Solid form of SGC stimulant

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] This disclosure relates to solid forms of soluble guanylate cyclase (sGC) stimulants. 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, as well as their use, alone or in combination with one or more further agents, to treat and / or prevent a variety of diseases or disorders, which 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 via both NO-dependent and NO-independent mechanisms. In response to this activation, sGC converts guanosine-5'-triphosphate (GTP) to the secondary mediator cGMP. Elevated levels of cGMP subsequently modulate 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 nitrates. Three different isoforms of NOS have been identified: inducible NOS (iNOS or NOS II) found in activated macrophage cells, commensal neural NOS (nNOS or NOS I) involved in neurotransmission and long-term potentiation, and commensal endothelial NOS (eNOS or NOS III) regulating 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 disease development.

[0004]

[0004] The NO-independent, heme-dependent sGC stimulators exhibit several important distinguishing features compared to sGC activators, which include a critical dependence on the presence of a reduced prosthetic heme moiety for their activity, strong synergistic enzyme activation when bound to NO, and stimulation of cGMP synthesis by direct stimulation of NO-independent sGC. 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 a NO-independent manner offer several significant advantages over other current alternative therapies that target abnormal NO pathways. There is a need to develop novel, well-characterized stimulators of sGC. Compound I is an sGC stimulator that has demonstrated efficacy in treating a number of NO-related disorders in preclinical models. Compound I was previously described as a pale orange solid in WO2014144100, Example 1. Compound I can exist in various crystalline forms and can also form several pharmaceutically acceptable salts.

[0006]

[0006] The properties of a solid with respect to its effectiveness as a drug can depend on its solid form. For example, in the case of a drug substance, the diversity of solid forms can 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, electrostatic charge, etc.), tablet properties (hardness, homogeneity, friability, disintegration, stability to heat and humidity, etc.), oral absorption, bioavailability, storage properties (caking, hygroscopicity), toxicological outcomes, and clinical trial results.

[0007] The characterization of polymorphs is useful, for example, in preventing certain problems that occur during the clinical trials and / or commercialization of a drug in order to avoid, for example, drug substance and product mismatches (e.g., lot-to-lot mismatches), hydration or dehydration of hydrates, chemical decomposition, amorphization or polymorphic transitions in pharmaceutical formulations. One polymorph may also be preferred when it improves solubility and / or bioavailability compared to another polymorph of the compound or its amorphous form. One polymorph may also be preferred because it imparts increased physical or chemical stability, provides a higher melting point (resulting in improved mechanical properties), has a more acceptable taste or odor, or a more neutral pH, etc.

Summary of the Invention

Problems to be Solved by the Invention

[0008]

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

[0009]

Chemical formula

[0010] relates to.

[0009] For the purposes of the present disclosure, "Compound I" refers to the free base or hydrochloride salt of the structure shown above, unless otherwise specified. Compound I is known to be highly polymorphic as its crystalline free base and to have seven crystalline forms (Forms A, B, D, E, F, G and H), as well as multiple solvates. Compound I was already described as a pale orange solid in WO2014144100, Example 1.

[0011]

[0010] 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 a hydrochloride salt. In one embodiment, the polymorph of Compound I is in the crystalline free base form. In another embodiment, they are solvates.

[0012]

[0011] In another embodiment, methods for preparing the above-described crystalline free form and salt of compound I are also provided herein.

[0012] In another embodiment, the present invention relates to a pharmaceutical composition comprising one or more polymorphs of compound I disclosed herein, or a 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 the pharmaceutical composition.

[0013]

[0013] In another embodiment, the present invention relates to a method for treating a disease, health condition or disorder in a subject requiring such treatment, comprising administering, alone or in combination, a therapeutically effective amount of a polymorph of Compound I disclosed herein, a mixture thereof, or its hydrochloride to the subject; the disease or disorder is treated from sGC stimulation or NO and / or cGMP A disease or disorder that may benefit from increased concentrations of [the substance]. [Brief explanation of the drawing]

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

[0015]

[0014] The figures are provided as examples and are not intended to limit the scope of the present invention. [Modes for carrying out the invention]

[0016]

[0015] Specific embodiments of the present invention are referenced in detail herein, and examples thereof are described in the appended structures and formulas. While the present invention is described in relation to the enumerated embodiments, it will be understood that the present invention is not intended to be limited to these embodiments. Rather, the present invention is intended to encompass all substitutes, modifications and equivalents that may fall within the scope of the present invention as defined by the claims. The present invention is described herein. This includes, but is not limited to, any methods and materials similar to or equivalent to those described herein that may be used in the practice of the present invention. If one or more incorporated references, patents, or similar materials differ from or conflict with this application, including but not limited to defined terms, terminology, and described techniques, this application shall prevail.

[0017] Definitions and General Terms

[0016] For the purposes of this disclosure, chemical elements are identified based on the Periodic Table, CAS versions, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, the general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th edition, Smith, MB and March, J., eds. John Wiley & Sons, New York: 2001, which are incorporated herein by reference in their entirety.

[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 atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. All isotopes of any given specific atom or element are contemplated within the scope of the compounds of the invention and their use. Isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, 18 , 13 , 11 , 15 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, etc. are included. Certain isotopically labeled compounds of the invention (e.g., 3 H and 14 C labeled compounds) are useful in tissue distribution assays of compounds and / or substrates. Tritium labeled (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are useful because of the ease of their preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced required dosage), and thus may be preferred depending on the situation. 15 O, 13 N, 11 C, and 18Positron-emitting isotopes such as 14F are useful in positron emission tomography (PET) studies to evaluate the receptor occupancy of substrates. The isotope-labeled compounds of the present invention can generally be prepared by replacing the unisotopologized reagent with an isotope-labeled reagent by the following procedure, which is similar to the procedure disclosed in the following diagrams and / or examples herein.

[0019]

[0018] As used herein, the “solid form” of compound I is characterized by or represents a specific solid-phase lattice structure (on a unit cell scale) of the compound.

[0019] Compounds such as compound I may exist in either a "neat form" or a "free base form," and the free base form may be either crystalline or amorphous. The free base form of a compound is formed solely by the molecules of the compound.

[0020]

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

[0021]

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

[0022]

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

[0023]

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

[0024]

[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) and a compound in a crystalline state (e.g., compound I), resulting in a crystalline solid with novel characteristics. This disclosure describes several “ansolvates” of the free base form of compound I (i.e., solid forms of compound I that are crystalline free and not solvates).

[0025]

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

[0026]

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

[0027]

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

[0028]

[0028] When two substances are mixed, whether a salt or a cocrystal is formed is determined by how large the difference between the pKa values ​​of the two components is.

[0029] This disclosure describes one solid form of compound I, which is a salt (hydrochloride salt).

[0029]

[0030] There are many crystallization techniques available that can be used by those skilled in the art to obtain crystalline substances. For crystallization to occur from a solution, the solution must be "supersaturated." This means that the solution must contain more dissolved solute (molecules or ions) than the amount of solute contained in a saturated solution at thermodynamic equilibrium. This can be achieved by various methods, for example: 1) "cold crystallization"; 2) addition of a second solvent to reduce the solubility of the solute (a technique known as "anti-solvent crystallization"); 3) chemical reactions; 4) changes in pH; and 5) slurry transformation in organic and / or aqueous solvent systems, which are the most common methods used in industrial operations. Other methods such as "solvent evaporation crystallization" may also be used. As used herein, "supersaturation" is the difference between the concentration (C) of a solution at the same temperature and the concentration (C*) at equilibrium. This is measured in units of concentration.

[0030]

[0031] The term "chemically stable" characterizes the solid form (e.g., polymorph or salt) of compound I, such that it remains stable under specified conditions, such as 40°C / 75% relative humidity, for a period of time such as 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, or 6 months. This indicates that, when exposed for a specified period, such as 12 months, 18 months, 24 months, or longer, the compound does not decompose into one or more new and different chemical compounds. In some embodiments, less than 25% of the polymorphs of compound I decompose under specified conditions; in some embodiments, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the polymorphs of compound I decompose. In some embodiments, a detectable amount of a given polymorph of compound I does not decompose under specified conditions after a particular period (determined by the minimum detection limit of the analytical technique used).

[0031]

[0032] The term "physically stable" characterizes the crystalline solid form of compound I (e.g., polymorph or salt) to mean that when exposed to specified conditions, such as 40°C / 75% relative humidity, for a specified period, such as 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, the crystalline solid form of compound I does not change into one or more different crystalline solid forms (e.g., polymorphs that change into different polymorphs of compound I when measured by analytical techniques such as XRPD) or amorphous forms. In some embodiments, when exposed to specified conditions, less than 25% of the crystalline solid form of compound I changes into one or more different solid forms (another crystalline solid form or amorphous form). In some embodiments, when exposed to 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 compound I in a crystalline solid form transforms into one or more different crystalline solid forms or amorphous forms of compound I. In some embodiments, a detectable amount of a given compound I in solid form does not transform into one or more different solid forms of compound I under specified conditions.

[0032]

[0033] When the term “substantially pure” refers to the crystalline solid form of a given compound I (e.g., a polymorph or salt of compound I as described herein), it means that the given crystalline solid form contains less than 20% (by weight) of residual components (such as another (alternate) polymorph(s) or amorphous form 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 alternating polymorphs or amorphous form of compound I, or additional solvent molecules or impurities. In other embodiments, this contains less than 5% (by weight) of alternating polymorphs or amorphous form of compound I, or additional solvent molecules or impurities. In yet another embodiment, this contains less than 1% (by weight) of alternating polymorphs or amorphous form of compound I, or additional solvent molecules or impurities.

[0033]

[0034] The term "substantially similar," as used herein, means that when representing spectra, traces, thermal curves, etc., the characteristics of the solid form of compound I shown (e.g., a polymorph or salt of compound I described herein) are represented as containing less than 10% of peaks different from the peaks in the spectrum, trace, or curve assigned to a particular solid form of compound I shown and considered herein as a figure. In other embodiments, this means containing less than 5% of different peaks. In yet another embodiment, this means containing less than 1% of different peaks.

[0034]

[0035] When comparing XRPD spectra, if a spectrum is "substantially similar" to that shown in this disclosure with respect to the solid form of a particular compound I, the characteristic peak in the spectrum is measured at the same °2θ value as shown in the figures of this disclosure, or within a °2θ range of + or -0.5 units from the peak shown in the figures. The XRPD of the solid form of compound I is considered "essentially unchanged" under specific conditions after a specific length of time if the XRPD of the solid form is "substantially similar" before and after a specific length of time under specific conditions.

[0035]

[0036] This disclosure often represents an evaluation of chemical, physical, or biological parameters disclosed herein. Those skilled in the art will understand that such parameters may be replaced by other chemical, physical, or biological parameters that are essentially similar with respect to the identification of solid forms, even if they are not disclosed herein.

[0036] Embodiment

[0037] In one embodiment, the present invention relates to the crystalline solid form of compound I as shown below:

[0037] [ka]

[0038] Regarding.

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

[0039]

[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 other free polymorphs or crystalline free forms: form A, form B, form D, form E, form F, form G and form H. Compound I has already been described in WO2014144100, Example 1, as a pale orange solid.

[0040]

[0040] In one embodiment, the crystalline solid form of compound I is polymorph 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, which is then filtered, the filtrate is heated at >60°C, water is added, it is cooled to room temperature (rt), which is then filtered, and it is dried under vacuum at 80°C for 72 hours.

[0041]

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

[0042]

[0042] In another embodiment, polymorph A is dissolved in ethyl acetate at >70°C to obtain a solution, which is then filtered, and the filtrate is further stirred at 20-25°C for 16 hours to obtain a slurry, which is concentrated under vacuum, and heptane is added to the obtained slurry further It is formed when the mixture is concentrated, filtered, and dried under vacuum at 100°C for 3 hours.

[0043]

[0043] In another embodiment, polymorph A can be heated in DMSO at a temperature higher than 60°C, followed by the addition of water to form a slurry, which can then be filtered to obtain directly from crude compound I.

[0044]

[0044] In another embodiment, polymorph A is also isolated when crude compound I is slurryed in a solvent at room temperature and stirred 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]

[0045] In another embodiment, the solid form of compound I is polymorph 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, which is then cooled to 20-30°C for 1 hour, filtered, and dried under vacuum at 80°C for 72 hours.

[0046]

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

[0047]

[0047] In another embodiment, the solid form of compound I is polymorph 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, which is then filtered, the filtrate is further heated at 70-75°C, water is added, and the slurry is cooled to 52-62°C to form a slurry, which is then cooled to 0-5°C for more than 4 hours, filtered, and dried under vacuum at 90-100°C for a minimum of 30 hours.

[0048]

[0048] In another embodiment, the solid form of compound I is polymorph F. Form F is obtained by heating form A, which is prepared as described in the Examples section, at 160°C without any other substances.

[0049]

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

[0050]

[0050] In another embodiment, the solid form of compound I is polymorph H. Form H is obtained when crude compound I, prepared as described in the Examples section, is mixed with acetone at 45-50°C to form a solution, which is then filtered and cooled to room temperature to form a slurry, which is then stirred at room temperature for 5 hours, followed by filtration and drying under vacuum at 30-40°C.

[0051]

[0051] In one embodiment, the solid form of compound I is polymorph A.

[0052] In some embodiments, morphology A is characterized by an FT-Raman spectrum substantially similar to that shown in Figure 10.

[0052]

[0053] In some embodiments, form A has an IR spectrum of 1730 cm⁻¹. -1It is characterized by exhibiting a band maximum at a certain frequency.

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

[0053]

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

[0054]

[0056] In other embodiments, morphology A is characterized by one or more peaks in the 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.

[0055]

[0057] In other embodiments, morphology A is characterized by one or more peaks in the XRPD spectrum selected from °2θ of 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.

[0056]

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

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

[0057]

[0060] In other embodiments, morphology A is characterized by one or more peaks in the XRPD spectrum selected from °2θ of 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%).

[0058]

[0061] In another embodiment, form A is characterized by exhibiting an essentially unchanged XRPD trace when stored for 14 months under stable conditions of 40°C and 75% relative humidity. The XRPD traces for form A before and after storage under these conditions are shown in Figure 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 Figure 10.

[0060]

[0064] In some embodiments, form B has an IR spectrum of 1200 cm⁻¹. -1 It is characterized by showing the peak maximum value in that respect.

[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 other embodiments, form B is described in 18.8-19.1 o 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 the XRPD spectrum selected from °2θ of 8.8, 16.4, 17.2, 18.8–19.1, 20.1, and 21.1–21.6.

[0062]

[0068] In another embodiment, form B is 8.8, 10.6, 12.6-13.0, 14. Characterized by one or more peaks in the XRPD spectrum selected from °2θ of 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.

[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, morphology B is characterized by one or more peaks in the XRPD spectrum selected from °2θ of 8.9 (relative intensity of 76.55%), 17.4 (57.67%), 19.1 (100.00%), and 25.5 (52.26%).

[0064]

[0071] In other embodiments, morphology B is characterized by one or more peaks in the XRPD spectrum selected from °2θ of 7.0 (relative intensity of 44.44%), 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%).

[0065]

[0072] In another embodiment, form B is characterized by exhibiting an essentially unchanged XRPD trace when stored for 14 months under stable conditions of 40°C and 75% relative humidity. The XRPD traces for form B before and after storage under these conditions are shown in Figure 4B.

[0066]

[0073] In one embodiment, the solid form of compound I is polymorph D.

[0074] In some embodiments, morphology D is characterized by an FT-Raman spectrum substantially similar to that shown in Figure 10.

[0067]

[0075] In some embodiments, form D has an IR spectrum of 1665, 1639, and 968 cm⁻¹. -1 It is characterized in that it exhibits a band maximum at 1665 cm⁻¹. In some embodiments, morphology D has an IR spectrum at 1665 cm⁻¹. -1 It is characterized in that it exhibits a band maximum at . In other embodiments, morphology D has an IR spectrum at 1639 cm⁻¹. -1 It is characterized in that it exhibits a band maximum at 968 cm⁻¹. In other embodiments, morphology D has an IR spectrum at 968 cm⁻¹. -1 It is characterized by exhibiting a band maximum at that point.

[0068]

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

[0077] In another embodiment, morphology D is characterized by exhibiting an essentially unchanged XRPD trace when stored for 14 months under stable conditions of 40°C and 75% relative humidity. The XRPD traces for morphology D before and after storage under these conditions are shown in Figure 5B.

[0069]

[0078] In other embodiments, form D is 18.8 o Characterized by a peak in the XRPD spectrum at 2θ.

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

[0070]

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

[0071]

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

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

[0072]

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

[0073]

[0084] In one embodiment, the solid form of compound I is polymorph E.

[0085] In some embodiments, morphology E is characterized by an FT-Raman spectrum substantially similar to that shown in Figure 10.

[0074]

[0086] In some embodiments, form E has an IR spectrum of 1690 and 1515 cm⁻¹. -1 It is characterized in that it exhibits a band maximum at 1690 cm⁻¹. In some embodiments, morphology E has an IR spectrum at 1690 cm⁻¹. -1 It is characterized in that it shows the maximum peak value at 1515 cm⁻¹. In some embodiments, morphology E has an IR spectrum at 1515 cm⁻¹. -1 It is characterized by showing the peak maximum value in that respect.

[0075]

[0087] In some embodiments, morphology E is characterized by an XRPD spectrum substantially similar to that shown in Figure 2 or Figure 6.

[0088] In other embodiments, morphology E is characterized by one or more peaks in the XRPD spectrum selected from °2θ of 7.4, 18.8–19.3, 21.1, 24.8, and 25.5.

[0076]

[0089] In other embodiments, morphology E is characterized by one or more peaks in the 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.

[0077]

[0090] In one embodiment, the solid form of compound I is polymorph F.

[0091] In some embodiments, morphology F is characterized by an XRPD spectrum substantially similar to that shown in Figure 7.

[0078]

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

[0079]

[0093] In another embodiment, morphology F is characterized by one or more peaks in the XRPD spectrum selected from °2θ values ​​of 5.3 (relative intensity of 100.00%), 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 polymorph G.

[0095] In some embodiments, morphology G is characterized by an XRPD spectrum substantially similar to that shown in Figure 8.

[0081]

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

[0082]

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

[0083]

[0098] In one embodiment, the solid form of compound I is polymorph H.

[0099] In some embodiments, morphology H is characterized by an XRPD spectrum substantially similar to that shown in Figure 9.

[0084]

[0100] In other embodiments, form H is 5.77 (relative intensity of 89.22%), 6.3 Characterized by one or more peaks in the XRPD spectrum selected from °2θ values ​​of 9 (100.00%), 9.1 (84.17%), and 18.5 (67.04%).

[0085]

[0101] In another embodiment, form H is 5.77 (relative intensity of 89.22%), 6.3 Characterized by one or more peaks in the XRPD spectrum selected from °2θ values ​​of 9 (100.00%), 9.1 (84.17%), 18.5 (67.04%), and 18.83 (67.04%). The pharmaceutically acceptable salt of the present invention.

[0086]

[0102] The phrase "pharmaceutically acceptable salt" as used herein refers to the drug of Compound I. This represents a pharmaceutically acceptable organic or inorganic salt. A pharmaceutically acceptable salt of compound I may be used in medicine. However, a pharmaceutically unacceptable salt may be useful as an intermediate in the preparation of other solid forms of compound I.

[0087]

[0103] A pharmaceutically acceptable salt is one in which another atom or molecule acts as a counterion. This includes the counterions, which can be any organic or inorganic part that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. If multiple charged atoms are part of a pharmaceutically acceptable salt, it may have multiple counterions. In some cases, the counterions may be identical. In other cases, they may differ depending on the respective charged atom. Thus, a pharmaceutically acceptable salt may 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 the salts is fully described in Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977: 66: pp. 1-19, and its entirety is incorporated herein by reference.

[0089]

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

[0106] The hydrochloride salt of compound I is the compound in its polymorph D, which was prepared as described above. I can be prepared by suspending it in 1M HCl, mixing it with i-PrOH, and stirring it with a heating rate of 40°C / hour and a cooling rate of 5°C / hour over a temperature cycle between 20 and 40°C.

[0090]

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

[0108] The hydrochloride salt of compound I has a water solubility of 0.5 mg / mL at pH 1.4. The salt was characterized. Its water solubility was determined at the pH of a saturated solution. The salt was shaken in water at 25°C for 24 hours. After filtration, its 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 Figure 11. Characterized by [this]. Pharmaceutical composition and method of administration

[0110] The crystalline solid forms disclosed herein are manufactured as pharmaceutical compositions or "formulations". It can be formulated into a drug.

[0092]

[0111] Typical formulations include the crystalline solid form of compound I and a carrier, diluent, or excipient. It is prepared by mixing. Suitable carriers, diluents, and excipients are well known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and / or swelling polymers, hydrophilic or hydrophobic substances, gelatin, oils and fats, solvents, and water. The specific carrier, diluent, or excipient used varies depending on the means and purpose for which the polymorph or pharmaceutically acceptable salt of compound I is formulated. Solvents are generally selected based on solvents that are considered safe to administer to mammals (GRAS - Generally Regarded as Safe) by those skilled in the art. Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble in water or miscible. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and mixtures thereof. The formulation may also include one or more buffers, stabilizers, anti-tacks, surfactants, wetting agents, lubricants, emulsifiers, binders, suspending agents, disintegrants, fillers, adsorbents, coating agents (e.g., enteric or slow-release), preservatives, antioxidants, opaquing agents, flow enhancers, processing aids, colorants, sweeteners, fragrances, flavorings, and other known excipients that provide a fine appearance to the drug or aid in the manufacture of pharmaceutical products (i.e., pharmaceuticals).

[0093]

[0112] The formulation may be prepared using conventional dissolution and mixing procedures. For example, by volume A high-purity active pharmaceutical ingredient (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 aforementioned excipients. The compound, having a desired degree of purity, is optionally mixed with a pharmaceutically acceptable diluent, carrier, excipient, or stabilizer to form a lyophilized formulation, crushed powder, or aqueous solution. Formulation may be carried out by mixing with a physiologically acceptable carrier at ambient temperature, at a suitable pH, and with a desired degree of purity. The pH of the formulation may range from about 3 to about 8, but mainly depends on the specific use and concentration of the compound. When the formulation described herein is a solid amorphous dispersion formed by a solvent process, and when additives, etc., form a mixture in which they are dissolved or suspended as a slurry in solution, the additives may be added directly to the spray-dried solution and then spray-dried. Alternatively, the additives may be added following the spray-dried process to assist in the formation of the final formulation product.

[0094]

[0113] Polymorphs or pharmaceutically acceptable salts of compound I are typically prepared into pharmaceutical dosage forms. The formulation provides easily controllable drug delivery and enables patient compliance with the prescribed regimen. Pharmaceutical formulations of polymorphs or pharmaceutically acceptable salts of compound I can be prepared for various routes and types of administration. Since different medical conditions justify the use of different routes of administration, various dosage forms may exist for the same compound.

[0095]

[0114] The amount of active material that can be combined with a carrier substance to provide a single dosage form is The dosage may vary depending on the target and specific mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of the active substance, combined with an appropriate and convenient amount of carrier material that can vary in weight from approximately 5% to approximately 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 approximately 3 to 500 μg of the active material per milliliter of solution, so that a suitable volume can be infused at a rate of approximately 30 mL / hour. As a general suggestion, the initial pharmaceutically effective dose of the inhibitor to be administered is in the range of approximately 0.01 to 100 mg / kg per dose, i.e., approximately 0.1 to 20 mg / kg of patient's body weight per day, with a typical initial range of 0.3 to 15 mg / kg / day for the compound used.

[0096]

[0115] The term "therapeutic effective dose" is used herein by researchers, veterinarians, physicians, etc. This refers to the amount of an active compound or pharmaceutical agent that elicits a biological or pharmacokinetic response in a tissue, system, animal, or human, as explored by other clinicians. The therapeutic or pharmacokinetic dose of a compound administered is the minimum amount necessary to improve, cure, or treat a disease or disorder or one or more of its symptoms, managed with such considerations.

[0097]

[0116] Pharmaceutical compositions of polymorphs or pharmaceutically acceptable salts of compound I are good medical treatments. Formulated in a manner consistent with the purpose, namely in terms of quantity, concentration, schedule, course, vehicle, and route of administration, divided into doses, and administered. Elements of consideration in this context include the specific disorder being treated, the specific mammal being treated, the individual patient's condition, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to healthcare professionals, such as the individual patient's age, weight, and response.

[0098]

[0117] The term "preventive effective dose" refers to the amount of medication that prevents or reduces the chance of developing a disease or disorder. This represents an amount that is effective in substantially reducing the severity of a disease or disability before it develops, or in reducing the severity of one or more of its symptoms before those symptoms develop. In general, preventive measures are divided into primary prevention (preventing the development of the disease) and secondary prevention (protecting the patient from the worsening of the disease once it has developed).

[0099]

[0118] The permissible diluents, carriers, excipients, and stabilizers are those used in the dosage and Buffers that are non-toxic to the recipient at concentrations and include phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (ammonium octadecyldimethylbenzyl chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkylparabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol, etc.); proteins such as serum albumin, gelatin, or immunoglobulins; Hydrophilic polymers such as livinylpyrrolidone; 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). The active pharmaceutical ingredient may also be contained in microcapsules prepared by coacervation technology or interfacial polymerization, for example, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively; colloidal drug delivery systems (e.g., liposomes, albumin spheres, microemulsifiers). They can be encapsulated in nanoparticles and nanocapsules, or in macroemulsions. Such techniques are described in Remington's: The Science and Practice. This information is disclosed in *of Pharmacy*, 21st edition, University of the Sciences in Philadelphia, Eds., 2005 (hereinafter referred to as "Remington's").

[0100]

[0119] The terms "administer," "administering," or "administering" refer to the solid form of the present invention. With respect to compositions or formulations, this means introducing the compound into the system of an animal requiring treatment. When the compound of the present invention is provided in combination with one or more other active agents, “administration” and its variations are understood to include the simultaneous and / or sequential introduction of the compound and the other active agents, respectively.

[0101]

[0120] The compositions described herein are, for example, administered orally (e.g., in capsules, powders). Depending on the severity and type of the disease being treated, it may be administered systemically or topically by means of a drug, liquid, suspension, tablet, sublingual tablet, etc., by inhalation (e.g., using aerosol, gas, inhaler, nebulizer or similar), in the ear (e.g., using ear drops), topically (e.g., using cream, gel, liniment, lotion, ointment, paste, transdermal patch, etc.), ophthalmally (e.g., using eye drops, ophthalmic gel, ophthalmic ointment), rectally (e.g., using enema or suppository), nasally, buccally, transvaginally (e.g., using injection device, intrauterine device, vaginal suppository, vaginal ring or tablet, etc.), via an implanted reservoir or similar device, or parenterally.

[0102]

[0121] The term "parenteral" as used herein refers to subcutaneous, intravenous, intramuscular, and intercutaneous administration. This includes, but is not limited to, intranodal, intrabursal, intrasternal, subarachnoid, intrahepatic, intralesional, and intracranial injection or infusion techniques. The composition is preferably administered orally, intraperitoneally, or intravenously.

[0103]

[0122] The pharmaceutical compositions described herein are capsules, tablets, aqueous suspensions, or liquids. The active compound may be administered orally in any orally acceptable dosage form, including but not limited to the active compound. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, 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, and dimethylformamide; oils and fats (in particular, cottonseed, tuber, corn, germ, olive, castor, and sesame oils and fats); glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters; and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, 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 may be at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) hydrating agents such as glycerin; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders such as paraffin; f) absorption enhancers such as quaternary ammonium compounds; g) For example, the tablets may be mixed with humectants such as cetyl alcohol and glyceryl monostearate, absorbents such as kaolin and bentonite clay, and lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. The tablets may or may not be coated, or they may be coated by known techniques, including microencapsulation, to mask unpleasant tastes or to delay disintegration and adsorption in the digestive tract, thereby providing a sustained effect over a long period. For example, time-delaying substances such as glyceryl monostearate or glyceryl distearate may be used alone or with wax. Water-soluble taste-masking substances 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 individual units such as tablets, pills, lozenges, medicinal drops, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules such as gelatin capsules, syrups or elixirs. Formulations of compounds intended for oral use may be prepared based on any method known in the art for the manufacture of pharmaceutical compositions.

[0106]

[0125] Oral formulations may contain active ingredients such as calcium carbonate and calcium phosphate. Alternatively, the active material may be provided as a hard gelatin capsule mixed with an inert solid diluent such as 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 is also microcapsules together with one or more of the excipients mentioned above. It can be a transformed form.

[0127] When an aqueous suspension is required for oral use, the active ingredients are emulsifiers and suspending agents. These can be combined with other ingredients. Certain sweeteners and / or flavorings may be added, if desired. Syrups and elixirs can be formulated with sweeteners such as glycerin, propylene glycol, sorbitol, or sucrose. Such formulations may also contain lubricants, preservatives, flavorings, colorings, and antioxidants.

[0108]

[0128] The sterile injectable forms (e.g., for parenteral administration) of the compositions described herein are These can be aqueous or oily suspensions. These suspensions can be formulated using suitable dispersants 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 a solution in 1,3-butanediol or PEG400. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solutions. In addition, sterile, non-volatile oils have conventionally been used as solvents or suspension media. For this purpose, any mild non-volatile oil, including synthetic mono-glycerides or di-glycerides, can be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectable preparations as naturally pharmaceutically acceptable oils and fats, such as olive oil or castor oil, especially its polyoxyethylated forms. These oil and fat liquids or suspensions may also contain diluents or dispersants of long-chain alcohols 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 and Span, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms may also be used for the purpose of injectable formulations.

[0109]

[0129] Oily suspensions include, for example, peanut oil, olive oil, sesame oil, or coconut oil. Compound I can be formulated by suspending a polymorph of compound I or a pharmaceutically acceptable salt thereof in a vegetable oil such as oil, or in a mineral oil such as liquid paraffin. The oily suspension may contain thickeners such as beeswax, solid paraffin, or cetyl alcohol. Sweeteners and flavorings, such as those indicated above, may 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 water The aqueous suspension contains an active substance when mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic, as well as dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensates of alkylene oxide and fatty acids (e.g., polyoxyethylene stearate), condensates of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), and condensates of ethylene oxide and partial esters derived from fatty acids and hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as p-hydroxybenzoate ethyl or p-hydroxybenzoate n-propyl, one or more colorants, one or more flavoring agents such as sucrose or saccharin, and one or more sweeteners.

[0111]

[0131] Injectable preparations are filtered, for example, by passing them through a bacterial-retaining filter, or sterilized. By incorporating the agent, the substance can be sterilized in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or another sterile injection medium before use.

[0112]

[0132] The liquid or microemulsified formulation for injection is administered into the patient's bloodstream via local bolus injection. It can be introduced into the system. Alternatively, it may be advantageous to administer a liquid or microemulsion of the compound in a manner that maintains a constant circulating concentration. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS® model 5400 intravenous pump.

[0113]

[0133] Compositions for rectal or vaginal administration are preferably solid compositions as described herein. The suppository can be prepared by mixing the body form with suitable non-irritating excipients or carriers such as cocoa butter, beeswax, and polyethylene glycol, or by mixing it with 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 may be provided as pessaries, tampons, creams, gels, pastes, foaming agents, or sprays.

[0114]

[0134] The pharmaceutical compositions described herein also treat diseases of the eyes, ears, skin, or lower intestines. Topical administration may be used when the target of treatment, including the patient, includes areas or organs that can be easily reached by topical application. Suitable topical formulations are readily prepared for each of these areas or organs.

[0115]

[0135] The dosage forms for topical or transdermal administration of the compounds described herein are ointments, This includes 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 this invention. In addition, the invention considers the use of transdermal patches, which have the further advantage of providing controlled delivery of compounds to the body. Dosage forms can be prepared by dissolving or distributing the compound in a suitable medium. Absorption enhancers may also be used to increase the fluidity of the compound through the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel. Topical application to the lower intestine can be achieved with rectal suppositories (see above) or suitable enema formulations. Topical transdermal patches may also be used.

[0116]

[0136] For topical application, the pharmaceutical composition is suspended in one or more carriers. Alternatively, it can be formulated into a suitable ointment containing the active ingredient that is dissolved. The solid form carrier for topical administration of the present invention includes, but is not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated into a suitable lotion or cream containing the active ingredient that is 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 is an isotonic, pH-adjusted, sterile physiological salt. The formulation may be prepared as a microparticle suspension in water, or preferably as a solution in isotonic, pH-adjusted sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be prepared as an ointment such as petrolatum. For treatment of the eyes or other external tissues such as the mouth and skin, the formulation may be applied as a topical ointment or cream containing, for example, 0.075 to 20% w / w of the active ingredient(s). When prepared as an ointment, the active ingredient may be used with an oil-based, paraffinic, or water-miscible ointment base.

[0118]

[0138] Alternatively, the active ingredient can be used in a cream formulation using an oil-in-water type cream base. It can be formulated. 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 PEG400) and mixtures thereof. Topical formulations may preferably contain compounds that enhance the absorption or permeation of the active material through the skin or other affected area. 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. The phase may contain only one emulsifier (or one known as a diuretic), while preferably it contains at least one emulsifier and a mixture of fats or oils or both fats and oils. A hydrophilic emulsifier may be included together with a lipophilic emulsifier acting as a stabilizer. In some embodiments, the emulsifier includes both oils and fats. Together, the emulsifier(s) with or without a stabilizer(s) constitute a so-called emulsifying wax, which, together with the oils and fats, constitutes a so-called emulsifying ointment base that forms the oily dispersion phase of the cream formulation. Suitable diuretics and emulsifying stabilizers for use in formulations of 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 composition may also be administered via nasal aerosol or by inhalation. Such compositions may be prepared based on techniques well known in the field of pharmaceutical formulations and may be prepared as a solution in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants. Formulations suitable for intrapulmonary or nasal administration are administered by rapid inhalation through the nostrils or by inhalation through the mouth to reach the alveolar sacs, and have particle sizes ranging from 0.1 to 500 micrometers (including particles in the range of 0.1 to 500 micrometers, increasing in micrometer units such as 0.5, 1, 30, 35 micrometers, etc.).

[0121]

[0141] The pharmaceutical composition (or formulation) used is the method used to administer the drug. Depending on the circumstances, the product may be packaged in various ways. Generally, the product for distribution includes a container holding the pharmaceutical preparation in an appropriate form. Suitable containers are well known to those skilled in the art and include bottles (plastic and glass), pouches, ampoules, plastic bags, and metal cylinders. The container may also include a combination of tamper-evident features to prevent unintentional access to the contents of the packaging. In addition, the container is affixed with a label indicating the contents of the container. The label may also include appropriate warnings.

[0122]

[0142] Formulations are, for example, sealed ampoules and vials or The preparations may be packaged in multi-dose containers and stored in a freeze-dried state, requiring only the addition of a sterile liquid carrier, such as water, immediately before injection. Ready-to-prepare injectable solutions and suspensions are prepared from sterile powders, granules, and tablets of the types already described. Preferred unit-dose formulations are those containing a daily dose, a unit daily subdose, or an appropriate fraction thereof of the active material, as described herein.

[0123]

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

[0144] In another aspect, the present invention relates to the crystalline solid form of compound I disclosed herein. This relates to the treatment of specific disorders by using them, either alone or in combination, or in pharmaceutical compositions containing them, in patients in need.

[0124]

[0145] This disclosure relates to the crystalline solid form of compound I, its pharmaceutical formulation, and, alone This relates to the use of NO, or cGMP, to treat and / or prevent various diseases, where an increase in NO concentration or cGMP concentration is desirable, either by itself or in combination with one or more further agents.

[0125]

[0146] Increased NO production or increased cGMP concentration in tissues have other effects. However, among other effects, it brings about vasodilation, inhibition of platelet aggregation and adhesion, antihypertensive effects, anti-remodeling effects, anti-fibrotic effects, anti-apoptotic effects, anti-inflammatory effects, and neuro-signaling effects.

[0126]

[0147] In other embodiments, the crystalline solid form of compound I disclosed herein is oxidized. It is useful in the prevention and / or treatment of diseases and disorders characterized by an undesirable reduction in bioavailability and / or sensitivity to NO in biological systems (e.g., in the human body), such as those associated with stress or nitrosation stress.

[0127]

[0148] The term “cardiovascular disease” (or “cardiovascular disorder”) is used herein. In some cases, it refers to a disease based on abnormal symptoms 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, among other things, heart disease, cerebrovascular disease, kidney, liver and related organs, or pulmonary vascular disease, as well as peripheral artery disease.

[0128]

[0149] "sGC-related cardiovascular diseases" involve the NO / sGC / cGMP system. Cardiovascular diseases that are known or suspected and can be treated or prevented by sGC activation / stimulation, activation of NO synthase, or addition of NO or NO donors or NO precursors such as L-arginine or L-citrulline, or inhibition of PDE (phosphodiesterase) enzymes that cause cGMP breakdown, or any combination of the above 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 superior vena cava, aorta, and smaller arterioles. Essentially, this process is the reverse of "vasoconstriction," which narrows the blood vessels. When blood vessels dilate, blood flow increases due to a decrease in vascular resistance. Therefore, dilation of arterial vessels (mainly arterioles) lowers blood pressure. This response can be endogenous (due to local processes in the surrounding tissues) or exogenous (due to hormones or the nervous system). In addition, this response can be localized to specific organs (during strenuous exercise, in response to the metabolic demands of specific tissues) or systemic (occurring throughout the entire systemic circulation).

[0130]

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

[0131]

[0152] As used herein, the term “bronchostenosis” refers to the constriction of the airways in the lungs. Used to define bronchoconstriction, it is caused by the tightening of the surrounding smooth muscles, resulting in cough, wheezing, and shortness of breath. The condition has many causes, the most common being asthma. Exercise and allergies can cause this condition in individuals who are otherwise asymptomatic. Other conditions, such as chronic obstructive pulmonary disease (COPD), can also present with bronchoconstriction.

[0132]

[0153] Throughout this disclosure, the terms “hypertension,” “arterial hypertension,” or “hypertension” may not be used. The term "(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 blood pressure. If left uncontrolled, it represents a significant risk factor for several serious cardiovascular and renal conditions. Hypertension can be a primary disease 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 "hypertension resistance" refers to different classes of antihypertensive drugs. This refers to hypertension that remains above the target blood pressure (usually less than 140 / 90 mmHg, but a lower target of less than 130 / 80 mmHg is recommended for patients with comorbid diabetes or kidney disease) despite the simultaneous use of three different antihypertensive drugs. Individuals requiring four or more medications to control their blood pressure are also considered to have resistant hypertension. Hypertension is a very common comorbidity in diabetes, affecting approximately 20-60% of patients with diabetes, and is dependent on obesity, ethnicity, and age. This type of hypertension is referred to herein as “diabetic hypertension.” In type 2 diabetes, hypertension This often manifests as part of insulin-resistant metabolic syndrome, which also includes central obesity and dyslipidemia. In type 1 diabetes, hypertension can lead to the development of diabetic nephropathy.

[0134]

[0155] When used herein, "pulmonary hypertension (PH)" refers to the pulmonary vascular system (pulmonary arteries, lungs). Pulmonary hypertension (PH) is a disease characterized by persistently elevated blood pressure in the veins and pulmonary capillaries, which leads to right ventricular hypertrophy and ultimately to right heart failure and death. Common symptoms of PH include shortness of breath, dizziness, and syncope, all of which are aggravated by 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 lung disease and / or hypoxemia, PH caused by chronic thrombotic and / or embolic diseases, and various other forms of PH. PAH is rare in the general population, but its prevalence increases in association with certain common conditions such as HIV infection, scleroderma, and sickle cell anemia. Other forms of PH are generally more common than PAH, and the association between PH and chronic obstructive pulmonary disease (COPD), for example, is of particular concern. Current treatment for pulmonary hypertension depends 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 describes a state of ischemia of the myocardium or myocardial layer. This reduced blood supply to the myocardial layer can lead to many "acute myocardial syndromes": chest pain (also called "angina" or "angina pectoris," stable or unstable) and different types of heart attacks ("myocardial infarction" or MI). One common cause of coronary artery disease is "atherosclerosis," which describes hardening of the arteries, caused by the deposition of fat in the artery walls, which can then narrow through the formation of atherosclerotic plaques and eventually lead to the blockage of blood flow in the arteries. This process of atherosclerosis can affect not only the arteries of the heart but also other arteries as well. Typically, arteries are already partially blocked due to atherosclerotic plaques (atheroma), so blood clots are the most common cause of arterial blockage. The atheroma can rupture or tear, leading to the formation of a blood clot. Occasionally, coronary artery disease is caused by spasms of the coronary arteries, which can occur spontaneously or as a result of the use of certain drugs (e.g., cocaine, nicotine). Rarely, the causes of coronary artery disease include congenital defects, viral infections (e.g., Kawasaki disease), systemic lupus erythematosus (lupus), inflammation of the arteries (arteritis), blood clots that have migrated from the heart chambers to one of the coronary arteries, or physical injury (e.g., from injury or radiation therapy).

[0136]

[0157] When used herein, "unstable angina" refers to persistent or worsened angina. This describes changes in the pattern of angina symptoms, including cardiac symptoms and initial severe symptoms.

[0158] MI (myocardial infarction) can be classified into two types: "non-ST elevation" MI and This is a type of "ST-elevation" myocardial infarction. Complications of acute coronary syndrome depend on the size, duration, and location of the coronary artery occlusion. If the occlusion affects a large portion of the myocardium, the heart will not pump efficiently. If the occlusion stops blood flow to the heart's electrical system, the heart rhythm may be affected. When a heart attack occurs, a portion of the myocardial layer 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. Consequently, there is less muscle pumping the blood. If enough muscle dies, the heart's pumping capacity can be so reduced that it cannot meet the body's demands for oxygen and blood. Heart failure, hypotension, or both may then occur. If more than half of the myocardial layer is damaged or dies, the heart is generally unable to function and may result in severe disability or death.

[0137]

[0159] As used herein, “heart failure” (HF) means impaired cardiac function and Heart failure is a progressive impairment of left ventricular (LV) myocardial remodeling, characterized by circulatory congestion, resulting in inadequate delivery of blood and nutrients to body tissues, ultimately leading to a complex clinical syndrome. This condition occurs when the heart is damaged or overworked and unable to pump all the blood back into it from the systemic circulation. As less blood is pumped out, more blood returns to the heart, and fluid accumulates in other parts of the body. Heart failure also impairs the kidneys' ability to eliminate sodium and water, further complicating fluid retention. Heart failure is characterized by autonomic dysfunction, neurohormonal activation, and overproduction of cytokines, contributing to progressive circulatory failure. Symptoms of heart failure include shortness of breath (dyspnea) during exercise, at rest, and while awake at night, often due to sudden shortness of breath, both suggestive of pulmonary edema; general fatigue or weakness; edema of the feet, ankles, and legs; short-term weight gain; or chronic cough, including that producing mucus or blood. Depending on its clinical presentation, heart failure is classified as new-onset, transient, acute, late-acute, or chronic. Acute heart failure, i.e., the rapid or gradual onset of symptoms requiring emergency treatment, can occur as a result of new-onset or decompensated chronic heart failure. The term “heart failure” is often used to mean “chronic heart failure.” The terms “congestive heart failure (CHF)” or “congestive cardiac failure (CCF)” are often used interchangeably for chronic heart failure. Common causes of heart failure include coronary artery disease, including a history of myocardial infarction (heart attack), hypertension, atrial fibrillation, valvular heart disease, and cardiomyopathy. 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 caused by left ventricular systolic dysfunction" or "Heart failure due to 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)." Ejection fraction is the percentage of blood pumped out of the heart during a single contraction. Normally, this percentage is between 50% and 75%.

[0139]

[0161] The term "acute" (as in "acute HF") is used to mean a rapid onset. The term "chronic" refers to a long duration. Chronic heart failure is a long-term condition, usually accompanied by overall symptoms that are managed stably. "Acute decompensated" heart failure is an episode of worsening or decompensated heart failure that may be characterized by the patient having changes in the signs and symptoms of heart failure, leading to the need for emergency treatment or hospitalization. Heart failure can also occur in a high-output condition 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 pumping of the heartbeat or cardiac cycle. It is defined as the proportion of blood in the left and right ventricles that is pumped out. In finite mathematics made possible by medical imaging, EF applies to both the right ventricle, which pumps blood into the pulmonary circulation via the pulmonary valve, or the left ventricle, which pumps blood into the cerebral and systemic circulations via the aortic valve.

[0141]

[0163] The term "heart failure with preserving ejection fraction (HFPEF)" generally refers to heart failure where the ejection fraction exceeds 55%. It is understood to represent the manifestation of signs and symptoms of heart failure with a high rate of release. It is characterized by decreased left ventricular compliance, leading to increased pressure in the left ventricle. The enlarged left atrial size, as a result of poor left ventricular function, carries an increased risk of 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, during diastole, the myocardium contracts well, but the ventricles are not filled well with blood.

[0142]

[0164] The term "heart failure with reduced ejection fraction (HFREF)" refers to a heart condition where the ejection fraction is less than 40%. This represents a type of heart failure.

[0165] Diabetes is a common comorbidity in patients with heart failure, and has a less severe outcome than other conditions. These are related to potentially impairing 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 sexes: 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 failure. Depression is a high-frequency comorbidity of heart failure, and the two conditions can and often occur together. Cachexia has long been recognized as a serious and high-frequency comorbidity of heart failure, affecting up to 15% of all heart failure patients and associated with a poor prognosis. Cardiac cachexia is defined as a 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 a 90% of people who have experienced a heart attack. This represents an abnormal heart rhythm that occurs more than % of the time. Sometimes the problem lies in a part of the heart that may cause the heartbeat to be too slow, and other times the problem lies in a part of the heart that may beat too fast or irregularly. Sometimes the heartbeat signal does not travel from one part of the heart to another, causing the heartbeat to slow down or stop. In addition, areas of the myocardial layer that are not dead but have poor blood flow can become hypersensitive. This can cause 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 is an inflammation of this membrane. The condition may develop as a result of a heart attack and may result in fever, pericardial effusion, inflammation of the membrane covering the lungs (pleura), pleural effusion, and joint pain. Other complications after a heart attack may include mitral valve dysfunction, myocardial rupture, bulging of the ventricular wall (ventricular aneurysm), blood clots, and hypotension.

[0145]

[0168] The term "cardiomyopathy" refers to a progressive disorder of the structure and function of the muscular walls of the heart chambers. Cardiomyopathy can be dilated, hypertrophic, or restrictive. Cardiomyopathy often presents with symptoms of heart failure, and can also cause chest pain, syncope, and sudden death.

[0146]

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

[0147]

[0170] The term "sleep apnea" refers to the most common sleep-disordered breathing disorder. This involves the upper airway. Sleep apnea is a condition characterized by intermittent, periodic reduction or complete cessation of airflow, with or without obstruction. 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 not a physical blockage of the airway, but rather a condition where breathing is impaired. It is caused by dysfunction in the brain's normal signaling pathways. The lack of respiratory effort leads to an increase in carbon dioxide in the blood, which can cause the patient to become aroused. CSA is rare in the general population but relatively common in patients with systolic heart failure.

[0149]

[0172] As used herein, the terms "metabolic syndrome" and "insulin" are used to mean "metabolic syndrome" and "insulin." "Type 2 diabetes-resistant syndrome" or "Syndrome X" refers to a group or group formation of metabolic conditions (abdominal obesity, elevated fasting blood glucose, dyslipidemia (i.e., elevated lipid levels), and elevated blood pressure (HBP)) that occur more frequently simultaneously than by chance, together with type 2 diabetes. It promotes the development of diseases and cardiovascular disorders. Metabolic syndrome is characterized by a specific lipid profile of increased 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 diseases” due to pressure from 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 deletion of 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 specified).

[0150]

[0173] The term "fatty degeneration" refers to the abnormal retention of lipids within cells. This is typically the case in triglycerides. This reflects a disruption in the normal processes of glyceride synthesis and removal. Excess fat accumulates in vesicles that replace the cytoplasm of cells. In severe cases, cells may rupture. Since the liver is the organ primarily involved in fat metabolism, fatty degeneration is typically observed in the liver. It is also observed in the heart, kidneys, and muscle tissue.

[0151]

[0174] As used herein, the term “peripheral vascular disease (PVD)” generally means “ Peripheral artery disease (PAD), also known as peripheral artery occlusive disease (PAOD), refers to an occlusion of the aorta, not within the coronary arteries, aortic arch vascular system, or brain. PVD can result from inflammatory processes leading to atherosclerosis, stenosis, embolism, platelet embolus formation, or other types of occlusion. This can result in either acute or chronic ischemia (lack of blood supply). PVD is often a term used to describe atherosclerotic occlusion found in the lower extremities. PVD also includes a subset of diseases classified as microvascular diseases resulting from intermittent narrowing of arteries (e.g., Raynaud's phenomenon) or dilation of arteries (erythromelitis), i.e., vasospasm. Peripheral artery disease includes occlusive thromboangiitis, peripheral artery occlusive disease, Raynaud's disease, and Raynaud's syndrome. Common symptoms include cold legs or feet, intermittent claudication, leg pain, and severe lower limb ischemia (ulcers and necrosis of the lower extremities). Guidelines for the diagnosis and treatment of peripheral artery disease can be found in Eur.J.Vasco Endovasc.Surg, 2007, 33(1), Sl.

[0152]

[0175] The term "stenosis," as used herein, refers to the narrowing of blood vessels or other tubular organs. This refers to an abnormal narrowing of a structure. This is also sometimes called "stricture" (for example, 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 stricture after treatment.

[0153]

[0176] The term "thrombosis" refers to a condition in which blood clots (platelets) form inside blood vessels, blocking blood flow in the circulatory system. The term "embolism" refers to the formation of a blood clot. When a blood vessel is damaged, the body uses platelets (thrombocytes) and fibrin to form a blood clot to prevent blood loss. Alternatively, even when a blood vessel is not damaged, a blood clot can form in the body if the right conditions are present. If the coagulation is too vigorous and the blood clot breaks apart, the moving blood clot is known here as an "embolism." The term "thromboembolism" refers to the combination of thrombosis and its major complication, "embolism." When a platelet embolus occupies more than 75% of the surface area of ​​the lumen of the ductus arteriosus, blood flow to the supplied tissue is reduced enough to cause symptoms caused by reduced oxygen (hypoxia) and the accumulation of metabolic products such as lactate ("gout"). Obstruction exceeding 90% can result in anoxia, a state of complete oxygen deficiency, and "infarction," a state of cell death.

[0154]

[0177] "Embronsis" (multiple embolisms) is a blockage (vascular occlusion) in a distant part of the body. This is an event that causes an embolus (a separated intravascular mass that can block the arterial capillary bed at a site far from its origin) in the narrow capillaries of the arterial bed. This should not be confused with platelet embolus, which block at the site of origin. The substances that form an embolus can have many different origins: if the substance is blood, the "embolus" is called a "platelet embolus"; solid substances can also include fat, bacterial residue, infected tissue, etc.

[0155]

[0178] "Ischemia" is a limitation in the blood supply to tissues, which affects cellular metabolism (the survival of tissues). It causes a deficiency of oxygen and glucose (which are necessary for blood vessels to function properly). Ischemia generally relates to blood vessels and is caused by problems related to resulting damage or tissue dysfunction. It can also sometimes refer to localized anemia in a given part of the body, resulting from congestion (such as vasoconstriction, thrombosis, or embolism). When “ischemia” occurs in the myocardium (or “myocardium layer”), it is called myocardial ischemia. Other types of ischemia include, for example, cerebral ischemia and severe lower limb ischemia.

[0156]

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

[0157]

[0180] "Reperfusion injury" refers to the return of blood supply to tissues after an ischemic period, and the restoration of normal function. Rather, it is 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 beyond the tissue. Activated endothelial cells, following reperfusion, produce more reactive oxygen species but less NO, and this imbalance triggers an inflammatory response. Leukocytes, in response to tissue damage, are carried to the area by the newly restored blood flow and release numerous inflammatory factors and free radicals. The restored blood flow, along with this, carries oxygen that damages cellular proteins, DNA, and cell membranes. This ischemia-reperfusion process is also thought to be responsible for the formation and failure of chronic wounds (e.g., pressure ulcers or diabetic ulcers) to heal.

[0158]

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

[0159]

[0182] A stroke, or cerebrovascular disorder (CVA), is caused by an obstruction in the blood supply to the brain. The cause is a rapid loss of brain function(s). This can be caused by “ischemia” (lack of blood flow and consequently insufficient oxygen and glucose supply to tissues) resulting from blockage (thrombosis, arterial embolism, fat accumulation or spasm) or bleeding (leakage of blood). As a result, the affected part of the brain may not function, and the person may be unable to move one or more limbs on one side of the body, be unable to understand or construct speech, or have vision loss on one side of the visual field. Risk factors for stroke include older age, high blood pressure, a history of 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” is sometimes treated in a hospital using thrombolytics (also known as “blood clot dissolving drugs”). Treated hemorrhagic strokes may benefit from neurological surgery. Prevention of recurrence may include administration of antiplatelet agents such as aspirin and dipyridamole, control and reduction of hypertension, and 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. This is more common among men and typically begins after age 70. It occurs more frequently in people with vascular risk factors (e.g., high blood pressure, diabetes, hyperlipidemia, smoking) and those who have experienced several strokes. Many people have both vascular dementia and Alzheimer's disease. Vascular dementia typically occurs when multiple small strokes (or occasional hemorrhages) cause enough neuronal or axonal loss to impair brain function. Vascular dementia includes the following types: multiple lacunar infarcts (in which microvessels are affected and infarcts occur deep within the white and gray matter hemispheres); polyinfarct dementia (in which medium-sized vessels are affected); strategic monoinfarct dementia (in which a single infarct occurs in a very important area of ​​the brain, such as the angular gyrus or thalamus); and Binswanger dementia or subcortical arteriosclerotic encephalopathy (small vessel dementia is associated with severe, poorly controlled hypertension and systemic vascular disease, resulting in widespread gliosis, tissue death, and diffuse and irregular loss of axons and myelin due to infarcts or loss of blood supply to the brain's white matter).

[0161]

[0184] The term "glioma" refers to a type of tumor that originates in the brain or spine. It is a tumor of the glial cells. They are called gliomas because they arise from the brain. The most common site of gliomas is the brain. Gliomas make up about 30% of all brain and central nervous system tumors and 80% of all malignant brain tumors.

[0162]

[0185] Diagnostic and Statistical Manual of Mental Disorders (America Psychiatric Association) Based on the Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), the term “sexual dysfunction” encompasses a range of conditions “characterized by disturbances in sexual desire and psychophysiological changes related to the sexual response cycle”; while this type of problem is common, sexual dysfunction is considered to exist only when the problem causes distress to the patient. This can be of either physical or psychological origin. Sexual dysfunction can exist as a primary condition, generally inherently hormonal, but most often it is secondary to other medical conditions or drug treatments for such conditions. All types of sexual dysfunction can be further classified as lifelong, acquired, contextual, or generalized (or a combination thereof).

[0163]

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

[0164]

[0187] "Female Sexual Stimulation Disorder (FSAD)" is a condition in which a woman is unable to reach a sufficient level of sexual arousal. FSAD is defined as a persistent or circulatory inability to maintain sexual arousal, causing personal distress. FSAD encompasses both a lack of subjective sensation of arousal (i.e., subjective sexual stimulation disorder) and a lack of bodily responses such as lubrication and swelling (i.e., genital / physical sexual stimulation disorder). While FSAD is generally caused or complicated by medical or physiological factors, it can strictly be of psychological origin. Hypoestrogenism is the most common physiological condition associated with FSAD, leading to genitourinary atrophy and decreased vaginal lubrication.

[0165]

[0188] As used herein, “erectile dysfunction (ED)” refers to the condition of the penis during sexual intercourse. Sexual dysfunction in men is characterized by the inability to develop or maintain an erection. Penile erection is the hydrostatic effect of blood entering and retaining the spongy tissue within the penis. This process often begins when signals are transmitted from the brain to nerves in the penis as a result of sexual arousal. Erectile dysfunction is indicated when it is difficult to achieve an erection. The most important organic causes are cardiovascular disease and diabetes, neurological problems (e.g., trauma from prostatectomy), hormone deficiencies (hypogonadism), and drug side effects.

[0166]

[0189] In one embodiment, polymorphs of compound I described herein and pharmaceutically acceptable The salts used are therefore useful in the prevention and / or treatment of the following types of circulatory disorders, conditions, and diseases of the heart, lungs, peripheral, liver, kidneys, or cerebral blood vessels / endothelium: 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 cardiac disease, stroke, cerebral ischemia, or renal failure; resistant hypertension; diabetic hypertension; essential hypertension; secondary hypertension; gestational hypertension; pre-eclampsia; 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 valvular malformations, mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, tricuspid stenosis, tricuspid regurgitation, pulmonary stenosis, pulmonary regurgitation, compound valvular malformations; diabetic heart failure; alcoholic cardiomyopathy or conservative hypertrophic cardiomyopathy; diastolic HF, systolic HF; pre-existing chronic HF in the acute phase (exacerbated HF); diastolic or systolic dysfunction; coronary insufficiency; arrhythmias; decreased 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-III) Atrioventricular block, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, polymorphic ventricular tachycardia, atrial and ventricular premature contractions, AV junction premature contractions, sick sinus syndrome, syncope, AV nodal reentrant tachycardia; Wolff-Parkinson-White syndrome or acute coronary syndrome; Boxer cardiomyopathy; ventricular premature contractions; cardiomyopathy; cancer-induced cardiomyopathy; chemotherapy-induced cardiotoxicity; • Thromboembolic disorders and ischemia; myocardial ischemia; infarction; myocardial infarction; heart attack; myocardial insufficiency; endothelial dysfunction; stroke; transient ischemic attack (TIA); thromboangiitis obliterans; stable or unstable angina; coronary spasm or peripheral artery spasm; variant angina; Prinzmetal's angina; cardiac hypertrophy; pre-eclampsia; thrombosis; ischemia-reperfusion injury; ischemia-reperfusion associated with organ transplantation; lung transplant, pulmonary transplant, heart transplant, venous graft failure; ischemia-reperfusion associated with conservative blood replacement in trauma patients; Peripheral vascular disease; peripheral artery disease; peripheral arterial occlusive disease; hypertonia; Raynaud's syndrome or phenomenon (primary and secondary); Raynaud's disease; severe lower limb ischemia; peripheral embolism; intermittent claudication; vaso-occlusive crisis; muscular dystrophy, Duchenne muscular dystrophy, Becker muscular dystrophy; microcirculatory abnormalities; control of vascular leakage or osmosis; lumbar spinal stenosis; thromboangiitis obliterans; thromboangiitis; peripheral perfusion impairment; arterial and venous thrombosis; microalbuminuria; peripheral and autonomic neuropathy; diabetic neuropathy pain; diabetic microangiopathy; hepatic vaso-occlusive disorder; vaso-occlusive crisis in sickle cell anemia; hypertensive crisis; • Edema; renal edema caused by heart failure; Alzheimer's disease; Parkinson's disease; vascular dementia; vascular cognitive impairment; cerebral vasospasm; congenital myasthenia gravis; subarachnoid hemorrhage; traumatic brain injury; improvement of perception, concentration, learning or memory performance after cognitive impairment, such as those occurring in mild cognitive impairment, age-related learning and memory impairment, age-related memory loss, vascular dementia, head injury, stroke, post-stroke dementia, post-traumatic head injury, general impairment of concentration, and impairment of concentration in children with learning and memory problems; Lewy body dementia; 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 high-end foods and addictive drugs; controlled cerebral perfusion; migraine; prevention and control of outcomes of stroke (apoplexia cerebri); prevention and control of outcomes 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 herpes zoster; 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 localized thrombosis and right ventricular hypertrophy; pulmonary hypertonia; primary pulmonary hypertension; secondary pulmonary hypertension; familial pulmonary hypertension; sporadic 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 arteropathy; multifactorial pulmonary arteropathy; cystic fibrosis; bronchoconstriction or pulmonary bronchoconstriction; acute respiratory syndrome; pulmonary fibrosis, lung transplant; asthmatic diseases; 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, anomalous pulmonary venous return, pulmonary veno-occlusive disease, pulmonary vasculitis, collagen vascular disease, congenital heart disease, elevated pulmonary venous pressure, interstitial lung disease, sleep-disordered breathing, sleep apnea, impaired alveolar ventilation, chronic exposure to high altitudes, neonatal lung disease, alveolar capillary dysplasia, sickle cell anemia, 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 disease, lupus, lupus nephritis, schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease, asthma, emphysema, chronic bronchitis, pulmonary capillary angiomatosis, histiocytosis X, lymphangiomatosis, compressed pulmonary vessels; compressed pulmonary vessels due to adenopathy, tumors, or fibrotic mediastinitis; • Arterosclerotic diseases or conditions: Atherosclerosis; atherosclerosis associated with endothelial damage, platelet and monocyte adhesion and aggregation, smooth muscle proliferation or migration; restenosis; restenosis that develops after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), transcatheter coronary angioplasty (PTCA), heart transplantation, bypass surgery, or inflammatory process; • Damage to microvessels and macrovessels (vasculitis); increased levels of fibrinogen and low density of DLD; increased concentrations of plasminogen activator inhibitor 1 (PA-1); Metabolic syndrome; metabolic diseases or diseases associated with metabolic syndrome: obesity; excess subcutaneous fat; excess body fat accumulation; diabetes mellitus; 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, hypolipoprotein anemia, sitosterolemia, fatty liver disease, alcoholic fatty liver disease (AFLD), non-alcoholic fatty liver disease (NAFLD), hepatitis; pre-eclampsia; progression of polynephropathy; hepatic steatosis or abnormal lipid accumulation in the liver, non-alcoholic steatohepatitis (NASH); fatty degeneration of the heart, kidneys or muscles; alpha-betalipoproteinemia; sitosterolemia; xanthomatous disease; Tangier disease; hyperammonemia and related diseases; hepatic encephalopathy; other toxic encephalopathy; Reye's syndrome; • Disorders of sexual, gynecological, and urological conditions: erectile dysfunction; impotence; premature ejaculation; female Sexual dysfunction; female sexual stimulation dysfunction; hypofunction of sexual stimulation; vaginal atrophy; dyspaneurosis; atrophic vaginitis; benign prostatic hyperplasia (BPH), prostatic hyperplasia, prostatic enlargement; subvesical urethral 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 genitourinary organs in men and women; Chronic kidney disease; acute and chronic renal failure; acute and chronic renal failure; lupus nephritis; underlying or related kidney diseases: hypoperfusion, hypotension during dialysis, obstructive urinary tract disease, glomerulosis, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial damage, renal disorders, primary and congenital kidney diseases, nephritis; diseases characterized by abnormally decreased creatinine and / or fluid 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 synthase; diseases characterized by altered urine osmolality or urine volume; diseases characterized by increased microalbuminuria, diseases characterized by overt albuminuria; diseases characterized by lesions of the glomeruli and arterioles, tubular dilation, hyperphosphatemia and / or the need for dialysis; complications of renal failure; pulmonary edema Renal dysfunction related to enema; HF-related renal dysfunction; uremia or anemia-related renal dysfunction; electrolyte abnormalities (hercaremia, hyponatremia); impaired 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 a reaction to harmful stimuli such as pathogens, damaged cells, or irritants. It represents a complex biological response of vascular tissue. Classical signs of acute inflammation are pain, fever, redness, swelling, and loss of function. Inflammation is a protective attempt by the living organism to remove a damaging stimulus and initiate the healing process. Although inflammation and infection often correlate, inflammation is not synonymous with infection (inflammation is often a consequence of infection). Inflammation can also occur in the absence of infection, but such types of inflammation are usually maladaptive (e.g., in atherosclerosis). Inflammation is a stylized response and is therefore considered a mechanism of innate immunity, compared to adaptive immunity, which is specific to each pathogen. Progressive destruction of tissue in the absence of inflammation endangers the survival of the organism. Chronic inflammation, on the other hand, 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 and strictly regulated by the body. Inflammation can be classified as either acute or chronic. Acute inflammation is the body's initial response to a harmful stimulus, achieved 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 vascular system, immune system, and various cells within the injured tissue. Long-term inflammation, known as chronic inflammation, is characterized by a progressive shift in the types of cells present at the site of inflammation and by the simultaneous destruction and healing of tissue from the inflammatory process.

[0168]

[0191] In another embodiment, polymorphs of compound I described herein and pharmaceutically acceptable The salts tolerable are therefore useful in the prevention and / or treatment of disorders, conditions, and diseases of the heart, lungs, peripheral, liver, kidneys, digestive, or central nervous system, which may include inflammation or inflammatory processes of the following types: Myocarditis; chronic myocarditis; acute myocarditis; viral myocarditis; Vasculitis; pancreatitis; peritonitis; rheumatic 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 Sjögren'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 an injury. This describes the intricate process of repairing the body. For example, in normal skin, the epidermis (outermost layer) and dermis (inner or deeper layer) exist in a steady-state equilibrium, forming a protective barrier against the external environment. Once this protective barrier is broken, the normal (physiological) process of wound healing is immediately activated. The classical model of wound healing is divided into three or four consecutive, and sometimes overlapping, phases: (1) hemostasis (some authors do not consider this a phase), (2) inflammation, (3) proliferation, and (4) reconstruction. When the skin is injured, a series of complex biochemical events occur in a tightly organized cascade to repair the injury. Within the first few minutes after the injury, platelets adhere to the injury site, are activated, aggregate (bind together), and form a blood clot of platelets aggregated within a network of cross-linked fibrin proteins, continuing the activation of the coagulation cascade. This blood clot stops active bleeding ("hemostasis"). During the inflammatory phase, bacteria and cell debris are phagocytosed and removed from the wound by leukocytes. Platelet-derived growth factors (stored in alpha granules of platelets) are released into the wound, causing 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 "fibrous proliferation" and granulation tissue formation, fibroblasts grow and release collagen and fibronectin to form a new, temporary extracellular matrix (ECM). Simultaneously, "re-epithelialization" of the epidermis occurs, with epithelial cells proliferating and "slowly moving" over the wound bed, providing new tissue coverage. During wound contraction, myofibroblasts reduce the size of the wound by firmly grasping the wound edges and contracting them using mechanisms similar to those in smooth muscle cells. As the cells near the completion of their role, unnecessary cells undergo apoptosis. During maturation and reconstruction, collagen is restructured and rearranged along tension lines, and cells no longer needed are removed by apoptosis. However, this process is not only complex but also fragile, prone to interruption or failure, and can lead to the formation of non-healing chronic wounds (one example being diabetic wounds or ulcers, and in detail, diabetic foot ulcers).Factors contributing to non-healing chronic wounds include diabetes, venous or arterial disease, infection, and metabolic deficiencies in older adults.

[0170]

[0193] The term "bone healing mechanism" or "fracture healing mechanism" refers to the body's mechanism for promoting the repair of a fracture. This represents a proliferative physiological process. In the fracture healing process, several recovery phases promote the proliferation and protection of the area surrounding the fracture and dislocation. The length of this process depends on the severity of the injury; most upper body fractures are given a normal margin of 2-3 weeks for repair; lower body injuries are given any period of more than 4 weeks. The healing process is primarily determined by the "periosteum" (the connective tissue membrane covering the bone). The periosteum is one source of progenitor cells that develop into "chondroblasts" and osteoblasts, which are essential for bone healing. Bone marrow (when present), endosteum, microvessels, and fibroblasts are other sources of progenitor cells.

[0171]

[0194] In another embodiment, polymorphs of compound I described herein and pharmaceutically acceptable The salts used are therefore useful in treating the following types of diseases, disorders, or conditions where stimulation of the wound or bone healing process is desirable: Healing of diabetic wounds or ulcers; improvement of microvascular perfusion; improvement of microvascular perfusion to counteract inflammatory responses following injury or in perioperative care; anal fissures; diabetic ulcers; diabetic foot ulcers; bone healing mechanisms; osteoclastic bone resorption and reconstruction; and neobogenesis.

[0172]

[0195] The term "connective tissue" (CT) refers to the tissue that supports, connects, or is a different type of body tissue. It represents 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, muscle, and nerve tissue. Connective tissue is a type of central nerve tissue. They are found everywhere, including in the transvesthal system. They are located between other tissues. All CTs have three main components: matrix, fibers, and cells, and all of these components are immersed in body fluids.

[0173]

[0196] The term "connective tissue disorder or condition" refers to a condition in which the connective tissue in one or more parts of the body is impaired. This term describes any condition involving abnormalities in connective tissue. Certain disorders are typically characterized by hyperactivity of the immune system, involving 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, while others have unknown etiologies.

[0174]

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

[0198] In "autoimmune disorders," antibodies or other cells produced by the body... It attacks 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 essential for maintaining life, such as the kidneys or gastrointestinal organs. The sac surrounding the heart (pericardium), the membrane covering the lungs (pleura), the mediastinum (a group of structures within the thoracic cavity that are not precisely represented, surrounded by loose connective tissue and including the heart, the great blood vessels of the heart, the esophagus, the trachea, the phrenic nerve, the cardiac nerves, the thoracic duct, the thymus, and the central thoracic lymph nodes), and even the brain can be affected.

[0175]

[0199] The term "fibrosis," as used herein, refers to a specific 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 as 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 process of scarring. Pathological conditions develop when the tissue in question is repeatedly and continuously damaged. A single episode of injury, even if severe, usually does not cause fibrosis. When injuries are repeated or continuous (for example, as occurs in chronic hepatitis), the body attempts to repair the injury, but this attempt instead results in an excessive accumulation of scar tissue. Scar tissue begins to replace the normal tissue of organs that perform certain functions that the scar tissue cannot perform; this can also obstruct blood flow and limit the blood supply to other cells. As a result, these other functional cells begin to die, and more scar tissue is formed. When this occurs in the liver, the blood pressure in the veins (portal veins) that carry blood from the intestines to the liver increases, leading to a condition known as "portal hypertension."

[0176]

[0200] The term "sclerosis" usually refers to a condition in which normal organ-specific tissue is replaced by connective tissue. This refers to the hardening or rigidity of tissues, structures, or organs that are normally flexible.

[0201] Pulmonary fibrosis (idiopathic pulmonary fibrosis, cystic fibrosis), hepatic fibrosis (or "cirrhosis") There are many types of fibrosis or fibrous diseases, including, but not limited to, endocardial fibrosis, old myocardial infarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis (affecting the bone marrow), retroperitoneal fibrosis, progressive nodular fibrosis (affecting the lungs), nephrogenic fibrosis (affecting the skin), Crohn's disease, arthral fibrosis, Peyronie's disease (affecting the penis), Dupuytren's contracture (affecting the hands and fingers), and several forms of adhesive capsulitis (affecting the shoulders).

[0177]

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

[0178]

[0203] The terms "scleroderma," "systemic sclerosis," or "progressive systemic sclerosis" are related to It describes a condition that includes joint, skin and visceral scarring, as well as vascular abnormalities. Systemic sclerosis can sometimes occur in a limited form, for example, sometimes affecting only the skin or mainly specific parts of the skin, or as CREST syndrome (which includes peripheral skin rather than the trunk). The usual initial symptom of systemic sclerosis is swelling, followed by thickening and hardening of the skin of the fingertips. Raynaud's phenomenon is common when the fingers suddenly and temporarily become very pale, throbbing, numb, painful, or both.

[0179]

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

[0205] The term "eosinophilic fasciitis" This describes a rare disorder in which eosinophilic immune cells are released, leading to inflammation and hardening of the "fascia," a tough layer of fibrous tissue located just beneath the skin, over and between the muscles. In the arms and legs, the fascia becomes painful, inflamed, swollen, and gradually hardens. As the skin of the arms and legs progressively hardens, movement of the arms and legs becomes difficult. Eventually, they become immobile in their normal positions. Occasionally, if the arms are involved, the patient may develop carpal tunnel syndrome.

[0180]

[0206] In another embodiment, polymorphs of compound I described herein or pharmaceutically acceptable The specific diseases of which disorders can be treated and / or prevented by administering the prescribed salts include, but are not limited to, the following types of diseases, including inflammation, autoimmunity, or fibrosis (i.e., fibrotic diseases): • Urogenital or renal disorders: diabetic nephropathy; renal fibrosis and renal failure due to chronic kidney disease or renal insufficiency; renal fibrosis and renal failure due to accumulation / deposition and tissue damage; nephrosclerosis; progressive sclerosis; glomerulonephritis; focal segmental glomerulosclerosis; nephrotic syndrome; benign prostatic hyperplasia; renal fibrosis; interstitial renal fibrosis; • Pulmonary system disorders: pulmonary fibrosis; idiopathic pulmonary fibrosis; cystic fibrosis; progressive mass fibrosis; progressive mass fibrosis affecting the lungs; • Cardiac disorders: Endocardial fibrosis; old myocardial infarction; atrial fibrosis; interstitial fibrosis; cardiac remodeling and fibrosis; cardiac hypertrophy; • Disorders of the liver and related organs: hepatic sclerosis or cirrhosis; cirrhosis associated with chronic liver disease; hepatic fibrosis; hepatic stellate cell activation; NASH; hepatic fibrous collagen and total collagen accumulation; necrotizing inflammatory and / or immunological liver diseases; primary biliary cirrhosis; primary sclerosing cholangitis; other cholestatic liver diseases: associated with granulomatous liver disease, hepatic malignancies, intrahepatic cholestasis during pregnancy, hepatitis, sepsis, drug or toxin, graft-versus-host disease, post-liver transplant, common bile duct stones, cholangiocarcinoma, pancreatic cancer, Militzi syndrome, AIDS cholangitis or parasitic infections; schistosomiasis; hepatocellular carcinoma; • Digestive system diseases or disorders: Crohn's disease; ulcerative colitis; gastrointestinal sclerosis; achalasia; • Diseases of the skin or eyes: nephrogenic fibrosis; proliferative vitreoretinopathy; diabetic retinopathy; ocular fibrosis; • Fibrous localized or skin disorders or conditions; dermal fibrosis; scleroderma, dermatofibrosis; morphea; hypertrophic scars; nevi; keloids; sarcoids; granulomas; • Diseases affecting the nervous system: Amyotrophic lateral sclerosis (ALS); hippocampal sclerosis, multiple sclerosis MS (Multiple Sclerosis); Focal segmental sclerosis; Primary lateral sclerosis; Bone diseases; osteosclerosis; Otosclerosis; other hearing disorders or impairments; hearing loss, partial or total hearing loss; partial or total hearing loss; tinnitus; noise-induced hearing loss; • Other diseases including autoimmune, inflammatory, or fibrotic conditions: scleroderma; localized scleroderma or limited scleroderma; mediastinal fibrosis; fibrotic mediastinitis; myelofibrosis; retroperitoneal fibrosis; arthral fibrosis; Peyronie's disease; Dupuytren's contracture; lichen sclerosing; 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, polymorphs of compound I described herein or pharmaceutically acceptable Specific diseases of disorders that can be treated and / or prevented by administering the salts tolerable include: certain types of cancer; sickle cell disease; sickle cell anemia; cancer metastasis; osteoporosis; gastroparesis; functional dyspepsia; diabetic complications; alopecia or hair loss; disorders associated with endothelial dysfunction; neuropathy associated with reduced nitric oxide production; arginosuccinic aciduria; neuromuscular diseases: including, but not limited to, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), limb-girdle muscular dystrophy, distal myopathy, type I and type II myotonic dystrophy, facioscapulofibular muscular dystrophy, autosomal and X-linked Emery-Dreyfus muscular dystrophy, oculopharyngeal muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy (SMA).

[0182]

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

[0183]

[0209] In another embodiment, the solid form of the invention can be delivered in the form of an implantable device such as a stent. A stent is a mesh-like "tube" inserted into a natural passage / conduit in the body to prevent or counteract disease-induced, local flow convergence. The term can also represent a tube used to keep such a natural conduit temporarily open to allow access for surgery.

[0184]

[0210] A drug-eluting stent (DES) is a peripheral stent or coronary stent (scaffold) that is placed into a narrowed, diseased peripheral artery or coronary artery and slowly releases a drug to block cell proliferation, typically smooth muscle cell proliferation. This prevents fibrosis, which, along with blood clots (platelet thrombi), can block the artery in which the stent was placed if there was no stent (a process called restenosis). Stents are typically placed into peripheral arteries or coronary arteries by an interventional cardiologist or interventional radiologist during an angioplasty procedure. Drugs commonly used in DES to block cell proliferation include paclitaxel or rapamycin analogs.

[0185]

[0185]

[0211] In some embodiments of the invention, the polymorph of Compound I or the pharmaceutically The salts permitted thereby, or pharmaceutical compositions thereof, can be delivered by a drug-eluting stent in solid form or coated with a pharmaceutical composition. The drug-eluting stent coated with the solid form (or pharmaceutical composition) of Compound I of the present invention can be useful for preventing stent restenosis and thrombosis during percutaneous coronary angioplasty. The drug-eluting stent coated with the solid form (or pharmaceutical composition) of Compound I of the present invention can prevent smooth cell proliferation and can also assist in revascularization and regeneration of the endothelial tissue of the artery into which the stent is inserted. It is possible.

[0186]

[0212] An alternative to percutaneous coronary angioplasty for the treatment of refractory angina due to coronary artery obstructive disease is a procedure named coronary artery bypass grafting (CABG). CABG only provides relief of the ongoing process, which is further complicated by the rapid development of graft atherosclerosis. The saphenous vein graft is the most commonly used conduit in CABG surgery. The long-term clinical success of venous CABG is hampered by three major reasons: accelerated graft atherosclerosis, incomplete endothelialization and thrombosis.

[0187]

[0213] In some embodiments, the solid form of Compound I of the present invention can be used for preventing saphenous graft failure during CABG. The solid form of the present invention can assist in the process of endothelialization and can help prevent thrombosis. In this efficacy, the solid form of Compound I is delivered locally in the form of a gel.

[0188]

[0214] The terms, "disease", "disorder" and "condition" can be used interchangeably herein to represent a medical or pathological condition mediated by sGC, cGMP and / or NO.

[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, quail, or turkeys, or mammals), more specifically “mammals” including non-primates (e.g., cattle, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice), as well as primates (e.g., monkeys, chimpanzees, and humans), and more specifically humans. In some embodiments, the subject is a non-human animal such as livestock (e.g., horses, cattle, pigs, or sheep) or pets (e.g., dogs, cats, guinea pigs, or rabbits). In some embodiments, the subject is a human.

[0190]

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

[0191]

[0217] The term "biological sample" as used herein refers to in vitro or ex vitro samples. This term represents, but is not limited to, a vivo sample, including cell cultures or their extracts; biopsy material or its extracts obtained from mammals; and blood, saliva, urine, feces, semen, tears, lymph, eye fluid, vitreous fluid, or other bodily fluids or their extracts.

[0192]

[0218] When used herein, the terms “treatment” or “to treat” are interchangeable. These terms are used to describe methods for achieving beneficial or desired results, including, but not limited to, therapeutic benefits. Therapeutic benefits include the eradication or improvement of the underlying disorder to be treated, and the eradication or improvement of one or more symptoms associated with the underlying disorder, in which improvement is seen in the patient, even though the patient may still be suffering from the underlying disorder.

[0193]

[0219] When used herein, the terms “to treat,” “treatment,” and “to treat” are used in this specification. "This is a progression resulting from the administration of one or more therapeutic agents (for example, one or more therapeutic agents such as polymorphs or pharmaceutically acceptable salts or compositions of Compound I of the present invention)." This refers to a reduction or improvement in the severity and / or duration of the condition mediated by sGC, cGMP, and / or NO, or improvement of one or more symptoms (preferably one or more identifiable symptoms) of the condition (i.e., "managing" the condition without "curing" it). In certain embodiments, the terms “to treat,” “treatment,” and “to treat” refer to improvement of at least one measurable physical parameter of the condition mediated by sGC, cGMP, and / or NO. In other embodiments, the terms “to treat,” “treatment,” and “to treat” refer to inhibition of the progression of the condition mediated by sGC, cGMP, and / or NO, either physically, such as by stabilization of identifiable symptoms, or physiologically, such as by stabilization of physical parameters, or both.

[0194]

[0220] The term "preventing" as used herein means preventing one of the diseases or disorders This refers to administering medication to prevent or preemptively stop the appearance of multiple symptoms. Those with ordinary skill in the medical field 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 its symptoms, and this is the main intent of this disclosure. The Physician's Desk Reference, the standard document in the art, uses the term “prevent” hundreds of times. When used in that document, the terms “prevent,” “preventing,” and “prevention” refer to preventing the cause, effect, symptoms, or progression of a disorder or disease before the disease or disorder itself becomes fully apparent.

[0195]

[0221] In one embodiment, the method of the present invention relates to sGC, cGMP and / or NO-related For patients who have a predisposition (e.g., a genetic predisposition) to developing a disease, disorder, or symptom, more specifically for humans, it is a preventive or "preemptive" measure.

[0196]

[0222] In other embodiments, the method of the present invention involves administering sGC, cGMP, or NO-related substances to a patient. For patients suffering from a disease, disorder, or condition that is at risk of developing into a disease, disorder, or symptom, it is more specifically a preventive or "preemptive" measure for humans.

[0197]

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

[0198]

[0224] The solid forms and compositions disclosed herein are also for dogs, cats, mice, and other animals. It is also useful for veterinary treatment of companion animals, exotic animals and livestock, including but not limited to cats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs and cows.

[0199]

[0225] In other embodiments, the invention provides a method of stimulating sGC activity in a biological sample, comprising contacting the biological sample with the solid form or composition of the invention. The use of sGC stimulators 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 preservation of biological specimens.

[0200] Combination therapy

[0226] The solid forms and pharmaceutical compositions described herein can be used in combination therapies using one or more additional therapeutic agents. For combination treatments using 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 agent can be before, simultaneous with, or after the administration of the other agent.

[0201]

[0227] When co-administered with other agents, for example, when co-administered with another therapeutic drug, the "effective amount" of the second agent depends on the type of drug used. Suitable dosages are known for approved drugs and can be adjusted by one of ordinary skill in the art based on the condition of the subject, the type of condition(s) being treated, and the amount of the compound described herein being used. Where the amount is not specified, an effective amount is assumed. For example, the solid forms described herein can be administered to a subject in a dosage range between 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, about 0.01 to about 100 mg / kg body weight / day.

[0202]

[0228] When "combination therapy" is used, the effective dose is the first amount of polymorph of compound I or This can be achieved using a pharmaceutically acceptable salt and a second amount of a further preferred therapeutic agent.

[0229] In one embodiment of the present invention, a polymorph or pharmaceutically acceptable salt of compound I is used. The compound I and any further therapeutic agents are administered in effective doses (i.e., doses that are therapeutically effective when administered alone). In another embodiment, a polymorph or pharmaceutically acceptable salt of compound I and any further therapeutic agent are administered in doses that do not provide a therapeutic effect when administered alone (sub-therapeutic doses). In yet another embodiment, a polymorph or pharmaceutically acceptable salt of compound I may be administered in an effective dose, while any further therapeutic agent is administered in a sub-therapeutic dose. In yet another embodiment, a polymorph or pharmaceutically acceptable salt of compound I may be administered in a sub-therapeutic dose, while any further therapeutic agent, such as a suitable cancer treatment agent, is administered in an effective dose.

[0203]

[0230] As used herein, the terms “combined” or “simultaneous administration” mean one type The terms may be used interchangeably to represent the use of a greater number of therapeutic agents (e.g., one or more prophylactic and / or therapeutic agents). The use of these terms does not restrict the order in which the therapeutic agents (e.g., prophylactic and / or therapeutic agents) are administered to the subject.

[0204]

[0231] Simultaneous administration may involve, for example, capsules containing a certain ratio of first and second amounts or This includes the administration of first and second amounts of a compound in an essentially simultaneous manner, such as a single pharmaceutical composition like a tablet, or 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 pharmaceutically acceptable salt of compound I and a second amount of a further therapeutic agent, the compounds are administered within a sufficiently close time interval to produce the desired therapeutic effect. For example, the interval between each administration that can produce the desired therapeutic effect can range from minutes to hours and can be determined by considering the properties of each compound, such as potency, solubility, bioavailability, plasma half-life, and kinetic properties. For example, the polymorph or pharmaceutically acceptable salt of compound I and the second therapeutic agent may be administered in any order within about 24 hours of each other, about 16 hours of each other, about 8 hours of each other, about 4 hours of each other, about 1 hour of each other, or within about 30 minutes of each other.

[0205]

[0232] More specifically, the first therapeutic agent (e.g., a prophylactic or therapeutic amount specified herein) A polymorph or pharmaceutically acceptable salt of Compound I described may be administered to a subject before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks 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 anticancer agent).

[0206]

[0233] It can be combined with polymorphs or pharmaceutically acceptable salts of compound I, and also separately. Examples of other therapeutic agents that may be administered in any of the same pharmaceutical compositions include: (1) Endothelial-derived release factors (EDRFs); (2) NO donors such as nitrosothiols, nitriles, sidnonimines, NONOates, N-nitrosamines, N-hydroxylnitrosamines, nitrosoimines, nitrotyrosine, diazetine dioxide, oxatriazole 5-imine, oximes, hydroxylamines, N-hydroxyguanidine, hydroxyureas, or antifloxan. Some examples of these types of compounds include: glyceryl trinitrate (GTN, also known as nitroglycerin, nitroglycerine, and trinitrogylcerin), a nitrate ester of glycerol; sodium nitroprusside (SNP), in which one molecule of nitric oxide coordinates to an iron metal to form a square bipyramidal complex; 3-morpholinosidenonimine (SIN-1), a zwitterionic compound formed by a combination of morpholine and sidenonimine; S-nitroso-N-acetylpenicillamine (SNAP), an N-acetylamino acid derivative having a nitrosothiol functional group; diethylenetriamine / NO (DETA / NO), a compound of nitric oxide covalently linked to diethylenetriamine; and NCX4016, an m-nitroxymethylphenyl ester of acetylsalicylic acid.Some more specific examples of NO donors in these classes include: classic nitrovasodilators such as organic nitrates and nitrites including nitroglycerin, amyl nitrite, isosorbide dinitrate, isosorbide 5-mononitrate, and nicorandil; isosorbide (Dilatrate®-SR, Imdur®, Ismo®, Isordil®, Titradose®, Monoket®), FK409 (NOR-3); FR144420 (NOR-4); 3-morpholinoside nonimine; lincidomin chlorohydrate ("SIN-1"); S-nitroso-N-acetylpenicillamine ("SNAP"); AZD3582 (CINOD The lead compounds include 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-hexaneamine (NOC-9) or diethylamine NONOate. Nitric oxide donors are also listed 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 (NO donors 14-17, etc.), and Nitric Oxide Donors for Pharmaceutical and Biological Research, Eds: Peng George Wang, Tingwei Bill Cai, Naoyuki Taniguchi, Wiley, also disclosed this in 2005. (3) Other substances that increase cGMP concentration, 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-butyl hydroxy Examples include c- and N-(3-methyl-2-butenyl)oxy-L-arginine, canavanine, epsilon anidine-carpoic acid, agmatine, hydroxyl-agmatine, and L-tyrosyl-L-arginine); N-alkyl-N'-hydroxyguanidine (such as N-cyclopropyl-N'-hydroxyguanidine and N-butyl-N'-hydroxyguanidine), N-aryl-N'-hydroxyguanidine (such as N-phenyl-N'-hydroxyguanidine and its para-substituted derivatives having -F, -Cl, -methyl, and -OH substituents, respectively); guanidine derivatives such as 3-(trifluoromethyl)propylguanidine; and others outlined in Cali et al. (2005, Current Topics in Medicinal Chemistry 5:721-736) and others disclosed in the literature 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, as well as corresponding patent documents such as US2003 / 0008915, US2003 / 0022935, US2003 / 0022939 and US2003 / 0055093. Other eNOS transcription promoters, including those described in US20050101599 (e.g., 2,2-difluorobenzo[1,3]dioxol-5-carboxylic acid indan-2-ylamide, and 4-fluoro-N-(indan-2-yl)-benzamide), as well as Sanofi-Aventis compounds AVE3085 and AVE9488 (CA Registry NO. 916514-70-0; Schafer et al., Journal of Thrombosis and Homeostasis, 2005; Vol. 3, Supplement 1: Abstract number P1487); (6) NO-independent heme-dependent sGC activators: BAY 58-2667 (See patent publication DE19943635)

[0207] [ka]

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

[0209] [ka]

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

[0211] [ka]

[0212] ; and HMR-1069 (Sanofi-Aventis) This includes, but is not limited to, the following:

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

[0214] [ka]

[0215] Riociguato (BAY 63-2521, Adempas, commercial product, listed in DE19834044)

[0216] [ka]

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

[0218] [ka]

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

[0220] [ka]

[0221] BAY 41-8543 (as listed in DE19834044)

[0222] [ka]

[0223] Etriciguat (as described in WO 2003086407)

[0224] [ka]

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

[0226] [ka]

[0227] A-344905, its acrylamide analog A-350619, and its 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. This includes, but is not limited to, the following:

[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, etc. For example, PDE9 inhibitors such as PF-04447943; etc. (9) Calcium channel blockers: Dihydropyridine calcium channel blockers: Amlodipine (Norvasc), Alanidipine (Sapresta), Azelnidipine (Calblock), Barnidipine (Hypoca), Benidipine (Coniel), Cilnidipine (Atelec, Synalong, Siscard), Clebidipine (Cleviprex), Diltiazem, Efonidipine (Randell), Felodipine (Plendil), Lasidipine (Motens, Lacipil), Relcanidipine (Zanidip), Manidipine (Calslot, Madipine), Nicardipine (Cardene, Cardene SR) Sr)), nifedipine (Procadia, Adalat), nilvadipine (Nivazil), nimodipine (Nimotop), nisoldipine (Baymicard, Sular, Syscor), nitrendipine (Cardif, Nitrepin, Byrotensin), pranidipine (Acalas), isradipine (Lomir); etc. Phenylalkylamine calcium channel blockers: Verapamil (Kalan, Isobutine)

[0232] [ka]

[0233] Garopamil (Procorum, D600); Benzothiazepine: Diltiazem (Cardigem);

[0234] [ka]

[0235] Non-selective calcium channel inhibitors: mibefladil, bepridil, and fluspirine, fendiline, etc. (10) Endothelin receptor antagonists (ERAs): For example, two types (ET) A and ET B ) Endothelin receptor antagonists, bosentan (marketed as Tracleer®); sitaxentan (marketed as Thelin®); ambrisentan (marketed in the US as Letairis®); two non-selective endothelin antagonists, Actelion-1, entered clinical trials in 2008; (11) Prostacyclin derivatives or analogues: e.g., prostacyclin (prostaglandin I2), epoprostenol (synthetic prostacyclin, marketed as Flolan®); treprostinil (Remodulin®), iloprost (Ilomedin®), iloprost (marketed as Ventavis®); Remodulin® in oral and inhalation forms under development; beraprost, an oral prostanoid available in Japan and Korea; (12) Anti-dyslipidemia drugs: Bile acid scavengers (e.g., cholestyramine, colestipol, colestylan, and coleseveram); statins such as atorvastatin, simvastatin, lovastatin, fluvastatin, pitavastatin, rosuvastatin, and pravastatin; cholesterol absorption inhibitors such as ezetimibe; other antihyperlipidemia agents such as ethyl icosapentaenoate, ethyl omega-3 fatty acid esters, and Reducol; clofibrate, bezafibrate Fibric acid derivatives such as clinofibrate, gemfibrozil, ronifibrate, binifibrate, fenofirate, cyprofibrate, and cholinefenofibrate; 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 disulfate; etc. (13) Anticoagulants, including the following types: • Coumarin (vitamin K antagonist): Warfarin® (coumadin), mainly used in the US and UK; Acenocoumaro® and P henprocoumon (registered trademark), primarily used in other countries; Phenindione (registered trademark); • Heparin and derivative substances: heparin; low molecular weight heparin, fondaparinax and hydraparinax; etc. Direct thrombin inhibitors: argatroban, repiridine, bivalirudine, and dabigatran; ximelagatran (Exanta®), not approved in the US; etc. • Tissue plasminogen activator, alteplase, etc., used to dissolve blood clots and remove arterial blockages; (14) Antiplatelet drugs: for example, thienopyridines such as lopidogrel and ticlopidine; dipyridamole; aspirin; (15) ACE inhibitors, for example, the following types: • Captopril (trademark name Capoten®), the first ACE inhibitor, and sulfhydryl-containing drugs such as zofenopril; • Dicarboxylate-containing drugs 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 drugs such as hosinopril; • Naturally occurring ACE inhibitors, such as casokinin and lactokinin, which are breakdown products of casein and whey that occur spontaneously after the consumption of dairy products, particularly fermented milk; lactotripeptides Val-Pro-Pro and Ile-Pro-Pro, produced by the live bacterium Lactobacillus helveticus or derived from casein, also possess ACE-inhibiting and antihypertensive functions; Other ACE inhibitors such as alacepril, delapril, cilazapril, imidapril, trandolapril, temocapril, moexipril, and spirapril, (16) Oxygen supplementation therapy; (17) Beta-blockers of the following types: Non-selective agents: Alprenolol®, Bucindolol®, Carteol®, Carvedilol® (with additional α-blocking effect), Labetalol® (with additional α-blocking effect), Nadolol®, Penbutolol® (with intrinsic sympathomimetic effect), Pindolol® (with intrinsic sympathomimetic effect), Oxprenonol, Acebutol, Sotalol, Mepindolol, Celiprolol, Arotinolol, Tertatol, Amosuralol, Nipradilol, Propranolol®, and Timol®; • β1-selective agents: Acebutolol® (with intrinsic sympathomimetic activity), Atenolol®, Betaxolol®, Bisoprolol®, Celiprolol®, Dobutamine hydrochloride, Ilsogladine maleate, Carvedilol, Tarinolol, Esmolol®, Metoprolol®, and Nebivolol®; • β2-selective agent: 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, cyclopentiazide, meticlothiazide, polythiazide, quinetazone, xipamide, metrazone, indapamide, and cicletanin; loop diuretics such as furosemide and toresamide; potassium-sparing diuretics such as amiloride, spironolactone, potassium canrenoate, eplerenone, and triamterene; combinations of these drugs; other diuretics such as acetazolamide and carperitide, etc. (20a) Direct-acting vasodilators such as hydralazine hydrochloride, diazoxide, sodium nitroprusside, and cadralazine; other vasodilators such as isosorbide dinitrate and isosorbide 5-mononitrate; (20b) Exogenous vasodilators: Adenocard®, an adenosine agonist, is primarily used as an antiarrhythmic drug; • Alpha-blockers (which block the vasoconstrictive effect of adrenaline): Alpha-1 adrenergic receptor antagonists such as prazosin, indramin, urapidil, bunazosin, terazosin, and doxazosin. • Atrial natriuretic peptide (ANP); ·ethanol Histamine inducers that complement the functions of proteins C3a, C4a, and C5a by inducing histamine release from mast cells and basophilic granulocytes; • Tetrahydrocannabinol (THC), the main active chemical in marijuana, has a mild vasodilatory effect; • Papaverine, an alkaloid found in the hypnotic agent of the poppy; etc. (21) Bronchodilators: There are two main types of bronchodilators, β2 agonists and anticholinergics, as exemplified below: • β2 agonists: Salbutamol® or albuterol (generic brand name: Ventolin) and Terbutaline® are short-acting β2 agonists for rapid relief of COPD symptoms. Long-acting β2 agonists (LABAs) include Salmeterol® and Formoterol®. • Anticholinergics: Ipratropium® is the most widely prescribed short-acting anticholinergic drug. Tiotropium® is the most commonly prescribed long-acting anticholinergic drug for COPD; • Theophylline®, a bronchodilator and phosphodiesterase inhibitor; (22) Adrenocortical steroids: beclomethasone, methylprednisolone, betamethasone, prednisone, prenisolone, triamcinolone, dexamethasone, fluticasone, flunisolide and hydrocortisone, as well as adrenocortical steroid analogs such as budesonide. (23) Dietary supplements: e.g., omega-3 oils; folic acid, niacin, zinc, copper, Korean red ginseng, ginkgo, pine bark, Tribulus terrestris, arginine, oats, horny goat weed, maca bulbs, 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 mixture / combination of proprietary drugs of natural origin, 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 O0178697, WO04032848, WO03097042, WO03097598, WO03022814, WO03022813, and WO04058164, European patent applications EP945450 and EP944614, as well as 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, including but not limited to these; (25) Immunosuppressants: Cyclosporine (Cyclosporine A, Sandimmune® Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (Sirolimus, Rapamune) and other FK-506 type immunosuppressants, as well as mycophenolates, such as mycophenolate mofetil (CellCept®); etc. (26) Nonsteroidal anti-asthmatic drugs: β2-agonists (e.g., terbutaline, metaproterenol, fenoterol, isoetalin, albuterol, salmeterol, bitolterol, and pirbuterol) and β2-agonist-corticosteroid combinations (e.g., salmeterol-fluticasone (Advair®), formoterol-budesonide (Symbicort®)), theophylline, cromoline, sodium cromoglycate, nedocromil, atropine, ipratropium, ipratropium bromide, leukotriene biosynthesis inhibitors (Ziloton, BAY1005); etc. (27) Non-steroidal anti-inflammatory drugs (NSAIDs): Propionic acid derivatives (e.g., aluminoprofen, benoxaprofen, buclociac, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxene, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), acetic acid derivatives (e.g., indomethacin, acemetacin, alclofenac, cridanac, diclofenac, fenclofenac, fenclosic acid, fentiazac, furofenac, ibufenac, isoxepac) Soxepac, oxpinac, sulindac, thiopinac, tolmetin, zidomethacin, and zomepirac; fenamic acid derivatives (e.g., flufenamic acid, meclofenamic acid, mefenamic acid, difluminic acid, and tolfenamic acid); biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal); oxicam (e.g., isoxicam, piroxicam, sudoxicam, and tenoxicam); salicylates (e.g., acetylsalicylic acid and sulfasalazine); and pyrazolones (e.g., apazon, bezpiperilone, feprazon, mofebutazone, oxyfenbutazone, and phenylbutazone), etc. (28) Cyclooxygenase-2 (COX-2) inhibitors: such as celecoxib (Celebrex®), rofecoxib (Vioxx®), valdecoxib, etoricoxib, parecoxib, and lumiracoxib; Opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyfen, buprenorphine, butorphanol, dezosine, nalbuffine and pentazocine; and (29) Antidiabetic agents: insulin and insulin-like drugs, sulfonylureas (e.g., glibride, glibenclamide, glipizide, gliclazide, glikidone, glimepiride, meglinatide, tolbutamide, chlorpropamide, acetohexamide, trazamide), biguanide drugs (e.g., metformin (Glucophage®)), α-glucosidase inhibitors (acarbose, epalrestat, voglibose, miglitol, etc.), thiazolidinone compounds (e.g., rosiglitazone (Avandia®), troglitazone (Rezulin®), siglitazone, pioglitazone (Actos®) and englitazone; and other 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 pramulintide; hypoglycemic agents such as chromium picolinate (optionally combined with biotin); dipeptidyl peptidase IV inhibitors such as sitagliptin, vildagliptin, saxagliptin, alogliptin, and linagliptin; vaccines currently under development for the treatment of diabetes; AVE-0277, Alum-GAD, BHT-3021, IBC-VS01; cytokine-targeted therapies under development for the treatment of diabetes, such as anakinra, canakinumab, diaselein, gevokizumab, LY-2189102, MABP-1, and GIT-027; (30) HDL cholesterol-raising agents: anacetrapib, MK-524A, CER-001, DRL-17822, dalcetrapib, JTT-302, RVX-000222, TA-8995, etc. (31) Anti-obesity drugs: methamphetamine hydrochloride, amfepramon hydrochloride (Tenuate®), phentermine (Ionamin®), benzfetamine hydrochloride (Didrex®), fendimethrazine tartrate (Bontril®, Prelu-2®, Plegine®), mazindol (Sanorex®), orlistat (Xenical®), Sibutramine hydrochloride monohydrate (Meridia®, Reductil®), limonabant (Acomplia®), amfepramon, chromium picolinate, RM-493, TZP-301; phentermine / topiramate, bupropion / naltrexone, sibutramine / metformin, bupropion SR / zonisamide SR, salmeterol, xinafoate / fluticasone propionate; lorcaserin hydrochloride, fe Centermin / 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, berneperito, 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;S-234462, Sobetirome, TM-38837, Tetrahydrocannabivarin, ZYO-1, Beta-Lapacon, and other combinations; etc. (32) Angiotensin receptor blockers: losartan, valsartan, candesartan cilexetil, eprosaran, irbesartan, telmisartan, olmesartan medoxomil, azilsartan medoxomil, etc. (33) Renin inhibitors: such as aliskiren hemifumate; (34) Centrally acting alpha-2-adrenergic receptor agonists: methyldopa, clonidine, guanfacine, etc. (35) Adrenergic neuronal blockers: guanethidine, guanadrel, etc. (36) Imidazolin I-1 receptor agonists: such as rimenidine dihydrogen phosphate and moxonidine hydrochloride hydrate; (37) Aldosterone antagonists: spironolactone and eplerenone, etc. (38) Potassium channel activators: pinacidil, etc. (39) Dopamine D1 agonists: such as phenoldopam mesylate; other dopamine agonists such as ivopamine, dopexamine, and docarpamine; (40) 5-HT2 antagonists: ketanserine, etc. (42) Vasopressin antagonists: tolvaptan, etc. (43) Calcium channel sensitizers: such as levocimendan or activators such as nicorandil; (44) PDE-3 inhibitors: amrinone, milrinone, enoximon, vesnarinone, pimobendan, olprinone, etc. (45) Adenylyl cyclase activators: such as colforsin dapropate hydrochloride; (46) Positive inotropic agents: such as digoxin and methyldigoxin; metabolic cardiac agents 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: for example, Razadyne (registered Cholinesterase inhibitors prescribed for mild to moderate Alzheimer's disease, including trademarked drugs (galantamine), Exelon® (rivastigmine), and Aricept® (donepezil), and Cognex® (tacrine); Namenda® (memantine), N-methyl-D-aspartate (NMDA) antagonists, and Aricept®, prescribed to treat moderate to severe Alzheimer's disease; and vitamin E (antioxidant).

[0238] (50) Antidepressants: Tricyclic antidepressants such as amitriptyline (Elavil®), desipramine (Norpramin®), imipramine (Tofranil®), amoxapine (Asendin®), and nortriptyline; selective serotonin reuptake inhibitors (SSRIs) such as paroxetine (Paxil®), fluoxetine (Prozac®), sertraline (Zoloft®), and citalopram (Celexa®); as well as others such as doxepin (Sinequan®) and trazodone (Desyrel®); SNRIs (e.g., venlafaxine and reboxetine); dopaminergic antidepressants (e.g., bupropion and amineptin).

[0239] (51) Neuroprotective agents: e.g., memantine, L-dopa, bromocriptine, pergoli, talipexole, pramipexole, cabergoline, neuroprotective agents currently under investigation, including anti-apoptotic drugs (CEP 1347 and CTCT346), lazaroids, bioenergetic therapies, anti-glutamate agents and dopamine receptors. Other clinically evaluated neuroprotective agents include, for example, the monoamine oxidase B inhibitors selegiline and rasagiline, dopamine agonists, and the complex I mitochondrial enhancer coenzyme Q10.

[0240] (52) Antipsychotic pharmacotherapy: e.g., ziprasidone (Geodon®), risperidone (Risperdal®), and olanzapine (Zyprexa®).

[0241] (53) NEP inhibitors: Sacubitril, omapatrilat, etc. (54) Methylene blue (MB) This includes, but is not limited to, the following:

[0242] kit

[0234] The solid forms and pharmaceutical formulations described herein may be included in the kit. The kit may contain two or more drugs in single or multiple doses, each individually packaged or formulated, or two or more drugs in single or multiple doses, packaged or formulated together. Therefore, 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 containers or a group of containers may be placed in a package, which may optionally include instructions for administration or dosage. The kit may further comprise a syringe or other means for administering diluents as well as drugs, or other means for formulation. Therefore, the kit may comprise: a) a pharmaceutical composition comprising the compounds described herein and pharmaceutically acceptable carriers, vehicles, or diluents; and b) a container or packaging. The kit may optionally include instructions describing one method of using the pharmaceutical composition among one or more methods described herein (e.g., for preventing or treating one or more diseases and disorders described herein). The kit may optionally include one or more additional drugs described herein for concurrent therapeutic use. The kit may contain a second pharmaceutical composition, a pharmaceutically acceptable carrier, a vehicle, or a diluent. The pharmaceutical composition containing the compounds described herein and the second pharmaceutical composition included in the kit may optionally be combined in the same pharmaceutical composition.

[0243]

[0235] The kit may include a container or packaging for containing the pharmaceutical composition, and a divided bottle. Alternatively, the packaging may include divided containers such as divided foil packets. Containers may be, for example, paper or cardboard boxes, glass or plastic bottles or wide-mouthed bottles, resealable bags (e.g., for keeping "refills" of tablets in different containers), or blister packaging containing individual doses for dispensing from the pack according to a treatment schedule. For the commercialization of a single dosage form, it is feasible that more than one container may be used together within a single package. For example, tablets may be contained in a bottle, which is then contained in a box.

[0244]

[0236] An example of a kit is so-called blister packaging. Blister packaging is a packaging product It is well known in the industry and is widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packaging generally consists of a sheet of a relatively rigid material covered with a foil, preferably made of transparent plastic material. During the packaging process, a recess is formed in the plastic foil. The recess may have the size and shape of the individual tablet or capsule to be packaged, or it may have the size and shape to accommodate multiple tablets and / or capsules to be packaged. The tablet or capsule is then placed into the recess to fit it, and the sheet of the relatively rigid material is sealed against the plastic foil on the foil surface in the opposite direction to the direction in which the recess was formed. As a result, the tablets or capsules are sealed individually or together in the recess between the plastic foil and the sheet, as desired. The strength of the sheet is preferably such that an opening is formed in the sheet at the location of the recess by applying pressure to the recess by hand, allowing the tablet or capsule to be removed from the blister packaging. The tablet or capsule can then be removed through the opening.

[0245]

[0237] Regarding when therapeutic drugs should be taken, consult with a physician, pharmacist or the patient. It may be desirable to provide written aids for memory, including information and / or instructions. “Daily dose” may be a single tablet or capsule or several tablets or capsules to be taken on a given day. When the kit contains separate compositions, one or more compositions of the kit’s daily dose may consist of one tablet or capsule, while another or more compositions of the kit’s daily dose may consist of several tablets or capsules. The kit may take the form of a dispenser designed for its intended use to dispense one daily dose at a time. The dispenser may be equipped with memory aids to further facilitate compliance with the regimen. One 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 integrated with a liquid crystal display or audible cue signal that reads the date the last daily dose was taken and / or reminds the user when the next dose should be taken. [Examples]

[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]

[0238] Isooxazole-3-carboxylic acid ((1'), 241.6g, 2137mm 1.0 equivalent of oxalyl chloride, 1450 mL of toluene, and 7.8 g of DMF (107 mmol, 0.05 equivalents) were added to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The resulting slurry was heated to 45-50°C. Next, 325 g of oxalyl chloride (2559 mmol, 1.2 equivalents) was added over 2 hours via an addition funnel while maintaining the reaction temperature between 45-50°C, and active gas generation was observed. After the addition, a brown mixture was obtained. The brown mixture was heated to 87-92°C for 1 hour and stirred at 87-92°C for 1 hour. The reaction was considered complete, as shown by HPLC. During heating, the brown mixture changed to a dark solution. The reaction was monitored by quenching a portion of the reaction mixture to 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 substances. The dark filtrate was concentrated under reduced pressure to a volume of 400 mL of dark oil.

[0249]

[0239] Potassium carbonate (413g, 2988mmole, 1.4 equivalents) and water (10 00 mL of the solution was placed in 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 equivalents) was placed in a suitable reaction vessel and dissolved in water (1000 mL). Next, the N,O-dimethylhydroxyamine solution and dichloromethane (2500 mL) were placed in the potassium carbonate solution.

[0250]

[0240] Next, the above dark oily substance (400 mL) is subjected to a reaction while maintaining the reaction temperature at -10 to 0°C. However, it was slowly added through an addition funnel. The addition was slightly exothermic, and a brown mixture was obtained after the addition. This mixture was stirred at 0-5°C for 20 minutes, and then heated to 20-25°C. The lower organic layer was collected, and the upper aqueous layer was extracted with dichloromethane (400 mL). The combined organic layers were washed with 15% sodium chloride solution (1200 mL). The organic layers were dehydrated over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain intermediate (2') as a dark oily substance. 1 ¹H-NMR determined the concentration at 261.9 g, 97% by mass, 76% yield, 3% by mass toluene, and 0.04% by mass water content (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 propioate to provide (E)-ethyl 4-(isoxazol-3-yl)-2-(methoxy(methyl)amino)-4-oxobuta-2-enoate (3').

[0252] [ka]

[0253]

[0241] Intermediate (2') (72.2g, 96% by mass, 444mmole, 1.0 equivalent) Ethyl propioate (65.7 g, 670 mmol, 1.5 equivalents) and anhydrous THF (650 mL) were added to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. This solution was cooled to -65 to -55°C. Next, sodium bis(trimethylsilyl)amide (1 M, 650 mL, 650 mmol, 1.46 equivalents) in the THF was slowly added through an addition funnel while maintaining the reaction temperature at -65 to -55°C. After the addition was complete, this mixture was stirred for 10 minutes at below -55°C. Next, 1N HCl (650 mL, 650 mmol, 1.46 equivalents) was added 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). The organic layers were concentrated under reduced pressure to obtain a dark oily substance.

[0254]

[0242] The dark oily substance is divided into dichloromethane / ethyl acetate / heptane (150 mL / 10 It was dissolved in a solution of 0 mL / 100 mL. This solution was placed on a silica pad (410 g), and the silica pad was eluted with ethyl acetate / heptane (1 / 1 v / v). The filtrate (approximately 3000 mL) was collected and then concentrated under reduced pressure to a volume of 150 mL to obtain a slurry. Next, heptane (200 mL) was added to the slurry, and the slurry was concentrated under reduced pressure to a volume of 150 mL. The obtained slurry was filtered, and the filtration cake was washed with heptane (150 mL). Next, the filtration cake was air-dried overnight to obtain the 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-(isoxazole-3-yl)-1H-pyrazole-3-carboxylate (4').

[0256] [ka]

[0257]

[0243] Intermediate (3') (72.9g, 287mmole, 1.0 equivalent) and anhydrous ester 730 mL of tanol was placed in a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The mixture was cooled to 0–5°C. Next, 48.2 g, 344 mmol, 1.2 equivalents of 2-fluorobenzylhydrazine were added to the mixture. The mixture was stirred at 0–10°C for 1 hour, then heated to 20–25°C and stirred at 20–25°C for 16 hours. The reaction was completed by HPLC. Concentrated HCl (33.9 g, 37% by mass, 344 mmol, 1.2 equivalents) was added to the reaction mixture over 1 minute, generating heat and raising the batch temperature from 20°C to 38°C. A slurry was obtained. This mixture was cooled to 0–10°C for 1 hour and stirred at 0–10°C for 1 hour. The obtained slurry was filtered, and the filtered cake was washed with 200 mL of ethanol. The filtered cake was dried under vacuum at 30-40°C for 16 hours to obtain the intermediate (4') as a grayish-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-(isoxazole-3-yl)-1H-pyrazole-3-carboxymidoamide hydrochloride (5'B)

[0259] [ka]

[0260]

[0244] Anhydrous ammonium chloride (267g, 4991 mmol, 5.0 equivalents) and 5400 mL of toluene was added to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. Trimethylaluminum (2 M, 2400 mL, 4800 mmol, 4.8 equivalents) in the toluene was slowly added through an addition funnel while maintaining the reaction temperature at 20–40°C (Note: Methane gas generation was observed during addition). Next, this mixture was heated to 75–80°C for 30 minutes to obtain a clear white solution. Intermediate (4') (315 g, 999 mmol, 1.0 equivalent) was added to the reaction mixture in four equal parts at 75–90°C for 1 hour. The reaction mixture 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 completed by HPLC. The reaction mixture was cooled to 10-20°C, and methanol (461 g, 14.4 moles, 14.4 equivalents) was slowly added via an addition funnel while maintaining the reaction temperature at 10-40°C. Note: The quench was very exothermic, and a large amount of gas was observed. A concentrated slurry was obtained. Next, 3N HCl (6400 mL, 3N, 19.2 moles, 19.2 equivalents) was slowly added via an addition funnel while maintaining the reaction temperature at 20-45°C. This mixture was heated to 80-85°C and stirred for 10 minutes to obtain a clear two-phase mixture. This mixture was cooled to 0-5°C over 3 hours and stirred for 1 hour at 0-5°C. The resulting slurry was then... The solution was filtered, and the filter cake was washed with water (3000 mL). The filter cake was dried under vacuum at 40-50°C for 24 hours to obtain the intermediate (5'B) as a grayish-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-(isoxazole-3-yl)-1H-pyrazole-3-yl)pyrimidine-4,6-diol (6').

[0262] [ka]

[0263]

[0245] Intermediate (5'B) (224.6g, 698mmole, 1.0 equivalent), methano 2250 mL of methanol and 187 g of diethyl fluoromalonate (1050 mmol, 1.5 equivalents) were added to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. Next, 567 g of sodium methoxide in methanol solution (30% by mass, 3149 mmol, 4.5 equivalents) was added via an addition funnel while maintaining the reaction temperature at 20–35°C. The mixture was stirred at 20–35°C for 30 minutes to obtain a dilute suspension. The reaction was completed by HPLC. 2300 mL of 1.5 N HCl solution (3450 mmol, 4.9 equivalents) was added via an addition funnel over 1 hour while maintaining the reaction temperature at 20–30°C. A white suspension was obtained. The pH of the reaction mixture was approximately 1 as measured by pH test paper. The slurry was stirred at 20–30°C for 30 minutes. The obtained slurry was filtered, and the filtered cake was washed with a pre-mixed methanol and water (500 mL / 500 mL) solution, followed by water (1000 mL). The filtered cake was dried under vacuum at 50-60°C for 16 hours to obtain intermediate (6') as a grayish-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-fluoropyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazole-5-yl)isoxazole (7')

[0265] [ka]

[0266]

[0246] Intermediate (6') (264g, 711mmole, 1.0 equivalent), acetonitrile 4000 mL of water and 138 g of N,N-dimethylaniline (1137 mmol, 1.6 equivalents) were placed in a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The slurry mixture was heated to 70-80°C. Next, 655 g of oxychloride phosphite (4270 mmol, 6.0 equivalents) was added over 1 hour via an additive funnel while maintaining the reaction temperature at 70-80°C. The mixture was stirred at 75-80°C for 22 hours to obtain a brown solution. The reaction was completed by HPLC. Next, the mixture was cooled to between 0 and 5°C, and a cottony solid precipitated at 25°C. 3000 mL of water was slowly added via an additive funnel while maintaining the reaction temperature at 0-10°C. The slurry was stirred at 0-10°C for 30 minutes. The obtained slurry was filtered, and the filtered cake was washed with a pre-mixed acetonitrile and water (500 mL / 500 mL) solution. The filtered cake was dried under vacuum at 35–45°C for 16 hours to obtain the intermediate (7') as a grayish-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-methoxypyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazole-5-yl)isoxazole (8').

[0268] [ka]

[0269]

[0247] Methanol (3400 mL) and sodium methoxide in methanol (1 54 mL, 5.4 M, 832 mmol, 1.2 equivalents) was placed in a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The reaction mixture was heated to 23–27°C. Intermediate (7') (283 g, 693 mmol, 1.0 equivalent) was added to the mixture in small amounts (5–10 g each) over 40 minutes while maintaining the reaction temperature at 23–27°C. The slurry was stirred at 23–27°C for 30 minutes. The reaction was completed 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 obtain intermediate (8') as a grayish-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-methoxypyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazole-5-yl)isoxazole (9')

[0271] [ka]

[0272]

[0248] Intermediate (8') (226g, 560mmole, 1.0 equivalent), palladium ( 10% of activated carbon (nominal 50% water-moistened, 22.6 g, 0.01 mole, 0.018 equivalents), tetrahydrofuran (3400 mL), and triethylamine (91 g, 897 mmol, 1.6 equivalents) were placed in a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. Nitrogen was blown into the reaction mixture through a Teflon® tube at 20-30°C for 10 minutes. The mixture was then heated to 40-50°C, and while maintaining the reaction temperature at 40-50°C, hydrogen gas was blown into the reaction mixture through a Teflon tube for 6 hours. The reaction was completed by HPLC. Nitrogen was then blown into the reaction mixture through a Teflon tube at 40-50°C for 10 minutes. The reaction mixture was thermally 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 obtain a slurry. Next, tetrahydrofuran was replaced with methanol by a continuous supply of methanol (3000 mL) under reduced pressure. The final volume after solvent exchange was 1300 mL. The obtained slurry was filtered, and the filtration cake was washed with methanol (500 mL). The filtration cake was dried under vacuum at 20-25°C for 16 hours to obtain 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-(isoxazole-3-yl)-1H-pyrazole-3-yl)pyrimidine-4-ol (10')

[0274] [ka]

[0275]

[0249] Intermediate (9') (230 g, 623 mmole, 1.0 equivalent), MeOH (3 450 mL of solution and concentrated HCl (307 g, 37% by mass, 3117 mmol, 5.0 equivalents) were placed in a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The mixture was heated to 60–65°C to obtain a solution. The mixture was then stirred at 60–65°C for 17 hours to obtain a slurry. The reaction was completed by HPLC. The slurry was cooled to 20–25°C for 2 hours and stirred at 20–25°C for 30 minutes. The obtained 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 obtain the 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-fluoropyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazole-5-yl)isoxazole (formula IV)

[0277] [ka]

[0278]

[0250] Intermediate (10') (214g, 602 mmol, 1.0 equivalent), acetonite 3000 mL of lyl and 109 g of N,N-dimethylaniline (899 mmol, 1.5 equivalents) were added to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The slurry mixture was heated to 70-80°C. Next, 276 g of oxychloride phosphite (1802 mmol, 3.0 equivalents) was added via an 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 to obtain a green solution. The reaction was completed by HPLC. Next, the mixture was cooled to 0-5°C. 1500 mL of water was slowly added via an addition funnel while maintaining the reaction temperature at 0-10°C. The slurry was stirred at 0-10°C for 30 minutes. The obtained slurry was filtered, and the filtered cake was washed with a pre-mixed acetonitrile and water (500 mL / 500 mL) solution and with water (500 mL). The filtered cake was dried under vacuum at 30-40°C for 16 hours to obtain the intermediate of formula IV as a grayish-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] Trimethylsilanecarbonitride (153g, 1.54 mole, 0.97g) (15), and triethylamine (4.44 mL, 3.22 g, 0.032 mole, 0.02 equivalents) were placed in 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 equivalent) was added via an addition funnel over 35 minutes while maintaining the reaction temperature between 10 and 20°C. After the addition, the mixture was stirred at 20 to 30°C for 3 hours to obtain intermediate (16) as a concentrated 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 a nitrile compound (16) to an amide to provide 2-(bromomethyl)-3,3,3-trifluoro-2-hydroxypropanamide (17)

[0283] [ka]

[0284]

[0252] Concentrated sulfuric acid (339 mL, 6.37 moles, 4.0 equivalents) is mixed with 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. The intermediate (16) was added via the addition funnel over 50 minutes while maintaining the temperature below 75°C. The reaction mixture was stirred at 75°C for 2 hours and then allowed to cool to room temperature. 11H-NMR indicated completion of the reaction. The reaction mixture was cooled to -15°C and diluted with ethyl acetate (1824 mL) over 45 minutes via an addition funnel while maintaining the temperature between -15 and 5°C (highly exothermic). Water (1520 mL) was slowly added over 1 hour and 20 minutes via an addition funnel at a temperature between -10 and 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 obtain 348 g of intermediate (17) as a pale yellow oil. The oil was dissolved in methanol (1200 mL) and concentrated to obtain 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]

[0253] 7N ammonia solution in methanol (600 mL, 4.28 mole, 10 The equivalent volume was placed in a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. This solution was cooled to 0-5°C. Next, intermediate (17) (102 g, 0.432 mole, 1 equivalent) was added via an addition funnel over 30 minutes at 0-5°C. The reaction mixture was heated to 20-25°C for 1 hour and held for 72 hours. The reaction was deemed 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 equivalent) was added over 2 minutes. Next, the reaction mixture was concentrated under reduced pressure to a volume of 300 mL. 2 L of ethyl acetate was added, and concentration was continued under reduced pressure to a volume of 700 mL to obtain 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 the mixture was stirred for 2 minutes to obtain a two-phase solution. These layers were separated. Reduce the volume of the ethyl acetate layer to 600 mL under reduced pressure. The mixture was concentrated. Next, the ethyl acetate layer was heated to >60°C, and heptane (600 mL) was slowly added between 55 and 60°C. The mixture was cooled to 15-20°C to obtain 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 obtain 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 a 1:1 salt with (D)-malic acid

[0289] [ka]

[0290]

[0254] Amine (14) (105g, 0.608mole, 1.0 equivalent), (D)-L 82 g of malic acid (0.608 mole, 1.0 equivalent) and acetone (1571 mL) were placed in 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 acetone (625 mL) was added. 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 obtain 82.4 g of a 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 intermediate (18A) 1:1(D)-malate with formula IV to provide (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazole-3-yl)-1H-pyrazole-3-yl)pyrimidine-4-yl)amino)methyl)-2-hydroxypropanamide (compound I),

[0292] [ka]

[0293]

[0255] 1:1 salt of intermediate (18A) and (D)-malic acid (74.1g, 0.214 2.5 equivalents of 0.086 moles and 44.8 mL of water were placed in 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. The acetone produced during the reaction was removed by blowing nitrogen. The reaction mixture was cooled to 30-40°C, and formula IV (32 g, 0.086 moles, 1.0 equivalent), DMSO (448 mL), and Hünig base (44.7 mL, 0.257 moles, 3.0 equivalents) were added. The reaction mixture was heated to 90°C and stirred at 90°C for 17 hours. The reaction was completed by HPLC. Next, this mixture was cooled to 60°C. A further amount of Hünig base (104 mL, 0.599 moles, 7.0 equivalents) was added, followed by 224 mL of water at 55-62°C. The reaction mixture was stirred at 55–60°C for 15 minutes to form a seed bed. Water (320 mL) was added via an addition funnel at 55–62°C over 30 minutes, and the resulting slurry was stirred at 55–60°C for 1 hour. The resulting slurry was filtered, and the filtered cake was washed with a pre-mixed methanol and water (320 mL / 320 mL) solution, followed by water (640 mL). The filtered cake was then dried under vacuum at 40°C for 16 hours to obtain compound I as a grayish-white solid (40 g, 92% yield, 99% purity and 98% ee by HPLC). 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]

[0256] Crude compound I, and its polymorphic forms, form A, form B, form D, form The interrelationships between morphology E, F, G, and H are explained in Figure 12. Example 2 Recrystallization of crude (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazole-3-yl)-1H-pyrazole-3-yl)pyrimidine-4-yl)amino)methyl)-2-hydroxypropanamide (crude compound I) into polymorph B.

[0257] Crude compound I (0.68 kg, 1.33 mol) and acetonitrile (2 0.4 L of the reaction mixture was added to a 30 L jacketed reaction vessel. The reaction mixture was stirred at low speed and heated to 70-75°C until most of the solids were dissolved. The solution in the 30 L jacketed reaction vessel was filtered in-line through a gas diffusion tube (coarse frit) into a 100 L jacketed reaction vessel. Next, the reaction mixture was heated to 70-75°C, and water (20.4 L) was added while maintaining the batch temperature >65°C for 1 hour. The material was cooled to 52-62°C and stirred at 52-62°C for a minimum of 1 hour to form a reaction seed source. The resulting slurry was cooled to 0-5°C for a minimum of 4 hours and held at 0-5°C for a minimum of 1 hour. The slurry was filtered, and the filtered cake was washed with a pre-mixed solution of acetonitrile and water (3.4 L / 3.4 L). Next, the filtered cake was dried under vacuum at 90-100°C for a minimum of 30 hours to obtain compound I as polymorph B, as a white solid (0.58 kg, 85% yield). 1 H-NMR (500 MHz, DMSO-d6) δ ppm 9.10 (s, 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-(isoxazole-3-yl)-1H-pyrazole-3-yl)pyrimidine-4-yl)amino)methyl)-2-hydroxypropanamide (compound I) into polymorph E.

[0258] Mechanical stirrers, condensers, dropping funnels, nitrogen inlets and outlets, thermocouples and heating-cooling devices. Crude compound I (67.4 g, 132 mmol) and methanol (2500 mL) were placed in a 5 L four-necked round-bottom flask equipped with the necessary capacity. The mixture was heated to >60°C (e.g., above 70°C) to obtain a solution. The solution was filtered, and the filtrate was heated to >60°C. Water (1500 mL) was added to the mixture while maintaining the temperature at >60°C. The mixture was allowed to cool to room temperature for 1 hour and held at this temperature for 1 hour. The slurry was filtered, and the filtration cake was rinsed with methanol / water (600 mL, 1 / 1 v / v). The filtration cake was collected and dried under vacuum at 80°C for 72 hours to obtain compound I as polymorph E, as a white solid (59.5 g, 88% yield).

[0296] Example 4A Recrystallization of polymorph E of (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazole-3-yl)-1H-pyrazole-3-yl)pyrimidine-4-yl)amino)methyl)-2-hydroxypropanamide to polymorph A

[0259] Mechanical stirrers, condensers, dropping funnels, nitrogen inlets and outlets, thermocouples and heating-cooling devices. Compound I (19.3 g, 38 mmol) as polymorph E and ethyl acetate (600 mL) were placed in a 1 L four-necked round-bottom flask equipped with the necessary capacity. This 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 approximately 150 mL. Heptane (300 mL) was added to the slurry over 20 minutes, and this mixture was concentrated under vacuum to a final volume of approximately 350 mL. The slurry was filtered, and the filtration cake was rinsed with heptane (50 mL). The filtration cake was collected and dried under vacuum at 100°C for 3 hours to obtain polymorph 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-(isoxazole-3-yl)-1H-pyrazole-3-yl)pyrimidine-4-yl)amino)methyl)-2-hydroxypropanamide (compound I) to polymorph A.

[0260] Polymorph A also uses crude compound I as the starting material instead of morph E. It was obtained directly from crude compound I by isolation from ethyl acetate using a method similar to that described in Example 4A.

[0298]

[0261] Polymorph A can also be isolated from DMSO / water after heating to a temperature above 60°C. It was obtained directly from crude compound I.

[0262] Polymorph A also uses crude compound I as a solvent, heptane, (isopropyl acetate) The substance was also isolated by slurring it in any solvent from among IPAC, ethanol, ethyl acetate, or decane at room temperature and stirring for 14–30 hours. This sample was filtered, and the residual solid was analyzed by XRPD.

[0299] Example 5A Recrystallization of polymorph E of (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazole-3-yl)-1H-pyrazole-3-yl)pyrimidine-4-yl)amino)methyl)-2-hydroxypropanamide to polymorph D

[0263] Mechanical stirrers, condensers, dropping funnels, nitrogen inlets and outlets, thermocouples and heating-cooling devices. Compound I (14.0 g, 28 mmol) as polymorph E and n-decane (560 mL) were placed in a 2 L four-necked round-bottom flask equipped with the necessary capacity. This 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 filtered cake was rinsed with heptane (280 mL). The filtered 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 Other methods for obtaining polymorph D

[0264] Polymorph D also includes many other polymorphic forms (excluding other substances), 180 The polymorphs were obtained by heating at °C as summarized in Figure 12 and described below. In some embodiments, compound I was heated to obtain polymorph D. In some embodiments, polymorph F was heated to obtain polymorph D. In some embodiments, polymorph B was heated to obtain polymorph D. In some embodiments, polymorph E was heated to obtain polymorph D. In some embodiments, polymorph G was heated to obtain polymorph D. In some embodiments, polymorph H was heated to obtain polymorph D.

[0301]

[0265] In a 100 mL round-bottom flask, combine compound I, morph F, morph B, morph E, and morph G. 5g of compound H was added. This solid was heated to 180°C and held at 180°C for 5 minutes. All of the compound I solids slowly melted and re-solidified to obtain a solid. This solid was ground using a mortar and pestle to obtain approximately 4.8g of powder. HPLC showed a purity of 99.8%. XRPD showed that it was morph D. DSC showed a sharp peak at 196°C.

[0302] Example 6 Preparation of morphology F

[0266] A new polymorph F was obtained when morph A was heated at 160°C without the presence of other substances. This form was considered unstable in rt and was not isolated in pure form.

[0303] Example 7 Recrystallization of crude (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazole-3-yl)-1H-pyrazole-3-yl)pyrimidine-4-yl)amino)methyl)-2-hydroxypropanamide (compound I) into polymorph G.

[0267] Put crude compound I (2.0g) and acetone into a flask equipped with a stirrer. 15.0 mL was added. This mixture was stirred at room temperature (22-25°C) for 2 hours. Next, the resulting slurry was filtered. The filtered cake was rinsed with acetone (5 mL). The cells were collected and dried under vacuum at 40°C for 15 hours to obtain polymorph G as a white solid.

[0304]

[0268] Polymorph G is also obtained by acetone, as described below. The mixture was then stirred at room temperature, followed by filtration and drying under vacuum at 30-40°C to obtain the result.

[0305] Example 8 Recrystallization of crude (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazole-3-yl)-1H-pyrazole-3-yl)pyrimidine-4-yl)amino)methyl)-2-hydroxypropanamide to polymorph H

[0269] Put crude compound I (2.0g) and acetone into a flask equipped with a stirrer. 15.0 mL was added. The mixture was heated to 45-50°C and stirred until a solution was formed. Next, this hot solution was filtered and slowly cooled to room temperature while stirring. The mixture was stirred for a further 15 hours, and the resulting slurry was then filtered. The filtered cake was rinsed with acetone (5 mL). The filtered cake was collected and dried under vacuum at 40°C for 15 hours to obtain polymorph H as a white solid.

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

[0307] Method: Using 32 scans and resolution 4, 525-4000 cm² -1 Over the wavenumber range, the analysis was performed using attenuated total internal reflection with the background obtained before each measurement. Example 10 Preparation of HCl salts Protocol 1: 50.5 mg of compound I as polymorph D and 98.2 mL of 1 M HCl were suspended in 2 mL of i-PrOH. This suspension was stirred under temperature cycles between 20°C and 40°C. A heating rate of 40°C / hour and a cooling rate of 5°C / hour were used. After 8 days, the suspension was filtered and the solid was dried under vacuum (approximately 5 mbar, 1 hour).

[0308] Protocol 2: 299.9 mg of compound I as polymorph D and a small amount of the hydrochloride salt obtained above (from Protocol 1) 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 / hour and a cooling rate of 5°C / hour were used. After 6 days, the suspension was filtered, and the solid was dried under vacuum (approximately 5 mbar, 1 hour).

[0309] Example 11 Characterization of HCl salts The HCl salt of compound I is characterized by the XRPD pattern shown in Figure 11.

[0310] The HCl salt of compound I was characterized by elemental analysis, and measured and calculated values ​​were obtained for the 1:1 ratio (form D:HCl) shown in the table below:

[0311] [Table 2]

[0312]

[0270] The terms used herein are intended solely to describe specific embodiments. This invention is intended to be a general overview and is not intended to limit the scope of the invention. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context makes it clear that they are not. 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 "contains" and "containing"), and any other grammatical variations thereof, will be further understood to be open-ended linking verbs. As a result, a method or apparatus that “comprises,” “has,” “includes,” or “contains” one or more steps or elements possesses, but is not limited to possessing only, these one or more steps or elements. Similarly, an element of a step or apparatus of a method that “comprises,” “has,” “includes,” or “contains” one or more features possesses, but is not limited to possessing only, these one or more features. Furthermore, an apparatus or structure configured in a particular manner may be configured in at least such manner, but may also be configured in a manner not included.

[0313]

[0271] When used herein, the terms "comprising" and "having" "(has)", "including", "containing", and other grammatical variations thereof encompass the terms "consisting of" and "consisting essentially of".

[0314]

[0272] The phrase “essentially from” or its grammatical variations are used herein when These are used to define the stated features, integers, steps, or components, but do not preclude the addition of one or more of these further features, integers, steps, components, or groups, provided that such further features, integers, steps, components, or groups do not substantially alter the basic and novel features of the composition, apparatus, or method described in the claim.

[0315]

[0273] All publications referenced herein are described in detail in each individual publication, It is incorporated herein by reference as if it were explicitly stated, as if it were individually stated, that it is incorporated herein by reference.

[0316]

[0274] Subject matter incorporated by reference is not any claim unless otherwise explicitly indicated. This should not be considered a replacement for the limitation.

[0275] Where one or more scopes are indicated throughout this specification, each scope is: The purpose is to provide information in a concise format, and such format is understood to encompass each discrete point within its range, as if the discrete points were fully explicitly stated herein.

[0317]

[0276] Several aspects and embodiments of the present invention are described and shown herein. However, alternative aspects and embodiments may be modified by those skilled in the art to achieve the same objectives. Accordingly, the scope of this disclosure and the appended claims is intended to encompass all such further and alternative aspects and embodiments so as to fall within the true spirit and scope of the invention. This specification includes the disclosure of the following inventions. [1] [ka] The crystalline solid form. [2] The crystalline solid form described in [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 described in [1], which is a hydrochloride salt. [4] Form E, a crystalline free form of compound I described in [2], characterized by one or more peaks in the XRPD spectrum selected from °2θ of 7.4, 18.8–19.3, 21.1, 24.8 and 25.5. [5] Form E, a crystalline free form of compound I described in [4], characterized by one or more peaks in the 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 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, which is the crystalline free form of compound I described in [2], is characterized by the IR spectrum showing the maximum peak value in [2]. [9] 1515cm -1 Form E, which is the crystalline free form of compound I described in [2], is characterized by the IR spectrum showing the maximum peak value in [2].

[10] 1690 and 1515 cm -1 In the IR spectrum showing a band maximum, Form E is a more characterized crystalline free form of compound I described in [2].

[11] Form A, a crystalline free form of compound I described in [2], characterized by one or more peaks in the 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 described in

[11] , characterized by one or more peaks in the 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] Form A, a crystalline free form of compound I described in

[12] , characterized by one or more peaks in the XRPD spectrum selected from °2θ of 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, which is the crystalline free form of compound I described in [2], characterized by one or more peaks in the XRPD spectrum selected from °2θ of 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).

[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, which is the crystalline free form of compound I described in [2], is characterized by an IR spectrum showing a band maximum in [2].

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

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

[21] Form D, a crystalline free form of compound I described in

[20] , characterized by one or more peaks in the 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 described in

[21] , characterized by one or more peaks in the 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, the crystalline free form of compound I described in [2], characterized by one or more peaks in the XRPD spectrum selected from °2θ of 4.7 (relative intensity of 97.11%), 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], is characterized by an IR spectrum showing a band maximum in [2].

[28] 1639cm -1 Characterized by the IR spectrum showing a band maximum in [location] Form D is the crystalline free form of compound I described in [2].

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

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

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

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

[33] Form B, a crystalline free form of compound I described in

[32] , characterized by one or more peaks in the 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 described in

[33] , characterized by one or more peaks in the XRPD spectrum selected from °2θ of 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 described in [2], characterized by one or more peaks in the XRPD spectrum selected from °2θ of 7.0 (relative intensity of 44.44%), 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, which is the crystalline free form of compound I described in [2], is characterized by the IR spectrum showing the maximum peak value in [2].

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

[41] Form F, a crystalline free form of compound I described in [2], characterized by one or more peaks in the XRPD spectrum selected from °2θ of 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 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 the XRPD spectrum selected from °2θ of 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 described in [2], characterized by an XRPD spectrum substantially similar to that shown in Figure 8.

[45] The compound described in [2] is characterized by one or more peaks in the 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 is 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 the 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] ​​Characterized by a melting point of 256°C, the hydrochloride salt described in [3].

[49] Characterized by its water solubility of 0.5 mg / mL at pH 1.4, the hydrochloride salt described in [3].

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

[51] A method for preparing form E, which is a crystalline free form of compound I, a. The crude compound I is dissolved in MeOH at a minimum temperature of 60°C to obtain a solution. b. The step of filtering the solution and heating the filtrate to a minimum of 60°C; c. Add water to the filtrate to form an aqueous solution, and cool the aqueous solution to room temperature (rt), d. The step of filtering the aqueous solution and drying the filtrate under vacuum. A method that includes this.

[52] A method for preparing form A, which is the crystalline free form of compound I, a. The step of dissolving form E, which is a crystalline free form, in ethyl acetate at a minimum temperature of 70°C to obtain a solution, b. Filter the solution and stir the resulting filtrate at 20-25°C for 16 hours to form a slurry. c. The slurry is concentrated under vacuum, filtered, and dried. A method that includes this.

[53] A method for preparing form A, which is a crystalline free form of compound I, a. The crude compound I is dissolved in ethyl acetate at a minimum temperature of 70°C to obtain a solution. b. Filter the solution and stir the resulting filtrate at 20-25°C for 16 hours to form a slurry. c. The slurry is concentrated under vacuum, filtered, and dried. A method that includes this.

[54] A method for preparing form A, which is the crystalline free form of compound I, a. The crude compound I in DMSO is heated to a minimum of 60°C to form a solution. b. The step of adding water to form a slurry, c. The slurry is filtered to isolate morphology A, which is the crystalline free form. A method that includes this.

[55] A method for preparing form A, which is the crystalline free form of compound I, a. A step of slurring crude compound I in a solvent selected from heptane, IPAC, ethanol, ethyl acetate, or decane or a mixture thereof, b. A step of stirring at rt for 14-30 hours, c. The slurry is filtered and dried under vacuum. A method that includes this.

[56] A method for preparing form D, which is a crystalline free form of compound I, a. A step of mixing form E, which is a crystalline free form, with n-decane at 145-155°C to obtain a slurry, b. A step of cooling the slurry to 20-30°C for 1 hour, c. The slurry is filtered and dried under vacuum. A method that includes this.

[57] A method for preparing form D, which is a crystalline free form of compound I, comprising the step of heating one of the crystalline free forms F, B, E, G, or H, or a mixture thereof, at 180°C, without containing any other substances.

[58] A method for preparing form B, which is a crystalline free form of compound I, a. A step of mixing crude compound I with acetonitrile to form a solution, b. The solution is filtered to form a filtrate, and the filtrate is heated to 70-75°C. c. The step of adding water to the heated filtrate, d. The step of cooling to 52~62℃ to form a slurry, e. The step of further cooling the slurry to 0-5°C for at least 4 hours, f. The cooled slurry is filtered, and the resulting filtrate is dried under vacuum. A method that includes this.

[59] A method for preparing form F, which is a crystalline free form of compound I, comprising the step of heating form A, which is free of other substances, at 160°C.

[60] A method for preparing morphology G, which is the crystalline free form of compound I, a. Mixing crude compound I in acetone at room temperature for about 2 hours to form a slurry, b. The slurry is filtered and dried under vacuum. A method that includes this.

[61] A method for preparing morphology G, which is the crystalline free form of compound I, a. The step of stirring form H in acetone at room temperature for about 2 hours to form a slurry; b. The slurry is filtered and dried under vacuum. A method that includes this.

[62] A method for preparing form H, which is the crystalline free form of compound I, a. A step of mixing crude compound I with acetone at 45-50°C to obtain a solution, b. The step of filtering and cooling to form a slurry, c. The slurry is stirred, filtered, and dried under vacuum. A method that includes this. A pharmaceutical composition comprising the crystalline free form of the compound described in

[63] [2] or the hydrochloride salt described in [3], and at least one pharmaceutically acceptable excipient or carrier. A pharmaceutical dosage form comprising the crystalline solid form of compound I described in any of

[64] [1], [2], or [3].

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

[50] , or a pharmaceutical composition described in

[63] , or a pharmaceutical dosage form described in

[64] , to the subject requiring treatment, wherein the disease, health condition or disorder is treated as follows: 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 cardiac disease, stroke, cerebral ischemia, or renal failure; resistant hypertension; diabetic hypertension; essential hypertension; secondary hypertension; gestational hypertension; pre-eclampsia; 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 valvular malformations, mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, tricuspid stenosis, tricuspid regurgitation, pulmonary stenosis, pulmonary regurgitation, compound valvular malformations; diabetic heart failure; alcoholic cardiomyopathy or conservative hypertrophic cardiomyopathy; diastolic HF, systolic HF; pre-existing chronic HF in the acute phase (exacerbated HF); diastolic or systolic dysfunction; coronary insufficiency; arrhythmias; decreased 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-III) Atrioventricular block, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation Ventricular flutter, ventricular tachyarrhythmia, polymorphic ventricular tachycardia, atrial and ventricular premature contractions, AV junction premature contractions, sick sinus syndrome, syncope, AV nodal reentrant tachycardia; Wolff-Parkinson-White syndrome or acute coronary syndrome; Boxer cardiomyopathy; ventricular premature contractions; cardiomyopathy; cancer-induced cardiomyopathy; chemotherapy-induced cardiotoxicity; • Thromboembolic disorders and ischemia; myocardial ischemia; infarction; myocardial infarction; heart attack; myocardial insufficiency; endothelial dysfunction; stroke; transient ischemic attack (TIA); thromboangiitis obliterans; stable or unstable angina; coronary or peripheral artery spasm; variant angina; Prinzmetal's angina; cardiac hypertrophy; pre-eclampsia; thrombosis; ischemia-reperfusion injury; ischemia-reperfusion associated with organ transplantation; lung transplant, pulmonary transplant, heart transplant, venous graft failure; ischemia-reperfusion associated with conserving blood substituents in trauma patients; Peripheral vascular disease; peripheral artery disease; peripheral arterial occlusive disease; hypertonia; Raynaud's syndrome or phenomenon (primary and secondary); Raynaud's disease; severe lower limb ischemia; peripheral embolism; intermittent claudication; vaso-occlusive crisis; muscular dystrophy, Duchenne muscular dystrophy, Becker muscular dystrophy; microcirculatory abnormalities; control of vascular leakage or osmosis; lumbar spinal stenosis; thromboangiitis obliterans; thromboangiitis; peripheral perfusion impairment; arterial and venous thrombosis; microalbuminuria; peripheral and autonomic neuropathy; diabetic neuropathy pain; diabetic microangiopathy; hepatic vaso-occlusive disorder; vaso-occlusive crisis in sickle cell anemia; hypertensive crisis; • Edema; renal edema caused by heart failure; Alzheimer's disease; Parkinson's disease; vascular dementia; vascular cognitive impairment; cerebral vasospasm; congenital myasthenia gravis; subarachnoid hemorrhage; traumatic brain injury; traumatic brain injury; improvement of perception, concentration, learning or memory performance after cognitive impairment, such as those occurring in mild cognitive impairment, age-related learning and memory impairment, age-related memory loss, vascular dementia, head injury, stroke, post-stroke dementia, post-traumatic head injury, general impairment of concentration, and impairment of concentration in children with learning and memory problems; Lewy body dementia; 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 high-end foods and addictive drugs; controlled cerebral perfusion; migraine; prevention and control of outcomes of stroke (apoplexia cerebri); prevention and control of outcomes 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 herpes zoster; 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 localized thrombosis and right ventricular hypertrophy; pulmonary hypertonia; primary pulmonary hypertension; secondary pulmonary hypertension; familial pulmonary hypertension; sporadic 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 arteropathy; multifactorial pulmonary arteropathy; cystic fibrosis; bronchoconstriction or pulmonary bronchoconstriction; acute respiratory syndrome; pulmonary fibrosis, lung transplant; asthmatic diseases; 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 dysplasia Commonly occurring pulmonary veno-occlusive disease, pulmonary vasculitis, collagen vascular disease, congenital heart disease, elevated pulmonary venous pressure, interstitial lung disease, sleep-disordered breathing, sleep apnea, impaired alveolar ventilation, chronic exposure to high altitudes, neonatal lung disease, alveolar capillary dysplasia, sickle cell anemia, 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 disease, lupus, lupus nephritis, schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease, asthma, emphysema, chronic bronchitis, pulmonary capillary angiomatosis, histiocytosis X, lymphangiomatosis, compressed pulmonary vessels; compressed pulmonary vessels caused by adenopathy, tumors or fibrotic mediastinitis; • Atherosclerotic diseases or conditions: Atherosclerosis; atherosclerosis associated with endothelial damage, platelet and monocyte adhesion and aggregation, smooth muscle proliferation or migration; restenosis; restenosis that develops after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), transcatheter coronary angioplasty (PTCA), heart transplantation, bypass surgery, or inflammatory process; • Damage to microvessels and macrovessels (vasculitis); increased levels of fibrinogen and low density of DLD; increased concentrations of plasminogen activator inhibitor 1 (PA-1); Metabolic syndrome; metabolic diseases or diseases associated with metabolic syndrome: obesity; excess subcutaneous fat; excess body fat accumulation; diabetes mellitus; 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, hypolipoprotein anemia, sitosterolemia, fatty liver disease, alcoholic fatty liver disease (AFLD), non-alcoholic fatty liver disease (NAFLD), hepatitis; pre-eclampsia; progression of polynephropathy; hepatic steatosis or abnormal lipid accumulation in the liver, non-alcoholic steatohepatitis (NASH); fatty degeneration of the heart, kidneys or muscles; alpha-betalipoproteinemia; sitosterolemia; xanthomatous disease; Tangier disease; hyperammonemia and related diseases; hepatic encephalopathy; other toxic encephalopathy; Reye's syndrome; • Disorders of sexual, gynecological, and urological conditions: erectile dysfunction; impotence; premature ejaculation; female sexual dysfunction; female sexual stimulation dysfunction; hypofunctional sexual stimulation disorder; vaginal atrophy; dyspareunia; atrophic vaginitis; benign prostatic hyperplasia (BPH), prostatic hyperplasia, prostatic enlargement; subvesical urethral 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 genitourinary system in men and women; Chronic kidney disease; acute and chronic renal insufficiency; acute and chronic renal failure; lupus nephritis; underlying or related kidney diseases: hypoperfusion, hypotension during dialysis, obstructive urinary tract disease, glomerulosis, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial damage, renal disorders, primary and congenital kidney diseases, nephritis; diseases characterized by abnormally decreased creatinine and / or fluid 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 glutamyl synthase activity; diseases characterized by altered urine osmolality or urine volume; diseases characterized by increased microalbuminuria; diseases characterized by overt albuminuria; diseases characterized by glomerular and arteriole lesions, tubular dilation, hyperphosphatemia and / or dialysis requirements; complications of renal failure; pulmonary edema-related renal failure; HF-related renal failure; uremia or anemia-related renal failure; electrolyte abnormalities (hercaremia, hyponatremia); interference with bone and carbohydrate metabolism; acute kidney injury; • Eye diseases or disorders such as glaucoma, retinopathy, and diabetic retinopathy A method to be selected from.

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

[50] , or a pharmaceutical composition described in

[63] , or a pharmaceutical dosage form described in

[64] , to the subject requiring treatment, wherein the disease, health condition or disorder is treated as follows: Myocarditis; chronic myocarditis; acute myocarditis; viral myocarditis; Vasculitis; pancreatitis; peritonitis; rheumatic 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; Methods selected from inflammatory eye diseases, blepharitis, dry eye syndrome, and Sjögren's syndrome; ocular fibrosis.

[67] A method for treating a disease, health condition or disorder in a subject requiring treatment, comprising administering to the subject requiring treatment 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 described in

[63] , a pharmaceutical composition thereof, or a pharmaceutical dosage form described in

[64] , wherein the disease, health condition or disorder is selected from: healing of diabetic wounds or ulcers; improvement of microvascular perfusion; improvement of microvascular perfusion to counteract inflammatory responses following injury or in perioperative care; anal fissures; diabetic ulcers; diabetic foot ulcers; bone healing mechanisms; osteoclastic bone resorption and reconstruction; and neoostogenesis.

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

[50] , or a pharmaceutical composition described in

[63] , or a pharmaceutical dosage form described in

[64] , to the subject requiring treatment, wherein the disease, health condition or disorder is: • Urogenital or renal disorders: diabetic nephropathy; renal fibrosis and renal failure due to chronic kidney disease or renal insufficiency; renal fibrosis and renal failure due to accumulation / deposition and tissue damage; nephrosclerosis; progressive sclerosis; glomerulonephritis; focal segmental glomerulosclerosis; nephrotic syndrome; benign prostatic hyperplasia; renal fibrosis; interstitial renal fibrosis; • Pulmonary system disorders: pulmonary fibrosis; idiopathic pulmonary fibrosis; cystic fibrosis; progressive mass fibrosis; progressive mass fibrosis affecting the lungs; • Cardiac disorders: Endocardial fibrosis; old myocardial infarction; atrial fibrosis; interstitial fibrosis; cardiac remodeling and fibrosis; cardiac hypertrophy; • Disorders of the liver and related organs: hepatic sclerosis or cirrhosis; cirrhosis associated with chronic liver disease; hepatic fibrosis; hepatic stellate cell activation; NASH; hepatic fibrous collagen and total collagen accumulation; necrotizing inflammatory and / or immunological liver diseases; primary biliary cirrhosis; primary sclerosing cholangitis; other cholestatic liver diseases: associated with granulomatous liver disease, hepatic malignancies, intrahepatic cholestasis during pregnancy, hepatitis, sepsis, drug or toxin, graft-versus-host disease, post-liver transplant, common bile duct stones, cholangiocarcinoma, pancreatic cancer, Militzi syndrome, AIDS cholangitis or parasitic infections; schistosomiasis; hepatocellular carcinoma; • Digestive system diseases or disorders: Crohn's disease; ulcerative colitis; gastrointestinal sclerosis; achalasia; • Diseases of the skin or eyes: nephrogenic fibrosis; proliferative vitreoretinopathy; diabetic retinopathy; ocular fibrosis; • Fibrous localized or skin disorders or conditions; dermal fibrosis; scleroderma, dermatofibrosis; morphea; hypertrophic scars; nevi; keloids; sarcoids; granulomas; • Diseases affecting the nervous system: Amyotrophic lateral sclerosis (ALS); hippocampal sclerosis; multiple sclerosis (MS); focal segmental sclerosis; primary lateral sclerosis; Bone diseases; osteosclerosis; Otosclerosis; other hearing disorders or impairments; hearing loss, partial or total hearing loss; partial or total hearing loss; tinnitus; noise-induced hearing loss; • Other diseases including autoimmune, inflammatory, or fibrotic diseases: scleroderma; localized scleroderma or limited scleroderma; mediastinal fibrosis; fibrotic mediastinitis; myelofibrosis; retroperitoneal fibrosis; arthral fibrosis; Peyronie's disease; Dupuytren's contracture; lichen sclerosing; several forms of adhesive capsulitis; atherosclerotic A method 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, health condition or disorder in a subject requiring treatment, comprising administering to the subject requiring treatment a therapeutically effective amount of a crystalline solid form of compound I described in any of [1] to

[50] , or a pharmaceutical composition described in

[63] , or a pharmaceutical dosage form described in

[64] , wherein the disease, health condition or disorder is a specific type of cancer; sickle cell disease; sickle cell anemia; cancer metastasis; osteoporosis; gastroparesis; functional dyspepsia; diabetic complications; alopecia or hair loss; endothelial dysfunction Methods selected from: diseases related to harm; neuropathy associated with reduced nitric oxide production; arginosuccinic aciduria; neuromuscular diseases; Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), limb-girdle muscular dystrophy, distal myopathy, type I and type II myotonic dystrophy, facioscapulofibular muscular dystrophy, autosomal and X-linked Emery-Dreyfus muscular dystrophy, oculopharyngeal muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy (SMA).

[70] A method for treating or preventing a disease, health condition or disorder in a subject requiring treatment or prevention, comprising administering to the subject, either alone or in combination, a therapeutically effective amount of a crystalline solid form of compound I described in any of [1] to

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

Claims

1. Compound I 【Chemistry 1】 It is a crystalline free form of morphological B crystal: The morphological B crystal is characterized by peaks in the XRPD spectrum (2θ) including 8.8, 16.4, 17.2, 19.1, 20.1, and 21.8°2θ.

2. A morphological B crystal of compound I according to claim 1, further characterized by peaks in the XRPD spectrum (2θ) including 8.8, 10.6, 12.6–13.0, 14.6, 16.4, 17.2, 19.1, 20.1, 21.8, 24.5, 25.3, 28.9, 29.8 and 30.5°2θ.

3. The morphological B crystal is 1200 cm －１ A morphological B crystal of compound I according to claim 1, further characterized by an IR spectrum showing a peak maximum value in [location].

4. A method for preparing a morphological B crystal of compound I according to any one of claims 1 to 3, a. A step of mixing crude compound I with acetonitrile to form a solution, b. The step of filtering the solution to form a filtrate and heating the filtrate to 70-75°C, c. The step of adding water to the heated filtrate, d. A step of cooling to 52-62°C to form a slurry, e. The step of further cooling the slurry to 0-5°C for at least 4 hours, f. The cooled slurry is filtered, and the resulting filtrate is dried under vacuum. A method that includes this.

5. A pharmaceutical composition comprising a morphological B crystal according to any one of claims 1 to 3, and at least one pharmaceutically acceptable excipient or carrier.

6. A pharmaceutical composition for use in the treatment of a disease, health condition, or disorder in a subject requiring treatment of the disease, health condition, or disorder, wherein the disease, health condition, or disorder is glaucoma, retinopathy, diabetic retinopathy, 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 malformations, mitral stenosis, mitral regurgitation, aortic valve Stenosis, aortic valve regurgitation, tricuspid valve stenosis, tricuspid valve regurgitation, pulmonary valve stenosis, pulmonary valve regurgitation, compound cardiac valve malformations; diabetic heart failure; alcoholic cardiomyopathy or conservative hypertrophic cardiomyopathy; diastolic HF, systolic HF; pre-existing chronic HF in the acute phase (exacerbated HF); diastolic or systolic dysfunction; coronary insufficiency; arrhythmias; decreased 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-III) Atrioventricular block, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, polymorphic ventricular tachycardia, atrial and ventricular premature contractions, AV junction premature contractions, sick sinus syndrome, syncope, AV nodal reentrant tachycardia; Wolff-Parkinson-White syndrome or acute coronary syndrome; Boxer cardiomyopathy; ventricular premature contractions; cardiomyopathy; cancer-induced cardiomyopathy; chemotherapy-induced cardiotoxicity; Pulmonary / Respiratory Conditions: Pulmonary hypertension (PH); pulmonary arterial hypertension (PAH) and associated pulmonary vascular remodeling; vascular remodeling in the form of localized thrombosis and right ventricular hypertrophy; pulmonary hypertonia; primary pulmonary hypertension; secondary pulmonary hypertension; familial pulmonary hypertension; sporadic 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 arteropathy; multifactorial pulmonary arteropathy; cystic fibrosis; bronchoconstriction or pulmonary bronchoconstriction; acute respiratory syndrome; pulmonary fibrosis, lung transplant; asthmatic diseases; Chronic kidney disease; acute and chronic renal insufficiency; acute and chronic renal failure; lupus nephritis; underlying or related kidney diseases: hypoperfusion, hypotension during dialysis, obstructive urinary tract disease, glomerulosis, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial damage, renal disorders, primary and congenital kidney diseases, nephritis; diseases characterized by abnormally decreased creatinine and / or fluid 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 synthase; diseases characterized by altered urine osmolality or urine volume; diseases characterized by increased microalbuminuria, diseases characterized by overt albuminuria; diseases characterized by lesions of the glomeruli and arterioles, tubular dilation, hyperphosphatemia and / or the need for dialysis; complications of renal insufficiency; pulmonary edema Renal dysfunction related to enema; HF-related renal dysfunction; uremia or anemia-related renal dysfunction; electrolyte abnormalities (hercarenia, hyponatremia); impaired bone and carbohydrate metabolism; acute kidney injury; Cardiac disease, cerebrovascular disease, renal, hepatic and related organs, or pulmonary vascular disease, as well as peripheral artery disease. A pharmaceutical composition according to claim 5, selected from the above.

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