, such as avanafil, lodenafil, mirodenafil, sildenafil citrate (Revatio®), tadalafil (Cialis® or Adcirca®), vardenafil (Levitra®), and udenafil; alprostadil; and dipyridamole; PF-00489791; For example, PDE9 inhibitors such as PF-04447943; (9) Calcium channel blockers: Dihydropyridine calcium channel blockers: amlodipine (Norvasc), aranidipine (Sapresta), azelnidipine (Calblock), barnidipine (Hypoca), benidipine (Coniel), cilnidipine (Atelec, Sinalong, Siscard), clevidipine (Cleviprex), diltiazem, efonidipine (Landel), felodipine (Plendil), lacidipine (Motens, Lacipil), lercanidipine (Zanidip), manidipine (Callot, Madipine), nicardipine (Cardene, Cardene SR) Sr), nifedipine (Procadia, Adalat), nilvadipine (Nivadil), nimodipine (Nimotop), nisoldipine (Bimicard, Sular, Syscor), nitrendipine (Cardif, Nitrepin, Byrotensin), pranidipine (Acalas), isradipine (Lomir); etc. Phenylalkylamine calcium channel blockers: Verapamil (Kalan, Isoptin)

[0232] [ka]

[0233] gallopamil (Procorum, D600); Benzothiazepines: Diltiazem (Cardizem);

[0234] [ka]

[0235] Non-selective calcium channel inhibitors: mibefradil, bepridil and fluspirilene, fendiline, etc.; (10) Endothelin receptor antagonists (ERAs): For example, two types of (ET A and E.T. B ) the endothelin receptor antagonist, bosentan (marketed as Tracleer®); sitaxentan, marketed under the name Thelin®; ambrisentan, marketed in the United States as Letairis®; Actelion-1, a dual / nonselective endothelin antagonist that entered clinical trials in 2008; (11) Prostacyclin derivatives or analogs: for example, prostacyclin (prostaglandin I2), epoprostenol (synthetic prostacyclin, commercially available as Flolan®); treprostinil (Remodulin®), iloprost (Ilomedin®), iloprost (commercially available as Ventavis®); oral and inhaled forms of Remodulin® under development; beraprost, an oral prostanoid available in Japan and Korea; (12) Antihyperlipidemic drugs: bile acid sequestrants (e.g., cholestyramine, colestipol, colestilan, and colesevelam); statins such as atorvastatin, simvastatin, lovastatin, fluvastatin, pitavastatin, rosuvastatin, and pravastatin; cholesterol absorption inhibitors such as ezetimibe; other antihyperlipidemic agents such as ethyl icosapentate, omega-3 fatty acid ethyl esters, and Reducol; clofibrate, bezafibrate Fibric acid derivatives such as fenofibrate, clinofibrate, gemfibrozil, lonifibrate, binifibrate, fenofibrate, ciprofibrate, and choline fenofibrate; nicotinic acid derivatives such as acipimox and niacin; also, combinations of statins, niacin, intestinal cholesterol absorption-inhibiting supplements (such as ezetimibe), and fibrates; antiplatelet therapies such as clopidogrel bisulfate; etc. (13) Anticoagulants, including the following: Coumarins (vitamin K antagonists): Warfarin® (Coumadin), used primarily in the US and UK; Acenocoumaro® and P henprocoumon®, mainly used in other countries; Phenindione®; Heparin and derivatives: heparin; low molecular weight heparin, fondaparinux and idraparinux; etc. Direct thrombin inhibitors: argatroban, lepirudin, bivalirudin, and dabigatran; ximelagatran (Exanta®, not approved in the US); etc. Tissue plasminogen activator, such as alteplase, which is used to dissolve blood clots and unblock arteries; (14) Antiplatelet drugs: for example, thienopyridines such as Lopidogrel and Ticlopidine; Dipyridamole; Aspirin; (15) ACE inhibitors, for example, of the following types: · Sulfhydryl-containing medications such as captopril (trade name Capoten®), the first ACE inhibitor, and zofenopril; Dicarboxylate-containing medications such as enalapril (Vasotec / Renitec®); ramipril (Altace / Tritace / Ramace / Ramiwin®); quinapril (Accupril®), perindopril (Covasil / Aceon®); lisinopril (Lisodur / Lopril / Novatec / Prinivil / Zestril®) and benazepril (Lotensin®); phosphonate-containing medications such as fosinopril; Naturally occurring ACE inhibitors such as casokinin and lactokinin, which are degradation products of casein and whey that occur naturally after the ingestion of dairy products, especially fermented milk; the lactotripeptides Val-Pro-Pro and Ile-Pro-Pro, produced by the probiotic Lactobacillus helveticus or derived from casein, also have ACE-inhibitory and antihypertensive functions; Other ACE inhibitors such as alacepril, delapril, cilazapril, imidapril, trandolapril, temocapril, moexipril, and spirapril (16) supplemental oxygen therapy; (17) Beta-blockers, such as the following types: Non-selective drugs: Alprenolol®, Bucindolol®, Carteolol®, Carvedilol® (with additional alpha-blocking action), Labetalol® (with additional alpha-blocking action), Nadolol®, Penbutolol® (with endogenous sympathomimetic action), Pindolol® (with endogenous sympathomimetic action), Oxprenonol, Acebutolol, Sotalol, Mepindolol, Celiprolol, Arotinolol, Tertatolol, Amosulalol, Nipradilol, Propranolol® and Timolol®; β1-selective drugs: Acebutolol® (having intrinsic sympathomimetic properties), Atenolol®, Betaxolol®, Bisoprolol®, Celiprolol®, dobutamine hydrochloride, irsogladine maleate, carvedilol, talinolol, Esmolol®, Metoprolol® and Nebivolol®; β2-selective drugs: Butaxamine® (weak α-adrenergic agonist effect); (18) Antiarrhythmic drugs: the following types, etc. Type I (sodium channel blockers): quinidine, lidocaine, phenytoin, propafenone Type III (potassium channel blockers): amiodarone, dofetilide, sotalol Type V: adenosine, digoxin (19) Diuretics: for example, thiazide diuretics such as chlorothiazide, chlorthalidone, and hydrochlorothiazide, bendroflumethiazide, cyclopenthiazide, methyclothiazide, polythiazide, quinethazone, xipamide, metolazone, indapamide, and cicletanine; loop diuretics such as furosemide and toresamide; potassium-sparing diuretics such as amiloride, spironolactone, potassium canrenoate, eplerenone, and triamterene; combinations of these drugs; and other diuretics such as acetazolamide and carperitide. (20a) Direct-acting vasodilators such as hydralazine hydrochloride, diazoxide, sodium nitroprusside, and cadralazine; other vasodilators such as isosorbide dinitrate and 5-isosorbide mononitrate; (20b) Exogenous vasodilators: Adenocard®, an adenosine agonist, primarily used as an antiarrhythmic drug; Alpha-blockers (block the vasoconstrictor effects of adrenaline): alpha-1-adrenergic receptor antagonists such as prazosin, indoramin, urapidil, bunazosin, terazosin, and doxazosin · Atrial natriuretic peptide (ANP); ·ethanol · Histamine inducer that complements the action of proteins C3a, C4a and C5a by inducing histamine release from mast cells and basophilic granulocytes; Tetrahydrocannabinol (THC), the main active chemical in marijuana, which has a minor vasodilator effect; Papaverine, an alkaloid found in the hypnotic plant Papaver somniferum; (21) Bronchodilators: There are two main types of bronchodilators, beta-2 agonists and anticholinergics, as exemplified below: Beta-2 agonists: Salbutamol® or albuterol (common brand name: Ventolin) and Terbutaline® are short-acting beta-2 agonists for rapid relief of COPD symptoms. Long-acting beta-2 agonists (LABAs) such as Salmeterol® and Formoterol®; Anticholinergics: Ipratropium® is the most widely prescribed short-acting anticholinergic. Tiotropium® is the most commonly prescribed long-acting anticholinergic in COPD; Theophylline®, a bronchodilator and phosphodiesterase inhibitor; (22) Corticosteroids: beclomethasone, methylprednisolone, betamethasone, prednisone, prenisolone, triamcinolone, dexamethasone, fluticasone, flunisolide, and hydrocortisone, as well as corticosteroid analogs such as budesonide. (23) Dietary supplements: for example, omega-3 oils; folic acid, niacin, zinc, copper, Korean red ginseng, ginkgo biloba, pine bark, Tribulus terrestris, arginine, oats, horny goat weed, maca bulb, muira puama, saw palmetto, and Swedish flower pollen; vitamin C, vitamin E, vitamin K2; testosterone supplements, testosterone transdermal patches; Zoraxel, naltrexone, Bremelanotide (formerly PT-141), Melanotan II, hMaxi-K; Prelox: a proprietary mixture / combination of natural ingredients, L-arginine aspartate, and Pycnogenol; etc. (24) PGD2 receptor antagonists: US Patent Publications US20020022218, US20010051624, and US20030055077, PCT Patent Publications W09700853, W09825919, WO03066046, WO03066047, WO03101961, WO03101981, WO04007451, W compounds described as having PGD2 antagonistic activity in WO0178697, WO04032848, WO03097042, WO03097598, WO03022814, WO03022813, and WO04058164, European patent applications EP945450 and EP944614, and those 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: cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (sirolimus, Rapamune) and other FK-506-type immunosuppressants, and mycophenolates, such as mycophenolate mofetil (CellCept®); and the like. (26) Nonsteroidal antiasthmatic drugs: β2-agonists (e.g., terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, salmeterol, bitolterol, and pirbuterol) and β2-agonist-corticosteroid combinations (e.g., salmeterol-fluticasone (Advair®), formoterol-budesonide (Symbicort®)), theophylline, cromolyn, sodium cromoglycate, nedocromil, atropine, ipratropium, ipratropium bromide, leukotriene biosynthesis inhibitors (zileuton, BAY1005); and the like. (27) Nonsteroidal anti-inflammatory drugs (NSAIDs): propionic acid derivatives (e.g., alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (e.g., indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, soxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (e.g., flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid, and tolfenamic acid), biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal), oxicams (e.g., isoxicam, piroxicam, sudoxicam, and tenoxicam), salicylates (e.g., acetylsalicylic acid and sulfasalazine), and pyrazolones (e.g., apazone, bezupiperylone, feprazone, mofebutazone, oxyphenbutazone, and phenylbutazone); (28) Cyclooxygenase-2 (COX-2) inhibitors: 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; and (29) Antidiabetic agents: insulin and insulin-like agents, sulfonylureas (e.g., glyburide, glibenclamide, glipizide, gliclazide, gliquidone, glimepiride, meglinatide, tolbutamide, chlorpropamide, acetohexamide, tolazamide), biguanides such as metformin (Glucophage®), α-glucosidase inhibitors (acarbose, epalrestat, voglibose, miglitol, etc.), thiazolidinone compounds such as rosiglitazone (Avandia®), troglitazone (Rezulin®), ciglitazone, pioglitazone (Actos®), and englitazone; insulins such as pioglitazone and rosiglitazone. insulin sensitizers; insulin secretagogues such as repaglinide, nateglinide, and mitiglinide; incretin-like agents such as exanatide and liraglutide; amylin analogs such as pramlintide; hypoglycemic agents such as chromium picolinate (optionally combined with biotin); dipeptidyl peptidase IV inhibitors such as sitagliptin, vildagliptin, saxagliptin, alogliptin, and linagliptin; vaccines currently in development for the treatment of diabetes; AVE-0277, Alum-GAD, BHT-3021, IBC-VS01; cytokine-targeted therapies in development for the treatment of diabetes, such as anakinra, canakinumab, diacerein, gevokizumab, LY-2189102, MABP-1, GIT-027, and the like; (30) HDL cholesterol-raising agents: anacetrapib, MK-524A, CER-001, DRL-17822, dalcetrapib, JTT-302, RVX-000222, TA-8995, etc.; (31) Antiobesity drugs: 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; phentermine / topiramate, bupropion / naltrexone, sibutramine / metformin, bupropion SR / zonisamide SR, salmeterol, xinafoate / fluticasone propionate; lorcaserin hydrochloride, phentermine Intermine / Topiramate, Bupropion / Naltrexone, Cetilistat, Exenatide, KI-0803, Liraglutide, Metformin Hydrochloride, Sibutramine / Metformin, 876167, ALS-L-1023, Bupropion SR / Zonisamide SR, CORT-108297, Canagliflozin, Chromium Picolinate, GSK-1521498, LY-377604, Metreleptin, Obinepitide, P-57 AS3, PSN-821, salmeterol xinafoate / fluticasone propionate, sodium tungstate, somatropin (recombinant), TM-30339, TTP-435, tesamorelin, tesofensine, belneperit, zonisamide, BMS-830216, ALB-127158, AP-1030, ATHX-105, AZD-2820, AZD-8329, beloranib hemioxalate hemioxalate), CP-404, HPP-404, ISIS-FGFR4Rx, insulinotropin, KD-3010PF, 05212389, PP-1420, PSN-842, peptide YY3-36, resveratrol, S-234462;Combinations of S-234462, Sobetirome, TM-38837, Tetrahydrocannabivarin, ZYO-1, beta-lapachone, etc.; (32) Angiotensin receptor blockers: losartan, valsartan, candesartan cilexetil, eprosaran, irbesartan, telmisartan, olmesartan medoxomil, azilsartan medoxomil, etc.; (33) Renin inhibitors: aliskiren hemifumirate, etc.; (34) Centrally acting alpha-2-adrenergic receptor agonists: methyldopa, clonidine, guanfacine, etc.; (35) Adrenergic neuron blockers: guanethidine, guanadrel, etc.; (36) Imidazoline I-1 receptor agonists: Rimenidine dihydrogen phosphate and Moxonidine hydrochloride hydrate, etc.; (37) Aldosterone antagonists: Spironolactone, Eplerenone, etc. (38) Potassium channel activators: pinacidil, etc. (39) Dopamine D1 agonists: such as fenoldopam mesylate; other dopamine agonists such as ibopamine, dopexamine, and docarpamine; (40) 5-HT2 antagonists: ketanserin, etc.; (42) Vasopressin antagonists: tolvaptan, etc.; (43) Calcium channel sensitizers: such as levosimendan or activators such as nicorandil; (44) PDE-3 inhibitors: amrinone, milrinone, enoximone, vesnarinone, pimobendan, olprinone, etc.; (45) Adenylate cyclase activators: colforsin dapropate hydrochloride, etc.; (46) Positive inotropes: such as digoxin and methyldigoxin; metabolic inotropes such as ubidecarenone; brain natriuretic peptides such as nesiritide; (47) Drugs used to treat erectile dysfunction: alprostadil, aviptadil, phentolamine mesylate, Weige, alprostadil, etc.; (48) Anti-obesity drugs:

[0236] [Table 1]

[0237] (49) Drugs used to treat Alzheimer's disease: e.g., Razadyne cholinesterase inhibitors prescribed for mild to moderate Alzheimer's disease, including Exelon® (galantamine), Exelon® (rivastigmine), and Aricept® (donepezil), Cognex® (tacrine); Namenda® (memantine), an N-methyl-D-aspartate (NMDA) antagonist, and Aricept®, prescribed to treat moderate to severe Alzheimer's disease; vitamin E (antioxidant).

[0238] (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 citalopram (Celexa®); and others such as doxepin (Sinequan®) and trazodone (Desyrel®); SNRIs (e.g., venlafaxine and reboxetine); dopaminergic antidepressants (e.g., bupropion and amineptine).

[0239] (51) Neuroprotective drugs: e.g., memantine, L-dopa, bromocriptine, pergol, talipexole, pramipexole, cabergoline; neuroprotective drugs currently under development include antiapoptotic drugs (CEP 1347 and CTCT346), lazaroids, bioenergetic therapy, antiglutamate agents, and dopamine receptor antagonists. Other clinically evaluated neuroprotective drugs include the monoamine oxidase B inhibitors selegiline and rasagiline, dopamine agonists, and the complex I mitochondrial enhancer coenzyme Q10.

[0240] (52) Antipsychotic medications: for example, ziprasidone (Geodon™), risperidone (Risperdal™), and olanzapine (Zyprexa™).

[0241] (53) NEP inhibitors: sacubitril, omapatrilat, etc. (54) Methylene Blue (MB) Including, but not limited to:

[0242] kit

[0234] The solid forms and pharmaceutical formulations described herein can be included in kits. A kit may contain two or more drugs, each individually packaged or formulated, in single or multiple doses, or two or more drugs packaged or formulated in combination, in single or multiple doses. Thus, one or more drugs may be present in a first container, and the kit may optionally contain one or more drugs in a second container. The container or multiple containers are placed within a package, which may optionally contain instructions for administration or dosage. The kit may include additional components, such as a syringe or other means for administering the drug as well as the diluent or other means for formulation. Thus, a kit may include: a) a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier, vehicle, or diluent; and b) a container or package. The kit may optionally include instructions describing one of the methods of using the pharmaceutical composition in one or more of the methods described herein (e.g., preventing or treating one or more of the diseases and disorders described herein). The kit optionally contains one or more additional agents described herein for simultaneous therapeutic use. The pharmaceutical composition comprising the compound described herein and the second pharmaceutical composition included in the kit may optionally be combined in the same pharmaceutical composition.

[0243] The kit may include a container or package for containing the pharmaceutical composition, and may also include a divided bottle. Or it may also have divided containers such as divided foil packets. The container may be, for example, a paper or cardboard box, a glass or plastic bottle or jar, a resealable bag (for example, to keep "supplements" of tablets in different containers), or a blister pack containing individual doses to be extruded from the pack based on a treatment schedule. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets can be contained in a bottle, which in turn is contained in a box.

[0244]

[0236] An example of a kit is a so-called blister pack. Blister packs are well known in the industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively stiff material covered with a foil, preferably a transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses may have the size and shape of individual tablets or capsules to be packaged, or may have the size and shape to accommodate multiple tablets and / or capsules to be packaged. The tablets or capsules are then placed into the recesses to fit them, and the sheet of relatively stiff material is sealed to the plastic foil at the foil surface opposite to the direction in which the recesses were formed. As a result, the tablets or capsules are individually sealed or collectively sealed within the recesses between the plastic foil and the sheet, as desired. The strength of the sheet is preferably such that manual pressure on the recesses forms openings in the sheet at the locations of the recesses, allowing the tablets or capsules to be removed from the blister pack. The tablets or capsules can then be removed through the openings.

[0245]

[0237] For a physician, pharmacist, or subject regarding when a therapeutic drug should be taken It may be desirable to provide a written memory aid containing information and / or instructions. A "daily dose" may be a single tablet or capsule or several tablets or capsules to be taken in a given day. When a kit contains separate compositions, one or more of the daily dose compositions of the kit may consist of one tablet or capsule, while another one or more of the daily dose compositions of the kit may consist of several tablets or capsules. The kit may take the form of a dispenser designed to dispense one daily dose at a time for its intended use. The dispenser may be equipped with a memory aid to further promote compliance with the regimen. An example of such a memory aid is a mechanical counter that indicates the number of daily doses dispensed. Another example of such a memory aid is a battery-powered microchip memory with an LCD display or an audible cue, for example, that reads the date the last daily dose was taken and / or reminds the user when the next dose should be taken. [Example]

[0246] Example 1 Preparation of crude compound I i): Coupling of compound (1') with N,O-dimethylhydroxylamine to provide N-methoxy-N-methylisoxazole-3-carboxamide (2').

[0247] [ka]

[0248] Isoxazole-3-carboxylic acid ((1'), 241.6 g, 2137 mm A suitable reaction vessel equipped with a mechanical stirrer and digital thermometer was charged with 1.0 equiv. of toluene (1450 mL), and DMF (7.8 g, 107 mmole, 0.05 equiv.). The resulting slurry was heated to 45-50°C. Oxalyl chloride (325 g, 2559 mmole, 1.2 equiv.) was then charged via addition funnel over 2 hours, maintaining the reaction temperature between 45-50°C; vigorous gas evolution was observed. After the addition, a brown mixture was obtained. The brown mixture was heated to 87-92°C over 1 hour and stirred at 87-92°C for 1 hour. The reaction was complete as indicated by HPLC. During heating, the brown mixture turned to a dark solution. The reaction was monitored by quenching a portion of the reaction mixture into piperidine and monitoring the piperidine amide by HPLC. The dark mixture was cooled to 20-25°C and then filtered through a sintered glass funnel to remove insoluble material. The dark filtrate was concentrated under reduced pressure to a volume of 400 mL of a dark oil.

[0249] Potassium carbonate (413 g, 2988 mmole, 1.4 eq.) and water (10 A solution of N,O-dimethylhydroxyamine hydrochloride (229 g, 2348 mmol, 1.1 equiv.) was added to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The reaction solution was cooled to -10 to -5°C. N,O-dimethylhydroxyamine hydrochloride (229 g, 2348 mmol, 1.1 equiv.) was added to a suitable reaction vessel and dissolved in water (1000 mL). The N,O-dimethylhydroxyamine solution and dichloromethane (2500 mL) were then added to the potassium carbonate solution.

[0250]

[0240] Next, the above dark oil (400 mL) was added to a reaction mixture maintained at a temperature of -10 to 0°C. The solution was slowly added via an addition funnel while stirring. The addition was slightly exothermic, resulting in a brown mixture after the addition. The mixture was stirred at 0-5°C for 20 minutes and then warmed to 20-25°C. The lower organic layer was collected and the upper aqueous 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 ( 1 261.9 g, 97% by mass, 76% yield by H-NMR, 3% by mass toluene, 0.04% by mass water content by KF). 1 H-NMR (500 MHz, CDCl3) δ ppm 8.48 (s, 1 H); 6.71(s, 1 H); 3.78 (s, 3 H); 3.38 (s, 3 H).

[0251] ii): Alkylation of compound (2') with ethyl propiolate to provide (E)-ethyl 4-(isoxazol-3-yl)-2-(methoxy(methyl)amino)-4-oxobut-2-enoate (3').

[0252] [ka]

[0253]

[0241] Intermediate (2') (72.2g, 96% by mass, 444mmole, 1.0 equivalent) Ethyl propiolate (65.7 g, 670 mmole, 1.5 equiv.) and anhydrous THF (650 mL) were charged to a suitable reaction vessel equipped with a mechanical stirrer and digital thermometer. The solution was cooled to -65 to -55 °C. Sodium bis(trimethylsilyl)amide in THF (1 M, 650 mL, 650 mmole, 1.46 equiv.) was then slowly charged via addition funnel while maintaining the reaction temperature at -65 to -55 °C. The mixture was stirred below -55 °C for 10 minutes after the addition was complete. 1 N HCl (650 mL, 650 mmole, 1.46 equiv.) was then charged to quench the reaction while maintaining the reaction temperature below -20 °C, followed immediately by the 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) and concentrated under reduced pressure to give a dark oil.

[0254] The dark oil was dissolved in dichloromethane / ethyl acetate / heptane (150 mL / 10 The resulting slurry 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% purity by HPLC). 1H-NMR (500 MHz, CDCl3) δ ppm 8.42 (d, J=1.53 Hz, 1 H); 6.76 (d, J=1.53 Hz, 1 H); 6.18 (s, 1 H); 4.47 (q, J=7.07 Hz, 2H); 3.75 (s, 3 H); 3.21 (s, 3 H); 1.41 (t, J=7.17 Hz, 3 H).

[0255] iii): Cyclization of compound 3' and 2-fluorobenzylhydrazine to provide ethyl 1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboxylate (4').

[0256] [ka]

[0257]

[0243] Intermediate (3') (72.9 g, 287 mmol, 1.0 eq) and anhydrous ethylenediamine Ethanol (730 mL) was 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 mmole, 1.2 equiv.) was then charged to the mixture. The mixture was stirred at 0-10°C for 1 hour, then warmed to 20-25°C and stirred at 20-25°C for 16 hours. The reaction was complete by HPLC. Concentrated HCl (33.9 g, 37% by weight, 344 mmole, 1.2 equiv.) was charged to the reaction mixture over 1 minute, resulting in an exotherm that raised the batch temperature from 20°C to 38°C. A slurry was obtained. The mixture was cooled to 0-10°C over 1 hour and stirred at 0-10°C for 1 hour. The resulting slurry 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% purity by HPLC). 1H-NMR (500 MHz, CDCl3) δ ppm 8.47 (d, J=1.68 Hz, 1 H); 7.15 - 7.26 (m, 2 H); 6.94 - 7.08 (m, 2H); 6.77 - 6.87 (m, 1 H); 6.55 (d, J=1.68 Hz, 1 H); 5.95 (s, 2 H); 4.43 (q, J=7.02 Hz, 2H); 1.41 (t, J=7.17Hz, 3H).

[0258] iv): Amination of compound (4') to provide 1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamide hydrochloride (5'B)

[0259] [ka]

[0260] Anhydrous ammonium chloride (267 g, 4991 mmole, 5.0 equiv.) and Toluene (5400 mL) was charged to a suitable reaction vessel equipped with a mechanical stirrer and digital thermometer. Trimethylaluminum in toluene (2 M, 2400 mL, 4800 mmole, 4.8 equiv.) was slowly charged via addition funnel while maintaining the reaction temperature between 20 and 40°C (Note: methane gas evolution was observed during the addition). The mixture was then heated to 75-80°C over 30 minutes, resulting in a clear white solution. Intermediate (4') (315 g, 999 mmole, 1.0 equiv.) was charged in four equal portions to the reaction mixture over 1 hour at 75-90°C. The reaction was stirred at 80-90°C for 30 minutes, then heated to 100-110°C and stirred at 100-110°C for 3 hours. The reaction was complete by HPLC. The reaction mixture was cooled to 10-20°C, and methanol (461 g, 14.4 moles, 14.4 equiv.) was slowly charged via addition funnel while maintaining the reaction temperature between 10-40°C. Note: The quench was very exothermic, and much gas evolution was observed. A thick slurry was obtained. 3N HCl (6400 mL, 3N, 19.2 moles, 19.2 equiv.) was then slowly charged via addition funnel while maintaining the reaction temperature between 20-45°C. The mixture was heated to 80-85°C and stirred at 80-85°C for 10 minutes, resulting in a clear, biphasic mixture. The mixture was cooled to 0-5°C over 3 hours and stirred at 0-5°C for 1 hour. The resulting slurry was After filtration, the filter cake was washed with water (3000 mL) and 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% purity by HPLC). 19.33 (s, 2 H); 9.18 (d, J=1.53 Hz, 1 H); 7.88 (s, 1 H); 7.29 - 7.38 (m, 1 H); 7.19 - 7.25 (m, 1 H); 7.10 - 7.16 (m, 1 H); 7.03 (d, J=1.53 Hz, 1 H); 6.92 - 6.98 (m, 1 H); 5.91 (s, 2 H). MP 180-185℃.

[0261] v): Cyclization of compound (5'B) and diethyl fluoromalonate to provide 5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidine-4,6-diol (6').

[0262] [ka]

[0263] Intermediate (5'B) (224.6 g, 698 mmole, 1.0 eq.), methanoic acid A suitable reaction vessel equipped with a mechanical stirrer and digital thermometer was charged with ethanol (2250 mL) and diethyl fluoromalonate (187 g, 1050 mmole, 1.5 equiv.). Next, sodium methoxide in methanol (567 g, 30% by weight, 3149 mmole, 4.5 equiv.) was added via addition funnel while maintaining the reaction temperature between 20 and 35°C. The mixture was stirred at 20 and 35°C for 30 minutes, resulting in a thin suspension. The reaction was complete by HPLC. A 1.5 N HCl solution (2300 mL, 3450 mmole, 4.9 equiv.) was added via addition funnel over 1 hour while maintaining the reaction temperature between 20 and 30°C. A white suspension was obtained. The pH of the reaction mixture was approximately 1 by pH paper. The slurry was stirred at 20 and 30°C for 30 minutes. The resulting slurry was filtered, and the filter cake was washed with a premixed solution of methanol and water (500 mL / 500 mL), followed by 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% purity by HPLC). 1 7.18 H-NMR (500 MHz, DMSO-d6) δ ppm 12.82 (br. s., 1 H); 12.31 (br. s., 1 H); 9.14 (d, J=1.53 Hz, 1 H); 7.55 (s, 1 H); - 7.25 (m, 1 H); 7.10 - 7.15 (m, 2 H); 6.97 - 7.02 (t, J=7.55 Hz, 1 H); 5.88 (s, 2 H).

[0264] vi): Chlorination of compound (6') to provide 3-(3-(4,6-dichloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (7').

[0265] [ka]

[0266] Intermediate (6') (264 g, 711 mmole, 1.0 equivalent), acetonitrile A suitable reaction vessel equipped with a mechanical stirrer and digital thermometer was charged with ethanol (4000 mL) and N,N-dimethylaniline (138 g, 1137 mmole, 1.6 equiv.). The slurry mixture was heated to 70-80°C. Next, phosphorous oxychloride (655 g, 4270 mmole, 6.0 equiv.) was charged via 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, resulting in a brown solution. The reaction was complete by HPLC. The mixture was then cooled to between 0-5°C, and a flocculent solid precipitated at 25°C. Water (3000 mL) was slowly charged via addition funnel while maintaining the reaction temperature at 0-10°C. The slurry was stirred at 0-10°C for 30 minutes. The resulting slurry was filtered, and the filter cake was washed with a premixed 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% purity by HPLC). 1 6.60 (d, J=1.68 Hz, 1 H); 6.03 (s, 2 H).

[0267] vii): Substitution of compound (7') with methoxide to provide 3-(3-(4-chloro-5-fluoro-6-methoxypyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (8').

[0268] [ka]

[0269] Methanol (3400 mL) and sodium methoxide (1 mL) in methanol A suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer (54 mL, 5.4 M, 832 mmole, 1.2 equiv.) was charged with intermediate (7') (283 g, 693 mmole, 1.0 equiv.) in small portions (5-10 g each) was charged to the mixture over 40 minutes, maintaining the reaction temperature at 23-27°C. The slurry was stirred at 23-27°C for 30 minutes. The reaction was complete by HPLC. The resulting slurry was filtered, and the filter cake was washed with methanol (850 mL) and then with water (850 mL). The filter cake was dried under vacuum at 35-45°C for 16 hours to afford intermediate (8') as an off-white solid (277 g, 99% yield, 97% purity by HPLC). 1 H-NMR (500 MHz, CDCl3) δ ppm 8.47 (d, J=1.83 Hz, 1 H); 7.38 (s, 1 H); 7.18 - 7.25 (m, 1 H); 7.01 - 7.08 (m, 1 H); 6.94 - 7.00 (m, 1 H); 6.81 - 6.88 (m, 1 H); 6.60 (d, J=1.68 Hz, 1 H); 6.00 (s, 2 H); 4.21 (s, 3 H).

[0270] viii): Hydrogenation of compound (8') to provide 3-(3-(5-fluoro-4-methoxypyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (9').

[0271] [ka]

[0272] Intermediate (8') (226 g, 560 mmole, 1.0 equivalent), palladium ( A suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer was charged with activated carbon (10%, nominally 50% water wet, 22.6 g, 0.01 mole, 0.018 equiv.), tetrahydrofuran (3400 mL), and triethylamine (91 g, 897 mmole, 1.6 equiv.). Nitrogen was bubbled through the reaction mixture via a Teflon tube at 20-30°C for 10 minutes. The mixture was then heated to 40-50°C, and hydrogen gas was bubbled through the reaction mixture via a Teflon tube for 6 hours while maintaining the reaction temperature at 40-50°C. The reaction was determined to be complete by HPLC. Nitrogen was then bubbled through the reaction mixture via a Teflon tube at 40-50°C for 10 minutes. 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 approximately 1300 mL to give a slurry. Tetrahydrofuran was then solvent exchanged with methanol via a continuous feed of methanol (3000 mL) under reduced pressure. The final volume after the solvent exchange was 1300 mL. The resulting slurry 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% purity by HPLC). 1 H-NMR (500 MHz, CDCl3) δ ppm 8.47 (d, J=1.68 Hz, 1 H); 8.41 (d, J=2.59 Hz, 1 H); 7.36 (s, 1 H); 7.17 - 7.24 (m, 1 H); 6.95 - 7.07 (m, 2 H); 6.83 - 6.90 (m, 1 H); 6.60 (d, J=1.68 Hz, 1 H); 5.99 (s, 2 H); 4.19 (s, 3 H).

[0273] ix: Demethylation of compound (9') to provide 5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-ol (10').

[0274] [ka]

[0275]

[0249] Intermediate (9') (230 g, 623 mmole, 1.0 equivalent), MeOH (3 A suitable reaction vessel equipped with a mechanical stirrer and digital thermometer was charged with concentrated HCl (307 g, 37% by weight, 3117 mmole, 5.0 equiv.). The mixture was heated to 60-65°C to give a solution. The mixture was then stirred at 60-65°C for 17 hours to give a slurry. The reaction was complete by HPLC. The slurry was cooled to 20-25°C over 2 hours and stirred at 20-25°C for 30 minutes. The resulting slurry 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% purity by HPLC). 1 H-NMR (500 MHz, DMSO-d6) δ ppm 12.90 - 13.61 (br. s., 1 H); 9.11 (d, J=1.68 Hz, 1 H); 8.16 (s, 7.64 (s, 1 H); 7.29 - 7.42 (m, 1 H); 7.17 - 7.28 (m, 2 H); 7.08 - 7.15 (m, 1 H); 6.97 (s, 1 H); 5.91 (s, 3 H).

[0276] x): Chlorination of compound (10') to provide 3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (Formula IV)

[0277] [ka]

[0278] Intermediate (10') (214 g, 602 mmole, 1.0 eq.), acetonite A suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer was charged with methyl methyl aniline (3000 mL) and N,N-dimethylaniline (109 g, 899 mmole, 1.5 equiv.). The slurry mixture was heated to 70-80°C. Phosphorous oxychloride (276 g, 1802 mmole, 3.0 equiv.) was then charged via addition funnel over 30 minutes while maintaining the reaction temperature at 70-80°C. The mixture was stirred at 75-80°C for 2 hours, resulting in a green solution. The reaction was complete by HPLC. The mixture was then cooled to 0-5°C. Water (1500 mL) was slowly charged via addition funnel while maintaining the reaction temperature at 0-10°C. The slurry was stirred at 0-10°C for 30 minutes. The resulting slurry was filtered, and the filter cake was washed with a premixed solution of acetonitrile and water (500 mL / 500 mL) and with water (500 mL). The filter cake was dried under vacuum at 30-40° C. for 16 hours to give the intermediate of Formula IV as an off-white to pink solid (214 g, 95% yield, >99% purity by HPLC). 1 H NMR (500 MHz, CDCl3) δ ppm 8.65 (s, 1 H); 8.48 (d, J=1.68 Hz, 1 H); 7.44 (s, 1 H); 7.21 - 7.25 (m, 1 H); 6.97 - 7.06 (m, 2 H); 6.83 - 6.87 (m, 1 H); 6.61 (d, J=1.68 Hz, 1 H); 6.03 (s, 2 H).

[0279] a): Cyanation of intermediate (15) to provide 2-(bromomethyl)-3,3,3-trifluoro-2-((trimethylsilyl)oxy)propanenitrile (16).

[0280] [ka]

[0281]

[0251] Trimethylsilanecarbonitrile (153 g, 1.54 moles, 0.97 equivalents) Amount of 15 (16), and triethylamine (4.44 mL, 3.22 g, 0.032 mole, 0.02 equiv.) were charged to 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 mole, 1.0 equiv.) was charged via addition funnel over 35 minutes, maintaining the reaction temperature between 10-20°C. After the addition, the mixture was stirred at 20-30°C for 3 hours to afford intermediate 16 as a thick oil, which was used directly in the next step. 1 H-NMR (500 MHz, CDCl3) δ ppm 3.68 (d, J=11.14 Hz, 1 H); 3.57 (d, J=11.14 Hz, 1 H), 0.34 - 0.37 (m, 9 H).

[0282] b): Conversion of the nitrile compound (16) to an amide to provide 2-(bromomethyl)-3,3,3-trifluoro-2-hydroxypropanamide (17).

[0283] [ka]

[0284] Concentrated sulfuric acid (339 mL, 6.37 moles, 4.0 equiv.) was added to a 1000 ml flask using a mechanical stirrer. The mixture was stirred in a suitable reaction vessel equipped with a digital thermometer and an addition funnel. The sulfuric acid was heated to 45° C. Intermediate 16 was added via the addition funnel over 50 minutes, keeping the temperature below 75° C. The reaction mixture was stirred at 75° C. for 2 hours and then allowed to cool to room temperature. 1H-NMR indicated the reaction was complete. The reaction mixture was cooled to -15°C and diluted with ethyl acetate (1824 mL) via an addition funnel over 45 minutes, maintaining the temperature between -15 and 5°C (highly exothermic). Water (1520 mL) was added slowly via an addition funnel over 1 hour and 20 minutes at -10 to 0°C (highly exothermic). 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 give 348 g of intermediate (17) as a pale yellow oil. The oil was dissolved in methanol (1200 mL) and concentrated to give 380 g of intermediate (17). (Corrected weight: 296 g, 79% yield). 1 H-NMR (500 MHz, CDCl3) δ 6.61 - 6.94 (m, 1 H); 5.92 - 6.26 (m, 1 H); 3.93 - 4.00 (m, 1 H); 3.68 (d, J=11.14 Hz, 1 H).

[0285] c): N-alkylation of compound (17) to provide 2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropanamide (14).

[0286] [ka]

[0287] 7N ammonia solution in methanol (600 mL, 4.28 moles, 10 (equivalent) was charged to a suitable reaction vessel equipped with a mechanical stirrer and digital thermometer. The solution was cooled to 0-5°C. Intermediate (17) (102 g, 0.432 mole, 1 equiv) was then added via addition funnel over 30 minutes at 0-5°C. The reaction mixture was warmed to 20-25°C over 1 hour and held for 72 hours. The reaction was complete by HPLC. The reaction mixture was cooled to 0-5°C, and sodium methoxide (78 mL, 5.4 M, 0.421 mole, 0.97 equiv) was added over 2 minutes. The reaction mixture was then concentrated under reduced pressure to a volume of 300 mL. 2 L of ethyl acetate was added, and concentration under reduced pressure was continued to a volume of 700 mL, yielding a slurry. 700 mL of ethyl acetate was added to the slurry to a final volume of 1400 mL. 102 mL of water was added and stirred for 2 minutes to yield a biphasic solution. The layers were separated. The ethyl acetate layer was reduced to a volume of 600 mL under reduced pressure. The ethyl acetate layer was then heated to >60°C and heptane (600 mL) was added slowly between 55-60°C. The mixture was cooled to 15-20°C to give a slurry. The slurry was stirred at 15-20°C for 2 hours and filtered. The solid was dried under vacuum at 25°C for 16 hours to give the amine (14) as a white solid (48 g, 64% yield). 1 H-NMR (500 MHz, MeOH-d4) δ ppm 2.94 (d, J= 13.73 Hz, 1H); 3.24 (d, J= 13.58 Hz, 1H).

[0288] d): (R)-2,2-dimethyl-5-(trifluoromethyl)oxazolidine-5-carboxamide (18A) Chiral resolution of amine (14) as its 1:1 salt with (D)-malic acid

[0289] [ka]

[0290] Amine (14) (105 g, 0.608 mole, 1.0 equiv.), (D)-ribonucleotides ... Malic acid (82 g, 0.608 mole, 1.0 equiv.) and acetone (1571 mL) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The reaction mixture was stirred at 20-25°C for 16 hours. The resulting slurry was filtered, and the wet cake was washed with acetone (300 mL). The wet cake was returned to the reaction vessel and charged with acetone (625 mL). The slurry was heated to 53°C and held for 6 hours. The slurry was cooled to 20-25°C and held at this temperature for 16 hours. The slurry was filtered, and the wet cake was washed with acetone (200 mL). The wet cake was dried under vacuum at 40°C for 4 hours to provide 82.4 g of the 1:1 salt of (18A) and (D)-malic acid as a white solid (82.4 g, 39% yield, 97% ee). 1 H-NMR (500 MHz, D2O) δ ppm 4.33 (br, s, 1H); 3.61 (br, d, J= 13.58 Hz, 1H); 3.40 - 3.47 (m, 1H); 2.76 (br, d, J= 15.87 Hz, 1H); 2.53 - 2.63 (m, 1H); 2.16 (br, s, 4H).

[0291] e): Coupling of the 1:1(D)-malate salt of intermediate (18A) with formula IV to provide (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).

[0292] [ka]

[0293]

[0255] The 1:1 salt of intermediate (18A) with (D)-malic acid (74.1 g, 0.214 Formula IV (32 g, 0.086 mole, 1.0 equiv.), DMSO (448 mL), and Hunig's base (44.7 mL, 0.257 mole, 3.0 equiv.) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The reaction mixture was heated to 70°C and stirred for 20 minutes. Acetone produced during the reaction was removed by blowing with nitrogen. The reaction mixture was cooled to 30-40°C and charged with Formula IV (32 g, 0.086 mole, 1.0 equiv.), DMSO (448 mL), and Hunig's base (44.7 mL, 0.257 mole, 3.0 equiv.). The reaction mixture was heated to 90°C and stirred at 90°C for 17 hours. The reaction was complete by HPLC. The mixture was then cooled to 60°C. Additional Hunig's base (104 mL, 0.599 mole, 7.0 equiv.) was charged, followed by water (224 mL) at 55-62°C. The reaction mixture was stirred at 55-60°C for 15 minutes to form a reaction seed bed. Water (320 mL) was added via an addition funnel over 30 minutes at 55-62°C, and the resulting slurry was stirred at 55-60°C for 1 hour. The resulting slurry was filtered, and the filter cake was washed with a premixed solution of methanol and water (320 mL / 320 mL), followed by water (640 mL). The filter cake was then dried under vacuum at 40°C for 16 hours to give compound I as an off-white solid (40 g, 92% yield, 99% purity by HPLC, 98% ee). 1 H-NMR (500 MHz, DMSO-d6) δ ppm 9.10 (s, 1 H); 8.33 (d, J=2.90 Hz, 1 H); 7.93 (s, br, 1 H); 7.90 (s, 1 H); 7.78 (s, br, 1 H); 7.69 (s, br, 1 7.52 (s, 1 H); 7.33 (q, J=7.02 Hz, 1 H); 7.17 - 7.25 (m, 1 H); 7.17 - 7.25 (m, 1 H); 7.10 (t, J=7.48 Hz,1 H); 6.98 (t, J=7.55 Hz, 1 H); 5.90 (s, 2 H); 3.92-4.05 (m, 2 H).

[0294] Crude Compound I and its polymorphic forms Form A, Form B, Form D, Form B The interrelationship between E, Form F, Form G and Form H is illustrated in FIG. Example 2 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 (crude Compound I) to polymorphic Form B Crude compound I (0.68 kg, 1.33 mol) and acetonitrile (2 A 30 L jacketed reactor was charged with 0.4 L of ethanol. The reaction mixture was stirred slowly and heated to 70-75°C until most of the solids were dissolved. The solution in the 30 L jacketed reactor was in-line filtered through a gas diffusion tube (coarse frit) into a 100 L jacketed reactor. The reaction mixture was then heated to 70-75°C and water (20.4 L) was charged while maintaining the batch temperature at >65°C for 1 hour. The mixture was cooled to 52-62°C and stirred at 52-62°C for a minimum of 1 hour to form a reactive species source. The resulting slurry was cooled to 0-5°C over a minimum of 4 hours and held at 0-5°C for a minimum of 1 hour. The slurry was filtered, and the filter cake was washed with a premixed solution of acetonitrile and water (3.4 L / 3.4 L). The filter cake was then dried under vacuum at 90-100°C for a minimum of 30 hours to provide Compound I as polymorphic Form B as a white solid (0.58 kg, 85% yield). 1 H-NMR (500 MHz, DMSO-d6) δ ppm 9.10 (s, 1 H); 8.33 (d, J=2.90 Hz, 1 H); 7.93 (s, br, 1 H); 7.90 (s, 1 H); 7.78 (s, br, 1 H); 7.69 (s, br, 1 H); 7.52 (s, 1 H); 7.33 (q, J=7.02 Hz, 1 H); 7.17 - 7.25 (m, 1 H); 7.17 - 7.25 (m, 1 H); 7.10 (t, J=7.48 Hz,1 H); 6.98 (t, J=7.55 Hz, 1 H); 5.90 (s, 2 H); 3.92-4.05 (m, 2 H).

[0295] 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) to polymorphic form E Mechanical stirrer, condenser, dropping funnel, nitrogen inlet / outlet, thermocouple and heating-cooling Crude compound I (67.4 g, 132 mmol) and methanol (2500 mL) were placed in a 5 L four-neck round-bottom flask equipped with a pressure cooker. This mixture was heated to >60 ° C (for example, 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 this mixture while maintaining the temperature at >60 ° C. The mixture was allowed to cool to room temperature over 1 hour and maintained at this temperature for 1 hour. The slurry was filtered, and the filter cake was rinsed with methanol / water (600 mL, 1 / 1 v / v). The filter cake was collected and dried under vacuum at 80 ° C for 72 hours to obtain compound I as polymorphic form E as a white solid (59.5 g, 88% yield).

[0296] Example 4A Recrystallization of polymorphic form E of (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 to polymorphic form A Mechanical stirrer, condenser, dropping funnel, nitrogen inlet / outlet, thermocouple and heating-cooling A 1 L four-necked round-bottom flask equipped with a pressure cooker was charged with compound I (19.3 g, 38 mmol) as polymorphic form E and 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 slurry. The slurry was concentrated under vacuum to a final volume of about 150 mL. Heptane (300 mL) was added to the slurry over 20 minutes, and the mixture was concentrated under vacuum to a final volume of about 350 mL. The slurry was filtered, and the filter cake was rinsed with heptane (50 mL). The filter cake was collected and dried under vacuum at 100°C for 3 hours to obtain polymorphic form A as a white solid (19.1 g, 99% yield).

[0297] 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) to polymorphic Form A Polymorph Form A can also be prepared by using crude Compound I as the starting material instead of Form E. and was obtained directly from crude Compound I by isolation from ethyl acetate in a manner similar to that described in Example 4A.

[0298] Polymorph Form A can also be isolated from DMSO / water after heating above 60°C. This was obtained directly from crude compound I by Polymorph Form A can also be obtained by dissolving crude Compound I in a solvent such as heptane, (isopropyl acetate, It was also isolated when slurried in any of the following solvents: (Pi)IPAC, ethanol, ethyl acetate, or decane at room temperature and stirred for 14 to 30 hours. The samples were filtered, and the residual solids were analyzed by XRPD.

[0299] Example 5A Recrystallization of polymorphic form E of (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 to polymorphic form D Mechanical stirrer, condenser, dropping funnel, nitrogen inlet / outlet, thermocouple and heating-cooling A 2 L four-necked round-bottom flask equipped with a pressure cooker was charged with Compound I (14.0 g, 28 mmol) as polymorphic Form E and n-decane (560 mL). The mixture was heated to 145-155°C and held at 145-155°C for 45 minutes. The resulting slurry was cooled to 20-30°C over 1 hour and then filtered. The filter cake was rinsed with heptane (280 mL). The filter cake was collected and dried under vacuum at 80°C for 72 hours to obtain Compound I as Form D as a white solid (12.9 g, 92% yield).

[0300] Example 5B Another method to obtain polymorphic form D Polymorph Form D also contains many other polymorphic forms (excluding other substances) at 180°C. 12 and described below. In some embodiments, compound I was heated to give polymorphic form D. In some embodiments, polymorphic form F was heated to give polymorphic form D. In some embodiments, polymorphic form B was heated to give polymorphic form D. In some embodiments, polymorphic form E was heated to give polymorphic form D. In some embodiments, polymorphic form G was heated to give polymorphic form D. In some embodiments, polymorphic form H was heated to give polymorphic form D.

[0301]

[0265] In a 100 mL round bottom flask, Compound I, Form F, Form B, Form E, Form G, or Form I (5 g) was added. The solid was heated to 180°C and held at 180°C for 5 minutes. All Compound I solids slowly melted and resolidified to obtain a solid. The solid was crushed using a mortar and pestle to obtain approximately 4.8 g of powder. HPLC showed a purity of 99.8%. XRPD indicated it was Form D. DSC showed a sharp peak at 196°C.

[0302] Example 6 Preparation of Form F A new polymorphic form F was obtained when form A was heated neat at 160°C. This form was considered unstable at rt and was not isolated pure.

[0303] Example 7 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) to polymorphic form G In a flask equipped with a mechanical stirrer, crude Compound I (2.0 g) and acetone ( 15.0 mL) was added. The mixture was stirred at room temperature (22-25°C) for 2 hours. The resulting slurry was then filtered. The filter cake was rinsed with acetone (5 mL). The cake was collected and dried under vacuum at 40° C. for 15 hours to give polymorphic form G as a white solid.

[0304] Polymorphic Form G can also be prepared by reacting polymorphic Form H obtained as described below with acetone. The mixture was stirred at room temperature in a bromine-containing atmosphere, followed by filtration and drying under vacuum at 30-40°C.

[0305] 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 to polymorphic form H In a flask equipped with a mechanical stirrer, 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 allowed to cool slowly to room temperature with stirring. After stirring for an additional 15 hours, the resulting slurry was filtered. The filter cake was rinsed with acetone (5 mL). The filter cake was collected and dried under vacuum at 40°C for 15 hours to obtain polymorphic form H as a white solid.

[0306] Example 9 Polymorph characterization X-ray powder diffraction (XRPD): Powder X-ray diffraction traces were obtained using a D8 Advance, Bruker instrument; using one of two methods: 2-theta scan from 5 to 45°, 0.02° step size, 1 second per step; or 2-theta scan from 3 to 40°, 0.037° step size, 1.5 seconds per step Fourier transform infrared spectroscopy (FTIR): FTIR traces were obtained using a Nicolet iS10 FTIR instrument from ThermoFisher Scientific.

[0307] Method: 525-4000 cm using 32 scans and a resolution of 4. -1 The spectra were analyzed by attenuated total reflection over a wavenumber range of 100 kHz, with a background obtained before each measurement. Example 10 Preparation of HCl salt Protocol 1: 50.5 mg of compound I as its polymorphic form D and 98.2 mL of 1 M HCl were suspended in 2 mL of i-PrOH. The suspension was stirred with a temperature cycle between 20° C. and 40° C. A heating rate of 40° C. / h and a cooling rate of 5° C. / h were used. After 8 days, the suspension was filtered and the solid was dried under vacuum (approximately 5 mbar, 1 hour).

[0308] Protocol 2: 299.9 mg of compound I as its polymorphic form D and a few crystals of the hydrochloride salt (from protocol 1) obtained above were suspended in 5 mL of i-PrOH. Next, 589 mL of 1 M HCl and 5 mL of i-PrOH were added, and the suspension was stirred with a temperature cycle between 20 ° C. and 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 h).

[0309] Example 11 Characterization of the HCl salt The HCl salt of Compound I is characterized by the XRPD pattern in FIG.

[0310] The HCl salt of Compound I was characterized by elemental analysis, with the measured and calculated values obtained for a 1:1 ratio (Form D:HCl) shown in the table below:

[0311] [Table 2]

[0312]

[0270] The terminology used herein is for the purpose of describing particular embodiments only. and are not intended to limit the invention. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprise" (and any form of comprise such as "comprises" and "comprising"), "have" (and any form of have such as "has" and "having"), "include" (and any form of include such as "includes" and "including"), "contain" (and any form of contain such as "contains" and "containing"), and any other grammatical variations thereof, are open-ended linking verbs. Consequently, a method or apparatus that "comprises," "has," "includes," or "contains" one or more steps or elements possesses those one or more steps or elements, but is not limited to possessing only those one or more steps or elements. Similarly, a method step or apparatus element that "comprises," "has," "includes," or "contains" one or more features possesses those one or more features, but is not limited to possessing only those one or more features. Furthermore, an apparatus or structure that is configured in a particular way is configured in at least that way, but may also be configured in ways not listed.

[0313] As used herein, the terms "comprising" and "having" The terms "has," "including," "containing," and other grammatical variations thereof encompass the terms "consisting of" and "consisting essentially of."

[0314]

[0272] The phrase "consisting essentially of" or grammatical variations thereof, when used herein, , used to define a stated feature, integer, step, or component, does not preclude the addition of one or more of those additional features, integers, steps, components, or groups, so long as those additional features, integers, steps, components, or groups do not materially alter the basic and novel characteristics of the claimed composition, apparatus, or method.

[0315]

[0273] All publications cited herein are to be construed as being in accordance with the full disclosure and the principles set forth in the appended claims. No. 6,023,797, or any other reference thereto is incorporated by reference herein as if each such reference were specifically and individually indicated to be incorporated by reference.

[0316]

[0274] Subject matter incorporated by reference may be incorporated into any of the claims unless expressly indicated otherwise. should not be considered a change to the limitations of

[0275] Throughout this specification, where one or more ranges are given, each range shall mean: It is intended to be a concise format for presenting information, and the same is understood to include within its scope each discrete point as if that discrete point were fully set forth herein.

[0317]

[0276] Several aspects and embodiments of the present invention are described and illustrated herein. However, alternative aspects and embodiments can be devised by those skilled in the art to accomplish the same goals, and it is therefore intended that this disclosure and the appended claims encompass all such further and alternative aspects and embodiments as fall within the true spirit and scope of the invention. This specification includes the disclosure of the following inventions. [1] [ka] A crystalline solid form of. [2] The crystalline solid form of [1], which is a crystalline free form selected from Form A, Form B, Form D, Form E, Form F, Form H, or Form G. [3] The crystalline solid form of [1], which is a hydrochloride salt. [4] Form E, a crystalline free form of Compound I according to [2], characterized by one or more peaks in an XRPD spectrum selected from the group consisting of 7.4, 18.8-19.3, 21.1, 24.8 and 25.5 °2θ. [5] Form E, a crystalline free form of Compound I according to [4], characterized by one or more peaks in an XRPD spectrum selected from the following °2θ: 7.4, 13.9, 15.1, 16.3, 17.6, 18.8-19.3, 21.1, 22.3-22.5, 24.8, 25.5 and 27.1. [6] Form E, a crystalline free form of Compound I described in [2], characterized by an XRPD spectrum substantially similar to that shown in Figure 2 or Figure 6. [7] Form E, a crystalline free form of Compound I described in [2], characterized by an FT-Raman spectrum substantially similar to that shown in Figure 10. [8] 1690cm -1 Form E, a crystalline free form of Compound I described in [2], characterized by an IR spectrum exhibiting a peak maximum at [9] 1515cm -1 Form E, a crystalline free form of Compound I described in [2], characterized by an IR spectrum exhibiting a peak maximum at

[10] 1690 and 1515 cm -1 In the IR spectrum, which shows a band maximum at Form E, a crystalline free form of Compound I described in [2], is further characterized.

[11] Form A, a crystalline free form of Compound I according to [2], characterized by one or more peaks in an XRPD spectrum selected from °2θ of 6.0, 18.3, 19.3, 20.2 and 22.0.

[12] Form A, a crystalline free form of Compound I according to

[11] , characterized by one or more peaks in an XRPD spectrum selected from the following °2θ: 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.

[13] Form A, a crystalline free form of Compound I according to

[12] , characterized by one or more peaks in an XRPD spectrum selected from the following °2θ: 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, 24.1-24.8, 25.8, 30.1, and 34.1.

[14] Form A, a crystalline free form of Compound I described in [2], characterized by an XRPD spectrum substantially similar to that shown in Figure 2 or Figure 3A.

[15] Form A, a crystalline free form of Compound I described in [2], characterized by one or more peaks in an XRPD spectrum selected from 6.1 (80.81% relative intensity), 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.

[16] Form A, a crystalline free form of Compound I described in [2], characterized by an XRPD spectrum substantially similar to that shown in Figure 3C.

[17] Form A, a crystalline free form of Compound I described in [2], characterized by an FT-Raman spectrum substantially similar to that shown in Figure 10.

[18] 1730cm -1 Form A is a crystalline free form of Compound I described in [2], characterized by an IR spectrum showing a band maximum at

[19] Form A, a crystalline free form of Compound I described in [2], characterized by exhibiting an essentially unchanged XRPD trace when stored under stability conditions of 40°C and 75% relative humidity for 14 months.

[20] 18.8 o Form D, a crystalline free form of Compound I described in [2], characterized by peaks in the XRPD spectrum at 2θ.

[21] Form D, a crystalline free form of Compound I according to

[20] , characterized by one or more peaks in an XRPD spectrum selected from °2θ of 17.1, 18.1, 18.8, and 25.0.

[22] Form D, a crystalline free form of Compound I according to

[21] , characterized by one or more peaks in an XRPD spectrum selected from °2θ of 8.8, 17.1, 18.1, 18.8, and 25.0.

[23] Form D, a crystalline free form of Compound I described in [2], characterized by an XRPD spectrum substantially similar to that shown in Figure 2 or Figure 5A.

[24] Form D, a crystalline free form of Compound I described in [2], characterized by one or more peaks in an XRPD spectrum selected from the following °2θ: 4.7 (97.11% relative intensity), 8.3 (64.04%), 18.1 (80.97%), 18.6 (100.00%), and 26.8 (65.25).

[25] Form D, a crystalline free form of Compound I described in [2], characterized by an XRPD spectrum substantially similar to that shown in Figure 5C.

[26] Form D, a crystalline free form of Compound I described in [2], characterized by an FT-Raman spectrum substantially similar to that shown in Figure 10.

[27] 1665cm -1 Form D, a crystalline free form of Compound I described in [2], characterized by an IR spectrum showing a band maximum at

[28] 1639cm -1 It is characterized by an IR spectrum that shows a band maximum at Form D is a crystalline free form of Compound I described in [2].

[29] 968cm -1 Form D, a crystalline free form of Compound I described in [2], characterized by an IR spectrum showing a band maximum at

[30] 1665, 1639 and 968 cm -1 Form D, a crystalline free form of Compound I described in [2], characterized by an IR spectrum showing a band maximum at

[31] Form D, a crystalline free form of Compound I described in [2], characterized by exhibiting an essentially unchanged XRPD trace when stored under stability conditions of 40°C and 75% relative humidity for 14 months.

[32] Form B, a crystalline free form of Compound I described in [2], characterized by one or more peaks in an XRPD spectrum at °2θ between 18.8 and 19.1.

[33] Form B, a crystalline free form of Compound I according to

[32] , characterized by one or more peaks in an XRPD spectrum selected from °2θ of 8.8, 16.4, 17.2, 18.8-19.1, 20.1, and 21.1-21.6.

[34] Form B, a crystalline free form of Compound I according to

[33] , characterized by one or more peaks in an XRPD spectrum selected from the following °2θ: 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.

[35] Form B, a crystalline free form of Compound I described in [2], characterized by an XRPD spectrum substantially similar to that shown in Figure 2 or Figure 4A.

[36] Form B, a crystalline free form of Compound I according to [2], characterized by one or more peaks in an XRPD spectrum selected from the following °2θ: 7.0 (44.44% relative intensity), 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).

[37] Form B, a crystalline free form of Compound I described in [2], characterized by an XRPD spectrum substantially similar to that shown in Figure 4C.

[38] Form B, a crystalline free form of Compound I described in [2], characterized by an FT-Raman spectrum substantially similar to that shown in Figure 10.

[39] 1200cm -1 Form B, a crystalline free form of Compound I described in [2], characterized by an IR spectrum exhibiting a peak maximum at

[40] Form B, a crystalline free form of Compound I described in [2], characterized by exhibiting an essentially unchanged XRPD trace when stored under stability conditions of 40°C and 75% relative humidity for 14 months.

[41] Form F, a crystalline free form of Compound I described in [2], characterized by one or more peaks in an XRPD spectrum selected from the following °2θ: 5.3 (100.00% relative intensity), 8.6 (58.80%), 16.4 (62.95%), and 19.0 (48.51%).

[42] Form F, a crystalline free form of Compound I described in [2], characterized by an XRPD spectrum substantially similar to that shown in Figure 7.

[43] Form G, a crystalline free form of Compound I described in [2], characterized by one or more peaks in an XRPD spectrum selected from °2θ of 10.7 (55.47% relative intensity), 13.9 (42.47%), 18.33 (100.00%), and 21.6 (40.73%).

[44] Form G, a crystalline free form of Compound I described in [2], characterized by an XRPD spectrum substantially similar to that shown in Figure 8.

[45] The compound according to [2], characterized by one or more peaks in an XRPD spectrum selected from °2θ of 5.77 (relative intensity of 89.22%), 6.39 (100.00%), 9.1 (84.17%), and 18.5 (67.04%). Form H, the crystalline free form of I.

[46] Form H, a crystalline free form of Compound I described in [2], characterized by one or more peaks in an XRPD spectrum selected from °2θ of 5.77 (relative intensity of 89.22%), 6.39 (100.00%), 9.1 (84.17%), 18.5 (67.04%), and 18.83 (67.04%).

[47] Form H, a crystalline free form of Compound I described in [2], characterized by an XRPD spectrum substantially similar to that shown in Figure 9.

[48] The hydrochloride salt according to [3], characterized by a melting point of 256°C.

[49] The hydrochloride salt of [3], characterized by an aqueous solubility of 0.5 mg / mL at pH 1.4.

[50] The hydrochloride salt of [3], characterized by an XRPD pattern substantially similar to that shown in Figure 11.

[51] A method for preparing Form E, a crystalline free form of Compound I, comprising: a. dissolving crude Compound I in MeOH at a minimum of 60° C. to obtain a solution; b. filtering the solution and heating the filtrate to a minimum of 60°C; c. adding water to the filtrate to form an aqueous solution and cooling the aqueous solution to room temperature (rt); d. filtering the aqueous solution and drying the filtrate under vacuum; A method comprising:

[52] A method for preparing Form A, a crystalline free form of Compound I, comprising: a. dissolving crystalline free form Form E in ethyl acetate at a minimum of 70°C to obtain a solution; b. filtering the solution and stirring the resulting filtrate at 20-25°C for 16 hours to form a slurry; c. concentrating the slurry under vacuum, filtering and drying; A method comprising:

[53] A method for preparing Form A, a crystalline free form of Compound I, comprising: a. dissolving crude Compound I in ethyl acetate at a minimum of 70° C. to obtain a solution; b. filtering the solution and stirring the resulting filtrate at 20-25°C for 16 hours to form a slurry; c. concentrating the slurry under vacuum, filtering and drying; A method comprising:

[54] A method for preparing Form A, a crystalline free form of Compound I, comprising: a. Heating crude Compound I in DMSO to a minimum of 60° C. to form a solution; b. adding water to form a slurry; c. filtering the slurry to isolate Form A, the crystalline free form; A method comprising:

[55] A method for preparing Form A, a crystalline free form of Compound I, comprising: a. slurrying crude Compound I in a solvent selected from heptane, IPAC, ethanol, ethyl acetate, or decane, or a mixture thereof; b. stirring at rt for 14-30 hours; c. filtering the slurry and drying under vacuum; A method comprising:

[56] A method for preparing Form D, a crystalline free form of Compound I, comprising: a. mixing Form E, a crystalline free form, with n-decane at 145-155°C to obtain a slurry; b. cooling the slurry to 20-30°C over 1 hour; c. filtering the slurry and drying under vacuum; A method comprising:

[57] A method for preparing Form D, a crystalline free form of Compound I, comprising heating any one of Form F, Form B, Form E, Form G, or Form H, or a mixture thereof, in the absence of other substances, at 180°C.

[58] A method for preparing Form B, a crystalline free form of Compound I, comprising: a. mixing crude Compound I with acetonitrile to form a solution; b. filtering the solution to form a filtrate and heating the filtrate at 70-75°C; c. adding water to the heated filtrate; d. cooling to 52-62°C to form a slurry; e. further cooling the slurry to 0-5°C for at least 4 hours; f. filtering the cooled slurry and drying the resulting filtrate under vacuum; A method comprising:

[59] A method for preparing Form F, a crystalline free form of Compound I, comprising heating Form A, neat, at 160°C.

[60] A method for preparing Form G, a crystalline free form of Compound I, comprising: a. Mixing crude Compound I in acetone at room temperature for about 2 hours to form a slurry; b. filtering the slurry and drying under vacuum; A method comprising:

[61] A method for preparing Form G, a crystalline free form of Compound I, comprising: a. stirring Form H in acetone at room temperature for about 2 hours to form a slurry; b. filtering the slurry and drying under vacuum; A method comprising:

[62] A method for preparing Form H, a crystalline free form of Compound I, comprising: a. Mixing crude Compound I with acetone at 45-50°C to obtain a solution; b. filtering and cooling to form a slurry; c. stirring the slurry, filtering, and drying under vacuum; A method comprising:

[63] A pharmaceutical composition comprising the crystalline free form of the compound according to [2] or the hydrochloride salt according to [3], and at least one pharmaceutically acceptable excipient or carrier.

[64] A pharmaceutical dosage form comprising a crystalline solid form of Compound I according to any of [1], [2] or [3].

[65] A method for treating a disease, health condition, or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a crystalline solid form of Compound I according to any one of [1] to

[50] , or the pharmaceutical composition according to

[63] , or the pharmaceutical dosage form according to

[64] , to a subject in need thereof, wherein the disease, health condition, or disorder is: Hypertension and disorders related to reduced 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; diabetic hypertension; essential hypertension; secondary hypertension; gestational hypertension; preeclampsia; portal hypertension; myocardial infarction; Heart failure, HFPEF, HFREF; acute and chronic HF; more specific forms of HF: acute decompensated HF, right ventricular failure, left ventricular failure, total HF, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, HF with heart valve anomalies, mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, tricuspid stenosis, tricuspid regurgitation, pulmonary stenosis, pulmonary regurgitation, complex heart valve anomalies; diabetic heart failure; alcoholic or stored hypertrophic cardiomyopathy; diastolic HF, systolic HF; acute pre-existing chronic HF (worsening HF); diastolic or systolic dysfunction; coronary dysfunction; arrhythmias; reduced ventricular preload; cardiac hypertrophy; heart failure / cardiorenal syndrome; portal hypertension; endothelial dysfunction or injury; atrial and ventricular rhythm disturbances and conduction disturbances: stages I to III (AVB) I-III) atrioventricular block, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation Cardiac atrial fibrillation, ventricular flutter, ventricular tachyarrhythmia, polymorphic ventricular tachycardia, atrial and ventricular premature beats, AV junction premature beats, sick sinus syndrome, syncope, AV nodal reentrant tachycardia; Wolff-Parkinson-White syndrome or acute coronary syndrome; boxer cardiomyopathy; premature ventricular beats; cardiomyopathy; cancer-induced cardiomyopathy; chemotherapy-induced cardiotoxicity; Thromboembolic disorders and ischemia; myocardial ischemia; infarction; myocardial infarction; heart attack; myocardial dysfunction; endothelial dysfunction; stroke; transient ischemic attack (TIA); thromboangiitis obliterans; stable or unstable angina; coronary or peripheral arterial spasm; variant angina; Prinzmetal angina; cardiomegaly; preeclampsia; thrombogenic disorders; ischemia-reperfusion injury; ischemia-reperfusion associated with organ transplantation; lung transplant, pulmonary transplant, heart transplant, and vein graft failure; ischemia-reperfusion associated with conserving blood substituents in trauma patients; Peripheral vascular disease; peripheral arterial disease; peripheral arterial occlusive disease; muscle hypertonia; Raynaud's syndrome or phenomenon (primary and secondary); Raynaud's disease; critical limb ischemia; peripheral embolism; intermittent claudication; vaso-occlusive crisis; muscular dystrophy, Duchenne muscular dystrophy, Becker muscular dystrophy; microcirculatory abnormalities; vascular leakage or permeability control; lumbar spinal stenosis; thromboangiitis obliterans; thromboangiitis; peripheral perfusion disturbances; arterial and venous thrombosis; microalbuminuria; peripheral and autonomic neuropathies; diabetic neuropathic pain; diabetic microangiopathy; hepatic vaso-occlusive disorder; vaso-occlusive crisis in sickle cell disease; hypertensive crisis; · Edema; renal edema due to heart failure; Improvement of perception, concentration, learning or memory performance following cognitive impairment such as that occurring in Alzheimer's disease; Parkinson's disease; vascular dementia; vascular cognitive impairment; cerebral vasospasm; congenital myasthenic syndromes; subarachnoid hemorrhage; traumatic brain injury; traumatic brain injury; mild cognitive impairment, age-related learning and memory impairment, age-related memory loss, vascular dementia, head injury, stroke, post-stroke dementia, post-traumatic head injury, general disturbances of concentration and disturbances of concentration in children with learning and memory problems; dementia with Lewy bodies; dementia with frontal lobe degeneration including Pick's syndrome; progressive supranuclear 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;Movement disorders;Neuroprotection;Anxiety, tension and depression or post-traumatic stress disorder (PTSD);Bipolar disorder;Schizophrenia;CNS-related sexual dysfunction and sleep disorders;Pathological eating disorders and the use of luxury foods and addictive drugs;Controlling cerebral perfusion;Migraine;Prevention and control of the consequences of cerebral infarction (apoplexy cerebri);Prevention and control of the consequences of stroke, cerebral ischemia and head injury;Neuropathy associated with CNS diseases;Neuropathic pain associated with MS;Chemotherapy-induced neuropathic pain;Neuropathic pain associated with shingles;Neuropathic pain associated with spinal surgery; Shock; cardiogenic shock; sepsis; septic shock; anaphylactic shock; aneurysms; control of leukocyte activation; inhibition or regulation of platelet aggregation; multiple organ dysfunction syndrome (MODS); multiple organ failure (MOF); Pulmonary / Respiratory Conditions: Pulmonary hypertension (PH); pulmonary arterial hypertension (PAH) and associated pulmonary vascular remodeling; vascular remodeling in the form of focal thrombosis and right ventricular hypertrophy; pulmonary hypertonia; primary pulmonary hypertension; secondary pulmonary hypertension; familial pulmonary hypertension; isolated pulmonary hypertension; precapillary pulmonary hypertension; idiopathic pulmonary hypertension; other forms of PH; PH associated with left ventricular disease, HIV, SCD, thromboembolism (CTEPH), sarcoidosis, COPD, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), acute lung injury, alpha-1 antitrypsin deficiency (AATD), emphysema, smoking-induced emphysema, and cystic fibrosis (CF); thrombotic pulmonary arteriopathy; multifactorial pulmonary arteriopathy; cystic fibrosis; bronchoconstriction or pulmonary bronchoconstriction; acute respiratory syndromes; pulmonary fibrosis, lung transplantation; asthma; Left ventricular dysfunction, hypoxemia, WHO group I, II, III, IV and V hypertension, mitral valve disease, constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, pulmonary fibrosis, pulmonary venous return abnormalities Pulmonary hypertension associated with or related to pulmonary venous obstruction, pulmonary vasculitis, collagen vascular disease, congenital heart disease, elevated pulmonary venous pressure, interstitial lung disease, sleep-disordered breathing, sleep apnea, impaired alveolar hypoventilation, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease, other blood clotting disorders, chronic thromboembolism, pulmonary embolism; pulmonary embolism caused by tumors, parasites, or foreign bodies; connective tissue disease, lupus, lupus nephritis, schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease, asthma, emphysema, chronic bronchitis, pulmonary capillary hemangiomatosis, histiocytosis X, lymphangiomatosis, compressed pulmonary vessels; compressed pulmonary vessels caused by adenosis, tumors, or fibrosing mediastinitis; Arteriosclerotic diseases or conditions: atherosclerosis; atherosclerosis associated with endothelial injury, platelet and monocyte adhesion and aggregation, smooth muscle proliferation or migration; restenosis; restenosis developed after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), transluminal coronary angioplasty (PTCA), heart transplantation, bypass surgery or inflammatory processes; Damage to micro- and macrovascular vessels (vasculitis); increased levels of fibrinogen and low density DLD; increased concentrations of plasminogen activator inhibitor 1 (PA-1); Metabolic syndrome; metabolic disorders or disorders related to metabolic syndrome: obesity; excess subcutaneous fat; excess body fat accumulation; diabetes; hypertension; lipid-related disorders, hyperlipidemia, dyslipidemia, hypercholesterolemia, decreased high-density lipoprotein cholesterol (HDL-cholesterol), moderately elevated low-density lipoprotein cholesterol (LDL-cholesterol) levels, hypertriglyceridemia, hyperglyceridemia, hypolipoproteinemia, sitosterolemia, fatty liver disease, alcoholic fatty liver disease (AFLD), non-alcoholic fatty liver disease (NAFLD), hepatitis; preeclampsia; multiple kidney disease progression; hepatic steatosis or abnormal lipid accumulation in the liver, non-alcoholic steatohepatitis (NASH); fatty degeneration of the heart, kidneys, or muscles; alpha-betalipoproteinemia; sitosterolemia; xanthomatosis; Tangier disease; hyperammonemia and related disorders; hepatic encephalopathy; other toxic encephalopathies; Reye's syndrome; Sexual, gynecological and urological conditions: erectile dysfunction; impotence; premature ejaculation; female sexual dysfunction; female sexual arousal dysfunction; hypofunctioning sexual arousal disorder; vaginal atrophy; dyspareunia; atrophic vaginitis; benign prostatic hyperplasia (BPH), prostatic hyperplasia, prostatic enlargement; bladder outlet obstruction; bladder pain syndrome (BPS); interstitial cystitis (IC); overactive bladder; neurogenic bladder and incontinence; diabetic nephropathy; primary and secondary dysmenorrhea; lower urinary tract syndrome (LUTS); endometriosis; pelvic pain; benign and malignant diseases of the male and female genitourinary system; chronic kidney disease; acute and chronic renal insufficiency; acute and chronic renal failure; lupus nephritis; underlying or associated kidney diseases: hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disorders, nephropathic diseases, primary and congenital kidney diseases, nephritis; diseases characterized by abnormally decreased creatinine and / or water excretion; diseases characterized by abnormally increased blood concentrations of urea, nitrogen, potassium and / or creatinine; diseases characterized by altered activity of renal enzymes, Diseases characterized by altered activity of glutamyl synthetase; diseases characterized by altered urine osmolality or volume; diseases characterized by increased microalbuminuria, diseases characterized by macroalbuminuria; diseases characterized by glomerular and arteriolar lesions, tubular dilation, hyperphosphatemia, and / or the need for dialysis; sequelae of renal insufficiency; pulmonary edema-related renal insufficiency; HF-related renal insufficiency; uremia- or anemia-related renal insufficiency; electrolyte abnormalities (herkalemia, hyponatremia); disturbances of bone and carbohydrate metabolism; acute kidney injury; Eye diseases or disorders such as glaucoma, retinopathy and diabetic retinopathy A method selected from the following.

[66] A method for treating a disease, health condition, or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a crystalline solid form of Compound I according to any one of [1] to

[50] , or the pharmaceutical composition according to

[63] , or the pharmaceutical dosage form according to

[64] , to a subject in need thereof, wherein the disease, health condition, or disorder is: Inflammation of the heart muscle (myocarditis); chronic myocarditis; acute myocarditis; viral myocarditis; Vasculitis; pancreatitis; peritonitis; rheumatoid diseases; Inflammatory diseases of the kidney; immunological kidney diseases: kidney transplant rejection, immune complex-induced kidney disease, toxin-induced nephropathy, contrast-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; ocular inflammatory disease, blepharitis, dry eye syndrome, and Sjogren's syndrome; ocular fibrosis.

[67] A method for treating a disease, health condition, or disorder in a subject in need of treatment, comprising administering a therapeutically effective amount of a crystalline solid form of Compound I described in any of [1] to

[50] , or a pharmaceutically acceptable salt thereof, pharmaceutical composition described in

[63] , or pharmaceutical dosage form described in

[64] to a subject in need of treatment, wherein the disease, health condition, or disorder is selected from: diabetic wound or ulcer healing; improved microvascular perfusion; improved microvascular perfusion following injury or to counteract inflammatory responses in perioperative care; anal fissures; diabetic ulcers; diabetic foot ulcers; bone healing mechanisms; osteoclastic bone resorption and remodeling; and new bone formation.

[68] A method for treating a disease, condition, or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a crystalline solid form of Compound I according to any one of [1] to

[50] , or the pharmaceutical composition according to

[63] , or the pharmaceutical dosage form according to

[64] , to a subject in need thereof, wherein the disease, condition, or disorder is: Genitourinary system or kidney disorders: diabetic nephropathy; renal fibrosis and failure due to chronic kidney disease or renal insufficiency; renal fibrosis and failure due to accumulation / deposition and tissue injury; nephrosclerosis; progressive sclerosis; glomerulonephritis; focal segmental glomerulosclerosis; nephrotic syndrome; prostatic hyperplasia; renal fibrosis; interstitial renal fibrosis; Pulmonary system disorders: pulmonary fibrosis; idiopathic pulmonary fibrosis; cystic fibrosis; progressive massive fibrosis; progressive massive fibrosis affecting the lungs; Disorders affecting the heart: endomyocardial fibrosis; previous myocardial infarction; atrial fibrosis; cardiac interstitial fibrosis; cardiac remodeling and fibrosis; cardiac hypertrophy; Liver and related organ disorders: liver sclerosis or cirrhosis; cirrhosis associated with chronic liver disease; liver fibrosis; hepatic stellate cell activation; NASH; hepatic fibrocollagen and total collagen accumulation; liver diseases of necrotizing inflammatory and / or immunological origin; primary biliary cirrhosis; primary sclerosing cholangitis; other cholestatic liver diseases: those associated with granulomatous liver disease, hepatic malignancies, intrahepatic cholestasis of pregnancy, hepatitis, sepsis, drugs or toxins, graft-versus-host disease, post-liver transplant, common bile duct stones, bile duct tumors, pancreatic cancer, Mirizzi syndrome, AIDS cholangiopathy or parasites; schistosomiasis; hepatocellular carcinoma; Digestive system diseases or disorders: Crohn's disease; ulcerative colitis; gastrointestinal sclerosis; achalasia; Skin or eye diseases: renal fibrosis; proliferative vitreoretinopathy; diabetic retinopathy; ocular fibrosis; fibrotic localized or skin disorders or conditions; dermal fibrosis; scleroderma, dermal fibrosis; morphea; hypertrophic scars; nevi; 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 hearing diseases or disorders; hearing loss, partial or total hearing loss; partial or total hearing loss; tinnitus; noise-induced hearing loss; Other diseases involving autoimmune, inflammatory or fibrotic diseases: scleroderma; localized scleroderma or morphea; mediastinal fibrosis; fibrotic mediastinitis; myelofibrosis; retroperitoneal fibrosis; arthrofibrosis; Peyronie's disease; Dupuytren's contracture; lichen sclerosus; some forms of adhesive capsulitis; atheromatous The method is selected from arteriosclerosis; tuberous sclerosis; systemic sclerosis; polymyositis; dermatomyositis; polychondritis; eosinophilic fasciitis; systemic lupus erythematosus or lupus; bone marrow fibrosis, myelofibrosis or osteomyelofibrosis; sarcoidosis; uterine fibroids; endometriosis.

[69] A method for treating a disease, condition, or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a crystalline solid form of Compound I according to any one of [1] to

[50] , or the pharmaceutical composition according to

[63] , or the pharmaceutical dosage form according to

[64] , to a subject in need thereof, wherein the disease, condition, or disorder is selected from the group consisting of certain types of cancer; sickle cell disease; sickle cell anemia; cancer metastasis; osteoporosis; gastroparesis; functional dyspepsia; diabetic complications; alopecia or hair loss; endothelial dysfunction. neurological disorders associated with decreased nitric oxide production; argininosuccinic aciduria; neuromuscular diseases; selected from Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), limb-girdle muscular dystrophy, distal myopathy, myotonic dystrophy types I and II, facioscapuloperoneal muscular dystrophy, autosomal and X-linked Emery-Dreifuss muscular dystrophy, oculopharyngeal muscular dystrophy, amyotrophic lateral sclerosis, and spinal muscular atrophy (SMA).

[70] A method for treating or preventing a disease, condition, or disorder in a subject in need thereof, comprising administering to the subject, alone or in combination, a therapeutically effective amount of a crystalline solid form of Compound I according to any of [1] to

[50] , wherein the disease or disorder is a disease or disorder that may benefit from sGC stimulation or increased concentrations of NO and / or cGMP.

Claims

【Request 1】 【Chemical 1】 A crystalline solid form of.

2. 2. The crystalline solid form of claim 1, which is a crystalline free form selected from Form A, Form B, Form D, Form E, Form F, Form H or Form G.

3. 10. The crystalline solid form of claim 1, which is the hydrochloride salt.

4. 3. Form E, a crystalline free form of Compound I according to claim 2, characterized by one or more peaks in an XRPD spectrum selected from °2θ of 7.4, 18.8-19.3, 21.1, 24.8 and 25.

5.

5. 5. Form E, a crystalline free form of Compound I according to claim 4, characterized by one or more peaks in an XRPD spectrum selected from °2θ of 7.4, 13.9, 15.1, 16.3, 17.6, 18.8-19.3, 21.1, 22.3-22.5, 24.8, 25.5 and 27.

1.

6. Form E, a crystalline free form of Compound I of claim 2, characterized by an XRPD spectrum substantially similar to that shown in Figure 2 or Figure 6.

7. Form E, a crystalline free form of Compound I of claim 2, characterized by an FT-Raman spectrum substantially similar to that shown in Figure 10.

8. 1690 cm －１ Form E, a crystalline free form of Compound I according to claim 2, characterized by an IR spectrum exhibiting a peak maximum at

9. 1515cm －１ Form E, a crystalline free form of Compound I according to claim 2, characterized by an IR spectrum exhibiting a peak maximum at

10. 1690 and 1515 cm －１ Form E, a crystalline free form of Compound I according to claim 2, characterized by an IR spectrum exhibiting a band maximum at

11. Form A, a crystalline free form of Compound I according to claim 2, characterized by one or more peaks in an XRPD spectrum selected from °2θ of 6.0, 18.3, 19.3, 20.2 and 22.

0.

12. 12. Form A, a crystalline free form of Compound I according to claim 11, characterized by one or more peaks in an XRPD spectrum selected from °2θ of 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.

13. 13. Form A, the crystalline free form of Compound I of claim 12, characterized by one or more peaks in an XRPD spectrum 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, 24.1-24.8, 25.8, 30.1 and 34.1 °2θ.

14. Form A, a crystalline free form of Compound I of claim 2, characterized by an XRPD spectrum substantially similar to that shown in Figure 2 or Figure 3A.

15. 3. Form A, the crystalline free form of Compound I of claim 2, characterized by one or more peaks in an XRPD spectrum selected from: 6.1 (relative intensity of 80.81%), 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.

16. Form A, a crystalline free form of Compound I of claim 2, characterized by an XRPD spectrum substantially similar to that shown in Figure 3C.

17. Form A, a crystalline free form of Compound I of claim 2, characterized by an FT-Raman spectrum substantially similar to that shown in Figure 10.

18. 1730 cm －１ Form A, a crystalline free form of Compound I according to claim 2, characterized by an IR spectrum exhibiting a band maximum at

19. Form A, a crystalline free form of Compound I according to claim 2, characterized by exhibiting an essentially unchanged XRPD trace when stored for 14 months under stability conditions of 40°C and 75% relative humidity.

20. 18.8 ｏ Form D, a crystalline free form of Compound I of claim 2, characterized by peaks in an XRPD spectrum at 2θ.

21. Form D, a crystalline free form of Compound I according to claim 20, characterized by one or more peaks in an XRPD spectrum selected from °2θ of 17.1, 18.1, 18.8, and 25.

0.

22. 22. Form D, a crystalline free form of Compound I according to claim 21, characterized by one or more peaks in an XRPD spectrum selected from °2θ of 8.8, 17.1, 18.1, 18.8, and 25.

0.

23. Form D, a crystalline free form of Compound I of claim 2, characterized by an XRPD spectrum substantially similar to that shown in Figure 2 or Figure 5A.

24. 2. The compound of claim 1, characterized by one or more peaks in an XRPD spectrum selected from the following °2θ: 4.7 (97.11% relative intensity), 8.3 (64.04%), 18.1 (80.97%), 18.6 (100.00%), and 26.8 (65.25). Form D, a crystalline free form of Compound I described in

25. Form D, a crystalline free form of Compound I of claim 2, characterized by an XRPD spectrum substantially similar to that shown in Figure 5C.

26. Form D, a crystalline free form of Compound I of claim 2, characterized by an FT-Raman spectrum substantially similar to that shown in Figure 10.

27. 1665 cm －１ Form D, a crystalline free form of Compound I according to claim 2, characterized by an IR spectrum exhibiting a band maximum at

28. 1639 cm －１ Form D, a crystalline free form of Compound I according to claim 2, characterized by an IR spectrum exhibiting a band maximum at

29. 968 cm －１ Form D, a crystalline free form of Compound I according to claim 2, characterized by an IR spectrum exhibiting a band maximum at

30. 1665, 1639 and 968 cm －１ Form D, a crystalline free form of Compound I according to claim 2, characterized by an IR spectrum exhibiting a band maximum at

31. Form D, a crystalline free form of Compound I according to claim 2, characterized by exhibiting an essentially unchanged XRPD trace when stored for 14 months under stability conditions of 40°C and 75% relative humidity.

32. Form B, a crystalline free form of Compound I according to claim 2, characterized by one or more peaks in an XRPD spectrum at °2θ between 18.8 and 19.

1.

33. 33. Form B, a crystalline free form of Compound I according to claim 32, characterized by one or more peaks in an XRPD spectrum selected from °2θ of 8.8, 16.4, 17.2, 18.8-19.1, 20.1, and 21.1-21.

6.

34. 34. Form B, a crystalline free form of Compound I of claim 33, characterized by one or more peaks in an XRPD spectrum 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.

35. Form B, a crystalline free form of Compound I of claim 2, characterized by an XRPD spectrum substantially similar to that shown in Figure 2 or Figure 4A.

36. 3. Form B, a crystalline free form of Compound I according to claim 2, characterized by one or more peaks in an XRPD spectrum selected from the following °2θ: 7.0 (44.44% relative intensity), 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).

37. Form B, a crystalline free form of Compound I of claim 2, characterized by an XRPD spectrum substantially similar to that shown in Figure 4C.

38. Characterized by an FT-Raman spectrum substantially similar to that shown in FIG. Form B, which is a crystalline free form of Compound I according to claim 2.

39. 1200 cm －１ Form B, a crystalline free form of Compound I according to claim 2, characterized by an IR spectrum exhibiting a peak maximum at

40. Form B, a crystalline free form of Compound I according to claim 2, characterized by exhibiting an essentially unchanged XRPD trace when stored for 14 months under stability conditions of 40°C and 75% relative humidity.

41. Form F, a crystalline free form of Compound I according to claim 2, characterized by one or more peaks in an XRPD spectrum selected from the following °2θ: 5.3 (relative intensity of 100.00%), 8.6 (58.80%), 16.4 (62.95%), and 19.0 (48.51%).

42. Form F, a crystalline free form of Compound I of claim 2, characterized by an XRPD spectrum substantially similar to that shown in Figure 7.

43. Form G, a crystalline free form of Compound I according to claim 2, characterized by one or more peaks in an XRPD spectrum selected from the following °2θ: 10.7 (relative intensity of 55.47%), 13.9 (42.47%), 18.33 (100.00%), and 21.6 (40.73%).

44. Form G, a crystalline free form of Compound I of claim 2, characterized by an XRPD spectrum substantially similar to that shown in Figure 8.

45. Form H, a crystalline free form of Compound I according to claim 2, characterized by one or more peaks in an XRPD spectrum selected from the following °2θ: 5.77 (relative intensity of 89.22%), 6.39 (100.00%), 9.1 (84.17%), and 18.5 (67.04%).

46. Form H, a crystalline free form of Compound I according to claim 2, characterized by one or more peaks in an XRPD spectrum selected from the following °2θ: 5.77 (relative intensity of 89.22%), 6.39 (100.00%), 9.1 (84.17%), 18.5 (67.04%), and 18.83 (67.04%).

47. Form H, a crystalline free form of Compound I of claim 2, characterized by an XRPD spectrum substantially similar to that shown in Figure 9.

48. 4. The hydrochloride salt of claim 3, characterized by a melting point of 256°C.

49. 4. The hydrochloride salt of claim 3, characterized by an aqueous solubility of 0.5 mg / mL at pH 1.

4.

50. 4. The hydrochloride salt of claim 3, characterized by an XRPD pattern substantially similar to that shown in Figure 11.

51. 1. A method for preparing Form E, a crystalline free form of Compound I, comprising: a. dissolving crude Compound I in MeOH at a minimum of 60° C. to obtain a solution; b. filtering the solution and heating the filtrate to a minimum of 60°C; c. adding water to the filtrate to form an aqueous solution and cooling the aqueous solution to room temperature (rt); 、 d. filtering the aqueous solution and drying the filtrate under vacuum; A method comprising:

52. 1. A method for preparing Form A, a crystalline free form of Compound I, comprising: a. dissolving crystalline free form Form E in ethyl acetate at a minimum of 70°C to obtain a solution; b. filtering the solution and stirring the resulting filtrate at 20-25°C for 16 hours to form a slurry; c. concentrating the slurry under vacuum, filtering and drying; A method comprising:

53. 1. A method for preparing Form A, a crystalline free form of Compound I, comprising: a. dissolving crude Compound I in ethyl acetate at a minimum of 70° C. to obtain a solution; b. filtering the solution and stirring the resulting filtrate at 20-25°C for 16 hours to form a slurry; c. concentrating the slurry under vacuum, filtering and drying; A method comprising:

54. 1. A method for preparing Form A, a crystalline free form of Compound I, comprising: a. Heating crude Compound I in DMSO to a minimum of 60° C. to form a solution; b. adding water to form a slurry; c. filtering the slurry to isolate Form A, the crystalline free form; A method comprising:

55. 1. A method for preparing Form A, a crystalline free form of Compound I, comprising: a. slurrying crude Compound I in a solvent selected from heptane, IPAC, ethanol, ethyl acetate, or decane, or a mixture thereof; b. Stirring for 14-30 hours at rt; c. filtering the slurry and drying under vacuum; A method comprising:

56. 1. A process for preparing Form D, a crystalline free form of Compound I, comprising: a. mixing crystalline free form Form E with n-decane at 145-155°C to obtain a slurry; b. Cooling the slurry to 20-30°C over 1 hour; c. filtering the slurry and drying under vacuum; A method comprising:

57. A method for preparing Form D, a crystalline free form of Compound I, comprising heating any one of Form F, Form B, Form E, Form G, or Form H, or a mixture thereof, in the absence of other substances, at 180°C.

58. 1. A method for preparing Form B, a crystalline free form of Compound I, comprising: a. mixing crude Compound I with acetonitrile to form a solution; b. filtering the solution to form a filtrate and heating the filtrate at 70-75°C; c. adding water to the heated filtrate; d. Cooling to 52-62°C to form a slurry; e. Further cooling the slurry to 0-5°C for at least 4 hours; f. filtering the cooled slurry and drying the resulting filtrate under vacuum; A method comprising:

59. A method for preparing Form F, a crystalline free form of Compound I, comprising heating Form A, neat, at 160°C.

60. 1. A method for preparing Form G, a crystalline free form of Compound I, comprising: a. Mixing crude Compound I in acetone at room temperature for about 2 hours to form a slurry; b. filtering the slurry and drying under vacuum; A method comprising:

61. 1. A method for preparing Form G, a crystalline free form of Compound I, comprising: a. Stirring Form H in acetone at room temperature for about 2 hours to form a slurry; b. filtering the slurry and drying under vacuum; A method comprising:

62. 1. A method for preparing Form H, a crystalline free form of Compound I, comprising: a. Mixing crude Compound I with acetone at 45-50°C to obtain a solution; b. filtering and cooling to form a slurry; c. stirring the slurry, filtering and drying under vacuum; A method comprising:

63. A pharmaceutical composition comprising the crystalline free form of the compound of claim 2 or the hydrochloride salt of claim 3, and at least one pharmaceutically acceptable excipient or carrier.

64. 4. A pharmaceutical dosage form comprising a crystalline solid form of Compound I according to any one of claims 1, 2 or 3.

65. 62. A method of treating a disease, condition or disorder in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline solid form of Compound I according to any one of claims 1 to 50, or a pharmaceutical composition according to claim 63, or a pharmaceutical dosage form according to claim 64, wherein the disease, condition or disorder is: Hypertension and disorders related to reduced coronary blood flow; increased acute and chronic coronary blood pressure; arterial hypertension; vascular disorders due to cardiac and renal complications; vascular disorders due to heart disease, stroke, cerebral ischemia or renal failure; resistant hypertension; diabetic hypertension; essential hypertension; secondary hypertension; gestational hypertension; preeclampsia; portal hypertension; myocardial infarction; Heart failure, HFPEF, HFREF; acute and chronic HF; more specific forms of HF: acute decompensated HF, right ventricular failure, left ventricular failure, total HF, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, HF with heart valve anomalies, mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, tricuspid stenosis, tricuspid regurgitation, pulmonary stenosis, pulmonary regurgitation, combined heart valve anomalies; diabetic heart failure; alcoholic or chronic hypertrophic cardiomyopathy; diastolic HF, systolic HF; acute pre-existing chronic HF (worsening HF); diastolic or systolic dysfunction; coronary dysfunction; arrhythmias; reduced ventricular preload; cardiac hypertrophy; heart failure / cardiorenal syndrome; portal hypertension; endothelial dysfunction or injury; atrial and ventricular rhythm disturbances and conduction disturbances: stages I-III (AVB I to III) atrioventricular block, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, polymorphic ventricular tachycardia, atrial and ventricular premature contractions, AV junctional premature contractions, sick sinus syndrome, syncope, AV nodal reentrant tachycardia; Wolff-Pa Karkinson-White syndrome or acute coronary syndrome; Pugilistica cardiomyopathy; premature ventricular contractions; cardiomyopathy; cancer-induced cardiomyopathy; chemotherapy-induced cardiotoxicity; Thromboembolic disorders and ischemia; myocardial ischemia; infarction; myocardial infarction; heart attack; myocardial dysfunction; endothelial dysfunction; stroke; transient ischemic attack (TIA); thromboangiitis obliterans; stable or unstable angina; coronary or peripheral arterial spasm; variant angina; Prinzmetal angina; cardiac hypertrophy; pre-eclampsia; thrombogenic disorders; ischemia-reperfusion injury; ischemia-reperfusion associated with organ transplantation; lung transplant, pulmonary transplant, heart transplant, vein graft failure; ischemia-reperfusion associated with conservative blood substitution in trauma patients; Peripheral vascular disease; peripheral arterial disease; peripheral arterial occlusive disease; muscle hypertonia; Raynaud's syndrome or phenomenon (primary and secondary); Raynaud's disease; critical limb ischemia; peripheral embolism; intermittent claudication; vaso-occlusive crisis; muscular dystrophy, Duchenne muscular dystrophy, Becker muscular dystrophy; microcirculatory abnormalities; vascular leakage or permeability control; lumbar spinal stenosis; thromboangiitis obliterans; thromboangiitis; peripheral perfusion disturbance; arterial and venous thrombosis; microalbuminuria; peripheral and autonomic neuropathies; diabetic neuropathic pain; diabetic microangiopathy; hepatic vaso-occlusive disorder; vaso-occlusive crisis in sickle cell disease; hypertensive crisis; - Edema; renal edema due to heart failure; - Improvement of perception, concentration, learning or memory performance after cognitive disorders such as those occurring in Alzheimer's disease; Parkinson's disease; vascular dementia; vascular cognitive impairment; cerebral vasospasm; congenital myasthenic syndromes; subarachnoid hemorrhage; traumatic brain injury; traumatic brain injury; mild cognitive impairment, age-related impairment of learning and memory, age-related memory loss, vascular dementia, head injury, stroke, post-stroke dementia, after traumatic head injury, general disturbances of concentration and disturbances of concentration in children with learning and memory problems; dementia with Lewy bodies; dementia with frontal lobe degeneration including Pick's syndrome; progressive supranuclear 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; Movement disorders; Neuroprotection; Anxiety, tension and depression or Post-traumatic stress disorder (PTSD); Bipolar disorder; Schizophrenia; CNS-related sexual dysfunction and sleep disorders; Pathological eating disorders and the use of luxury foods and addictive drugs; Controlled cerebral perfusion; Migraine; Cerebral infarction (apoplexia) prevention and control of the consequences of stroke, cerebral ischemia and head injury; neuropathies associated with CNS diseases; neuropathic pain associated with MS; chemotherapy-induced neuropathic pain; neuropathic pain associated with shingles; neuropathic pain associated with spinal surgery; ·shock; Cardiogenic shock; sepsis; septic shock; anaphylactic shock; aneurysm; control of leukocyte activation; inhibition or regulation of platelet aggregation; multiple organ dysfunction syndrome (MODS); multiple organ failure (MOF); Pulmonary / Respiratory Conditions: Pulmonary hypertension (PH); Pulmonary arterial hypertension (PAH) and associated pulmonary vascular remodeling; Vascular remodeling in the form of focal thrombosis and right ventricular hypertrophy; Pulmonary hypertonia; Primary pulmonary hypertension; Secondary pulmonary hypertension; Familial pulmonary hypertension; Isolated pulmonary hypertension; Precapillary pulmonary hypertension; Idiopathic pulmonary hypertension; Other forms of PH; PH associated with left ventricular disease, HIV, SCD, thromboembolism (CTEPH), sarcoidosis, COPD, pulmonary fibrosis, Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury, Alpha-1 Antitrypsin Deficiency (AATD), Emphysema, Smoking-induced Emphysema and Cystic Fibrosis (CF); Thrombotic pulmonary arteriopathy; Multifactorial pulmonary arteriopathy; Cystic fibrosis; Bronchoconstriction or pulmonary bronchoconstriction; Acute respiratory syndromes; Pulmonary fibrosis, Lung transplant; Asthma disease; Left ventricular dysfunction, hypoxemia, WHO group I, II, III, IV and V hypertension, mitral valve disease, constrictive pericarditis, aortic valve stenosis, cardiomyopathy, mediastinal fibrosis, pulmonary fibrosis, anomalous pulmonary venous return, pulmonary venous obstruction, pulmonary vasculitis, collagen vascular disease, congenital heart disease, elevated pulmonary venous pressure, interstitial lung disease, sleep-disordered breathing, sleep apnea, alveolar hypoventilation, chronic exposure to high altitude, newborn Pulmonary hypertension associated with or related to lung disease, alveolar capillary dysplasia, sickle cell disease, other blood clotting disorders, chronic thromboembolic disease, pulmonary embolism; pulmonary embolism caused by tumors, parasites, or foreign bodies; connective tissue diseases, lupus, lupus nephritis, schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease, asthma, emphysema, chronic bronchitis, pulmonary capillary hemangiomatosis, histiocytosis X, lymphangiomatosis, compressed pulmonary vessels; compressed pulmonary vessels caused by adenosis, tumor, or fibrosing mediastinitis; - Arteriosclerotic diseases or conditions: atherosclerosis; atherosclerosis associated with endothelial injury, platelet and monocyte adhesion and aggregation, smooth muscle proliferation or migration; restenosis; restenosis developed after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), transluminal coronary angioplasty (PTCA), heart transplant, bypass surgery or inflammatory processes; - Microvascular and macrovascular damage (vasculitis); increased levels of fibrinogen and low density DLD; increased concentrations of plasminogen activator inhibitor 1 (PA-1); - Metabolic syndrome; metabolic diseases or disorders related to metabolic syndrome: obesity; excess subcutaneous fat; Excess body fat accumulation; diabetes; hypertension; lipid-related disorders, hyperlipidemia, dyslipidemia, hypercholesterolemia, decreased high-density lipoprotein cholesterol (HDL-cholesterol), moderately elevated low-density lipoprotein cholesterol (LDL-cholesterol) levels, hypertriglyceridemia, hyperglyceridemia, hypolipoproteinemia, sitosterolemia, fatty liver disease, alcoholic fatty liver disease (AFLD), non-alcoholic fatty liver disease (NAFLD), hepatitis; pre-eclampsia; multiple kidney disease progression; hepatic steatosis or abnormal lipid accumulation in the liver, non-alcoholic steatohepatitis (NASH); fatty degeneration of the heart, kidneys, or muscles; alpha-betalipoproteinemia; sitosterolemia; xanthomatosis; Tangier disease; hyperammonemia and related disorders; hepatic encephalopathy; other toxic encephalopathies; Reye's syndrome; Disorders of sexual, gynecological and urological conditions: erectile dysfunction; impotence; premature ejaculation; female sexual dysfunction; female sexual arousal dysfunction; hypofunctional sexual arousal disorder; vaginal atrophy; dyspareunia; atrophic vaginitis; benign prostatic hyperplasia (BPH), benign prostatic hyperplasia, prostatic enlargement; bladder outlet obstruction; painful bladder syndrome (BPS); interstitial cystitis (IC); overactive bladder; neurogenic bladder and incontinence; diabetic nephropathy; primary and secondary dysmenorrhea; lower urinary tract syndrome (LUTS); endometriosis; pelvic pain; benign and malignant diseases of the organs of the male and female urogenital system; - chronic kidney disease; acute and chronic renal insufficiency; acute and chronic renal failure; lupus nephritis; underlying or associated kidney diseases: hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disorders, nephropathic diseases, primary and congenital kidney diseases, nephritis; diseases characterized by abnormally decreased creatinine and / or water excretion; diseases characterized by abnormally increased blood concentrations of urea, nitrogen, potassium and / or creatinine; diseases characterized by altered activity of renal enzymes, Diseases characterized by altered activity of glutamyl synthetase; diseases characterized by altered urine osmolality or urine volume; diseases characterized by increased microalbuminuria, diseases characterized by macroalbuminuria; diseases characterized by glomerular and arteriolar lesions, tubular dilation, hyperphosphatemia and / or the need for dialysis; sequelae of renal insufficiency; renal insufficiency associated with pulmonary edema; renal insufficiency associated with HF; renal insufficiency associated with uremia or anemia; electrolyte abnormalities (herkalemia, hyponatremia); disturbances of bone and carbohydrate metabolism; acute kidney injury; Eye diseases or disorders such as glaucoma, retinopathy and diabetic retinopathy A method selected from the following.

66. 62. A method of treating a disease, condition or disorder in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline solid form of Compound I according to any one of claims 1 to 50, or a pharmaceutical composition according to claim 63, or a pharmaceutical dosage form according to claim 64, wherein the disease, condition or disorder is: Inflammation of the heart muscle (myocarditis); chronic myocarditis; acute myocarditis; viral myocarditis; Vasculitis; pancreatitis; peritonitis; rheumatoid diseases; Inflammatory diseases of the kidney; immunological kidney diseases: kidney transplant rejection, immune complex-induced kidney disease, toxin-induced nephropathy, contrast-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; - A method selected from ocular inflammatory diseases, blepharitis, dry eye syndrome, and Sjogren's syndrome; ocular fibrosis.

67. 64. A method of treating a disease, condition, or disorder in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline solid form of Compound I as defined in any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, pharmaceutical composition as defined in claim 63, or a pharmaceutical dosage form as defined in claim 64, wherein the disease, condition, or disorder is selected from: diabetic wound or ulcer healing; improved microvascular perfusion; improved microvascular perfusion following injury or to counteract inflammatory responses in perioperative care; anal fissures; diabetic ulcers; diabetic foot ulcers; bone healing mechanisms; osteoclastic bone resorption and remodeling; and new bone formation.

68. 62. A method of treating a disease, condition or disorder in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline solid form of Compound I according to any one of claims 1 to 50, or a pharmaceutical composition according to claim 63, or a pharmaceutical dosage form according to claim 64, wherein the disease, condition or disorder is: Genitourinary system or kidney disorders: diabetic nephropathy; renal fibrosis and failure due to chronic kidney disease or renal insufficiency; renal fibrosis and failure due to accumulation / deposition and tissue injury; nephrosclerosis; progressive sclerosis; glomerulonephritis; focal segmental glomerulosclerosis; nephrotic syndrome; prostatic hyperplasia; renal fibrosis; interstitial renal fibrosis; Pulmonary system disorders: pulmonary fibrosis; idiopathic pulmonary fibrosis; cystic fibrosis; progressive massive fibrosis; progressive massive fibrosis affecting the lungs; Disorders affecting the heart: endomyocardial fibrosis; previous myocardial infarction; atrial fibrosis; cardiac interstitial fibrosis; cardiac remodeling and fibrosis; cardiac hypertrophy; - Disorders of the liver and associated organs: liver sclerosis or cirrhosis; cirrhosis associated with chronic liver disease; liver fibrosis; hepatic stellate cell activation; NASH; hepatic fibrous collagen and total collagen accumulation; liver diseases of necrotizing inflammatory and / or immunological origin; primary biliary cirrhosis; primary sclerosing cholangitis; other cholestatic liver diseases: those associated with granulomatous liver disease, hepatic malignancies, intrahepatic cholestasis of pregnancy, hepatitis, sepsis, drugs or toxins, graft versus host disease, post liver transplant, common bile duct stones, bile duct tumors, pancreatic cancer, Mirizzi syndrome, AIDS cholangiopathy or parasites; schistosomiasis; hepatocellular carcinoma; Digestive system diseases or disorders: Crohn's disease; ulcerative colitis; gastrointestinal sclerosis; achalasia; Skin or eye diseases: renal fibrosis; proliferative vitreoretinopathy; diabetic retinopathy; ocular fibrosis; - fibrotic local or skin disorders or conditions; Dermal fibrosis; scleroderma, cutaneous fibrosis; morphea; hypertrophic scars; nevi; 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 hearing diseases or disorders; hearing loss, partial or total hearing loss; partial or total hearing loss; tinnitus; Noise-induced hearing loss; Other diseases involving autoimmune, inflammatory or fibrotic diseases: scleroderma; localized or localized scleroderma; mediastinal fibrosis; fibrotic mediastinitis; myelofibrosis; retroperitoneal fibrosis; arthrofibrosis; Peyronie's disease Dupuytren's contracture; Lichen sclerosus; Some forms of adhesive capsulitis; Atherosclerosis; Tuberous sclerosis; Systemic sclerosis; Polymyositis; Dermatomyositis; Polychondritis; Eosinophilic fasciitis; Systemic lupus erythematosus or lupus; Bone marrow fibrosis, myelofibrosis or osteomyelofibrosis; Sarcoidosis; Uterine fibroids; Endometriosis A method selected from the following.

69. 62. A method of treating a disease, condition or disorder in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline solid form of Compound I according to any one of claims 1 to 50, or a pharmaceutical composition according to claim 63, or a pharmaceutical dosage form according to claim 64, wherein the disease, condition or disorder is selected from the group consisting of certain types of cancer; sickle cell disease; sickle cell anemia; cancer metastasis; osteoporosis; gastroparesis; functional dyspepsia; diabetic complications; alopecia or hair loss; Diseases associated with endothelial dysfunction; neuropathies associated with reduced nitric oxide production; argininosuccinic aciduria; neuromuscular diseases; Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), limb-girdle muscular dystrophy, distal myopathy, myotonic dystrophy types I and II, facioscapuloperoneal muscular dystrophy, autosomal and X-linked Emery-Dreifuss muscular dystrophy, oculopharyngeal muscular dystrophy, amyotrophic lateral sclerosis, and spinal muscular atrophy (SMA). A method selected from the following.

70. 51. A method of treating or preventing a disease, condition or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline solid form of Compound I according to any one of claims 1 to 50, alone or in combination therapy, wherein the disease or disorder is a disease or disorder that may benefit from sGC stimulation or from increased concentrations of NO and / or cGMP.

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