Solid form of SGC activator

Abstract

Solid forms of activators of soluble guanylate cyclase (sGC) are disclosed. The invention also relates to methods for making these solid forms, pharmaceutical compositions containing these solid forms, and their use in medical conditions that respond to treatment with activators of sGC.

Description

[Technical Field]

[0001] The present invention relates to solid forms of activators of soluble guanylate cyclase (sGC). The invention also relates to methods for making these solid forms, pharmaceutical compositions containing these solid forms, and their use in medical conditions that respond to treatment with activators of sGC. [Background technology]

[0002] Compound 1 is an sGC activator and has the structure shown below. [ka] 1. Compound 1 is useful for treating some kidney and liver-related disorders, including, for example, chronic kidney disease, diabetic kidney disease, nonalcoholic steatohepatitis (NASH), cirrhosis, and portal hypertension. Other diseases that can be treated with 1 are described, for example, in International Publication Nos. 2014 / 039434 and 2020 / 011804. The preparation of 1 is described in International Publication No. 2014 / 039434 (see Compound 114). However, the process described in International Publication No. 2014 / 039434 does not describe any specific solid form of Compound 1. Therefore, there is a need for a solid form of Compound 1 that has advantageous pharmaceutical properties, such as processability, stability, and solubility. Summary of the Invention

[0003] The present invention relates to novel solid forms of Compound 1 (collectively referred to herein as "the compounds of the invention"). The present invention also relates to methods of making the compounds of the present invention and their use as activators of sGC. In a further aspect, the present invention relates to pharmaceutical compositions comprising a compound of the present invention, optionally together with one or more inert carriers and / or diluents. A further aspect of the present invention relates to a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of kidney and liver disorders. Yet another aspect of the present invention relates to a compound of the present invention or a pharmaceutical composition comprising said compound for use in the prevention and / or treatment of a disease or condition that can be affected by the activation of sGC, such as chronic kidney disease, diabetic kidney disease, non-alcoholic steatohepatitis (NASH), liver cirrhosis, portal hypertension, and systemic sclerosis (scleroderma). The use includes the manufacture of a medicament for treating the corresponding disease or disorder described herein.

[0004] In one embodiment, the present invention relates to any of the crystalline forms of Compound 1 set forth in Table 1 ("Compounds of the Invention"). [Table 1] One embodiment of the present invention relates to crystalline Form I (“Form I”) of Compound 1. Form I is anhydrous and ansolvate-free.

[0005] In another embodiment, the present invention relates to crystalline Form III (“Form III”) of Compound 1. Form III is a 1:1 adduct with water (“monohydrate”). In another embodiment, the present invention relates to crystalline Form IV (“Form IV”) of Compound 1. Form IV is a 1:1:1 adduct of acetonitrile and water. In another embodiment, the present invention relates to crystalline Form V (“Form V”) of Compound 1. Form V is a 1:1 adduct with water (monohydrate). [Brief explanation of the drawings]

[0006] [Figure 1A] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of Form I of Compound 1. [Figure 1B] FIG. 1 shows the 13CssNMR spectrum of Form I of Compound 1. [Figure 1C] FIG. 1 shows the thermal analysis profile of Form I of Compound 1 determined by DSC measurements. [Figure 1D] FIG. 1 shows thermal analysis of Form I of Compound 1 as determined by TGA. [Figure 1E] FIG. 1 shows the Raman spectrum of Form I of Compound 1. [Figure 2A] FIG. 1 shows the XRPD pattern of Form III of Compound 1. [Figure 2B] FIG. 1 shows the 13CssNMR spectrum of Form III of Compound 1. [Figure 2C] FIG. 1 shows the thermal analysis profile of Form III of Compound 1 determined by DSC measurements. [Figure 2D] FIG. 1 shows the thermal analysis profile of Form III of Compound 1 as determined by TGA. [Figure 2E] FIG. 1 shows the Raman spectrum of Form III of Compound 1. [Figure 3A] FIG. 1 shows the XRPD pattern of Form IV of Compound 1. [Figure 3B] 1 shows the 13CssNMR spectrum of Form IV of Compound 1. The asterisk indicates a signal from an impurity in Form I. [Figure 3C] FIG. 1 shows the thermal analysis profile of Form IV of Compound 1 as determined by DSC measurements. [Figure 3D] FIG. 1 shows the thermal analysis profile of Form IV of Compound 1 as determined by TGA. [Figure 4A] FIG. 1 shows the XRPD pattern of Form V of Compound 1. [Figure 4B] FIG. 1 shows the 13CssNMR spectrum of Form V of Compound 1. [Figure 4C] FIG. 1 shows the thermal analysis profile of Form V of Compound 1 determined by DSC measurements. [Figure 4D] FIG. 1 shows the thermal analysis profile of Form V of Compound 1 as determined by TGA. [Figure 5] FIG. 1 shows the XRPD pattern of the amorphous form of Compound 1. DETAILED DESCRIPTION OF THE INVENTION

[0007] Abbreviation: [Table 2] As noted above, the present invention relates to crystalline forms of Compound 1. More particularly, the present invention relates to the crystalline forms of Compound 1 set forth in Table 1. The present invention also relates to compositions comprising the crystalline compounds of the present invention, and the use of such compounds and compositions to treat diseases or disorders that respond to treatment with an activator of sGC.

[0008] In some embodiments, the present invention relates to mixtures of at least two of the crystalline forms of Compound 1 set forth in Table 1, compositions comprising such mixtures of crystalline forms, and uses of such crystalline forms and mixtures for treating diseases or disorders that respond to treatment with an activator of sGC. The preparation of Compound 1 is described in WO 2014 / 039434, but this publication does not mention any crystalline forms of Compound 1, any methods for preparing crystalline forms of Compound 1, or any of the properties of the crystalline forms of Compound 1 described herein. As described herein, Compound 1 prepared according to the methods described in WO 2014 / 039434 is amorphous (see Figure 5).

[0009] Forms I, III, and V have particularly advantageous properties (e.g., improved stability and reproducibility) compared to the amorphous form of Compound 1. Improvements over the amorphous form include, for example, reduced hygroscopicity, reduced tendency to convert to different solid forms, improved flow rate, increased bulk density, and increased resistance to mechanical abrasion. For example, the amorphous form of Compound 1 is more hygroscopic than the anhydrate form (Form I) and the monohydrate forms (Forms III, V), and is unstable at high RH, converting to Form III. Form IV is useful for the treatment of the diseases or disorders described herein, as well as being useful as a precursor for preparing Form V. In one embodiment, the present invention relates to Form I that is substantially free of any other forms of Compound 1, including the amorphous forms of the present invention and crystalline Forms III, IV, and V. As used herein, "substantially free" means that the solid compound contains at least about 75% Form I of Compound 1, based on the total molar amount of any other forms of Compound 1. The amount of any form of Compound 1 that may be present in Form I can be determined, for example, using the methods described herein.

[0010] In another embodiment, the present invention relates to Form III that is substantially free of any other forms of Compound 1, including the amorphous forms of the present invention and crystalline Forms I, IV, and V. As used herein, "substantially free" means that the solid compound contains at least about 75% Form III of Compound 1, based on the total molar amount of any other forms of Compound 1. The amount of any form of Compound 1 that may be present in Form III can be determined, for example, using the methods described herein. In another embodiment, the present invention relates to Form V that is substantially free of any other forms of Compound 1, including the amorphous form of the present invention and crystalline Forms I, III, and IV. As used herein, "substantially free" means that the solid compound contains at least about 75% Form V of Compound 1, based on the total molar amount of any other forms of Compound 1. The amount of any form of Compound 1 that may be present in Form V can be determined, for example, using the methods described herein.

[0011] Characterization The compounds of the invention can be characterized by the methods described below: Methods for preparing the compounds of the invention are described in the experimental section. X-ray powder diffraction (XRPD) XSPR was performed using a Bruker AXS X-ray powder diffractometer model D8 Advance equipped with a graphite monochromator and scintillation detector, using CuKa radiation (1.54 A) in parafocus mode. Each pattern was obtained by scanning over the range of 2° to 35° 2T with a step size of 0.05° 2T and a step time of 4 seconds per step. Exemplary XRPD spectra of compounds of the invention are shown in Figures 1A, 2A, 3A, and 4A. An exemplary XRPD spectrum of the amorphous form of Compound 1 is shown in Figure 5. X-ray powder diffraction (XRPD) characteristics of compounds of the invention reported herein have a standard deviation of ±0.2 2θ. Differential scanning calorimetry (DSC) DSC analysis is performed using a differential scanning calorimeter (Q2000, TA instruments, New Castle, Del.) using this general procedure: Approximately 5 mg of powder was weighed into a crimped aluminum pan with a pinhole. Using the Q2000 DSC, the sample is heated from room temperature to 300° C. at 10° C. / min. Exemplary DSC traces of compounds of the invention are shown in FIGS. 1C, 2C, 3C, and 4C. The results are reported below.

[0012] Thermogravimetric analysis (TGA) TGA analysis is performed using a TA TGA 2500, TA Instruments, New Castle, Del., using the following general procedure: Approximately 5 mg of powder is weighed into a platinum pan. The sample is then heated from room temperature to 300° C. at 10° C. / min using the TA TGA 2500. Exemplary TGA traces of compounds of the invention are shown in FIGS. 1D, 2D, 3D, and 4D. The results are reported below. Dynamic Vapor Sorption (DVS) Moisture sorption isotherms are determined using a dynamic vapor sorption system (Advantage 1, DVS, London, UK; DVS Intrinsic Plus, Surface Measurement Systems, Allentown, PA). Approximately 5–10 mg of solid is weighed into a tared aluminum pan. Samples are subjected to 0–90% RH in steps of 510% at 25°C. Equilibration criteria are a dm / dt of 0.002% over 5 min or 360 min at the specified %RH. Each sample is equilibrated for at least 60 min at each RH step, and is considered at equilibrium if the mass gain within 1 min is less than 0.1%, with a maximum duration of 6 h at each RH step. Thus, each sample is held at a given RH for 1–6 h, depending on how quickly it reaches equilibrium.

[0013] 13 C solid-state NMR (SSNMR) Samples of Form I, Form III (monohydrate), Form IV (ACN / HO solvate), and Form V (monohydrate) 13 C solid-state NMR (SSNMR) data was obtained at 11.7 T ( 1 H=500.28MHz, 13Acquisition was performed on a Bruker Avance III HD NMR spectrometer (Bruker Biospin, Inc., Billerica, MA) at C = 125.81 MHz. Samples were loaded into a 4 mm O.D. zirconia rotor equipped with a Kel-F® drive tip. A Bruker model BL4 VTN probe was used for data acquisition and sample spinning around the magic angle (54.74 degrees). A spinning rate of 12 kHz was used for sample spectrum acquisition. A standard cross-polarization pulse sequence was used with a gradient Hartman-Hahn match pulse in the proton channel at ambient temperature and pressure. The pulse sequence used a 4 ms contact pulse and recycle delays of 20, 3, 10, and 3.64 seconds for Form I, Form III (hydrate), Form IV (ACN / HO solvate), and Form V (hydrate), respectively. The pulse sequence also used SPINAL64 decoupling and TOSS sideband suppression. No exponential line broadening was used prior to Fourier transformation of the free induction decay. Chemical shifts were referenced using adamantane as a secondary standard, setting the radio frequency resonance to 38.48 ppm. The magic angle was measured using a 5 kHz spinning rate from KBr powder. 79 The Br signal is used to set up the sample. 13 The C SSNMR spectrum is shown in Figures 1B, 2B, 3B, and 3C and in the table below. The reported chemical shift uncertainties are ±0.3 ppm.

[0014] Raman Raman data are acquired in a transmission Raman, Agilent TRS100, SN6032, using an 830 nm laser at a power of 0.6 W. The experimental exposure time is 0.4 seconds and the number of accumulations is 20. Exemplary Raman spectra of samples of Form I and Form III of the present invention are shown in Figures 1E and 2E, and the results are reported in the following table. Characteristics of Form I The X-ray powder diffraction (XRPD) pattern of Form I of Compound 1 is shown in Figure 1A; 13The C solid-state NMR spectrum is shown in Figure 1B; the thermal analysis profiles of Form I of Compound 1 determined by DSC and TGA measurements are shown in Figures 1C and 1D, respectively; and the Raman spectrum of Form I of Compound 1 is shown in Figure 1E. Characteristic XRPD peaks, 13 The C solid-state nuclear magnetic resonance peaks and Raman peaks are shown in Tables 2, 3, and 4, respectively. [Table 3] [Table 4] [Table 5]

[0015] In one embodiment of the present invention, Form I of Compound 1 is characterized by the XRPD pattern of Figure 1A. In another embodiment of the present invention, Form I of Compound 1 has the XRPD characteristics shown in Table 2. In another embodiment of the present invention, Form I of Compound 1 is characterized by at least three XRPD peaks at 2θ angles selected from 4.1°, 8.2°, 11.9°, 17.0°, 21.8°, 22.6°, and 26.2°. In another embodiment of the present invention, Form I of Compound 1 is characterized by at least five XRPD peaks at 2θ angles selected from 4.1°, 8.2°, 11.9°, 17.0°, 21.8°, 22.6°, and 26.2°. In another embodiment of the present invention, Form I of Compound 1 is characterized by XRPD peaks at 2θ angles selected from 4.1°, 8.2°, 11.9°, 17.0°, 21.8°, 22.6°, and 26.2°.

[0016] In one embodiment of the present invention, Form I of Compound 1 is shown in FIG. 13 Characterized by C solid-state NMR spectroscopy. In another embodiment of the present invention, Form I of Compound 1 is as shown in Table 3 13C solid-state NMR characteristics. In another embodiment of the present invention, Form I of Compound 1 has a NMR spectrum at a chemical shift selected from 166.3 ppm, 146.1 ppm, 65.2 ppm, 52.7 ppm, and 44.2 ppm. 13 It is characterized by a C solid-state nuclear magnetic resonance peak. In another embodiment of the present invention, Form I of Compound 1 has a NMR spectrum at a chemical shift selected from 166.3 ppm, 152.9 ppm, 146.1 ppm, 140.6 ppm, 65.2 ppm, 52.7 ppm, 44.2 ppm, 31.5 ppm, and 29.3 ppm. 13 It is characterized by a C solid-state nuclear magnetic resonance peak. In one embodiment of the present invention, Form I of Compound 1 is characterized by the thermoanalytical profile determined by DSC shown in Figure 1C. There is one endothermic event, which is the melting point of Compound I, with an onset of 200°C and a peak temperature of 202°C.

[0017] In another embodiment of the present invention, Form I of Compound 1 is characterized by the thermal analysis profile determined by TGA shown in FIG. 1D, which shows no significant loss (more than 0.5%) upon heating to 200° C., the melting point of Compound 1. In one embodiment of the present invention, Form I of Compound 1 is characterized by Raman spectroscopy as shown in FIG. 1E. In another embodiment of the present invention, Form I of Compound 1 has the Raman properties shown in Table 4. Samples of Form I were kept at 25°C and 60% relative humidity for at least 9 months and at 40°C and 75% relative humidity for at least 6 months. Under both storage conditions, samples of Form I did not show an increase in moisture content, an increase in impurity levels, a change in particle size distribution, or a change in Raman spectrum.

[0018] Characteristics of Form III The X-ray powder diffraction (XRPD) pattern of Form III of Compound 1 is shown in Figure 2A; 13The C solid-state NMR spectrum is shown in Figure 2B; the thermal analysis profile of Form III of Compound 1 determined by DSC and TGA measurements is shown in Figures 2C and 2D, and the Raman spectrum of Form III of Compound 1 is shown in Figure 2E, respectively. Characteristic XRPD peaks of Form III, 13 The C solid-state nuclear magnetic resonance peaks and Raman peaks are shown in Tables 5, 6, and 7, respectively. [Table 6] [Table 7] [Table 8] In one embodiment of the present invention, Form III of Compound 1 is characterized by the XRPD pattern of Figure 2A. In another embodiment of the present invention, Form III of Compound 1 has the XRPD characteristics shown in Table 4. In another embodiment of the present invention, Form III of Compound 1 is characterized by at least three XRPD peaks at 2θ angles selected from 7.7°, 11.5°, 12.5°, 16.6°, and 22.9°.

[0019] In another embodiment of the present invention, Form III of Compound 1 is characterized by XRPD peaks at 2θ angles selected from 7.7°, 11.5°, 12.5°, 16.6°, and 22.9°. In one embodiment of the present invention, Form III of Compound 1 is shown in FIG. 13 Characterized by C solid-state NMR spectroscopy. In another embodiment of the present invention, Form III of Compound 1 is as shown in Table 5 13 C solid-state NMR characteristics. In another embodiment of the present invention, Form III of Compound 1 has a NMR spectrum at a chemical shift selected from 168.4 ppm, 167.4 ppm, 151.5 ppm, 60.6 ppm, 51.4 ppm, 47.7 ppm, and 42.7 ppm. 13It is characterized by a C solid-state nuclear magnetic resonance peak. In another embodiment of the present invention, Form III of Compound 1 has a NMR spectrum at a chemical shift selected from 168.4 ppm, 167.4 ppm, 151.5 ppm, 143.9 ppm, 142.8 ppm, 137.8 ppm, 113.2 ppm, 110.8 ppm, 73.0 ppm, 65.2 ppm, 61.7 ppm, 60.6 ppm, 51.4 ppm, 47.7 ppm, 42.7 ppm, 42.0 ppm, and 41.7 ppm. 13 It is characterized by a C solid-state nuclear magnetic resonance peak.

[0020] In one embodiment of the present invention, Form III of Compound 1 is characterized by the thermoanalytical profile determined by DSC shown in Figure 2C. The DSC is characterized by two events: a first endotherm with an onset at 83°C and a peak temperature of 98°C, followed by a second endotherm with an onset at 195°C and a peak temperature of 199°C. In another embodiment of the present invention, Form III of Compound 1 is characterized by the thermal analysis profile determined by TGA shown in FIG. 2D, which shows a loss of 3.6% upon heating from 25° C. to 100° C. (before Compound I, Form III melts). In one embodiment of the present invention, Form III of Compound 1 is characterized by Raman spectroscopy, as shown in Figure 2E. In another embodiment of the present invention, Form III of Compound 1 has the Raman properties shown in Table 7. Characteristics of Form IV The X-ray powder diffraction (XRPD) pattern of Form IV of Compound 1 is shown in Figure 3A; 13 The C solid-state NMR spectrum is shown in Figure 3B; the thermal analysis profile of Form IV of Compound 1 determined by DSC and TGA measurements is shown in Figures 3C and 3D, respectively.

[0021] Characteristic XRPD peaks of Form IV and 13 The C solid-state nuclear magnetic resonance peaks are shown in Tables 8 and 9, respectively. [Table 9] [Table 10] In one embodiment of the present invention, Form IV of Compound 1 is characterized by the XRPD pattern of Figure 3A. In another embodiment of the present invention, Form IV of Compound 1 has the XRPD characteristics shown in Table 8. In another embodiment of the present invention, Form IV of Compound 1 is characterized by at least three XRPD peaks at 2θ angles selected from 5.7°, 10.0°, 17.4°, 22.6°, and 28.3°. In another embodiment of the present invention, Form IV of Compound 1 is characterized by XRPD peaks at 2θ angles selected from 5.7°, 10.0°, 17.4°, 22.6°, and 28.3°. In another embodiment of the present invention, Form IV of Compound 1 is characterized by XRPD peaks at 2θ angles selected from 5.7°, 10.0°, 12.5°, 13.1, 17.4°, 22.6°, 26.3°, 27.3°, and 28.3°.

[0022] In one embodiment of the present invention, Form IV of Compound 1 is shown in FIG. 13 Characterized by C solid-state NMR spectroscopy. In another embodiment of the present invention, Form IV of Compound 1 is 13 C solid-state NMR characteristics. In another embodiment of the present invention, Form IV of Compound 1 is 13 It is characterized by a C solid-state nuclear magnetic resonance peak. In another embodiment of the present invention, Form IV of Compound 1 has a NMR spectrum at a chemical shift selected from 169.8 ppm, 139.1 ppm, 107.8 ppm, 75.1 ppm, 30.6 ppm, and 2.6 ppm. 13 It is characterized by a C solid-state nuclear magnetic resonance peak. In one embodiment of the present invention, Form IV of Compound 1 is characterized by the thermal analysis profile determined by DSC shown in Figure 3C. There are two consecutive endotherms with peak temperatures of 75°C (onset: 67°C) and 105°C (onset: 96°C). At 137°C, there is an exotherm with a peak temperature of 149°C, followed by a final endotherm with an onset at 199°C and a peak temperature of 201°C. In another embodiment of the present invention, Form IV of Compound 1 is characterized by the thermal analysis profile determined by TGA shown in Figure 3D. The total loss upon heating from 25°C to 125°C is 2.9%.

[0023] Characteristics of Form V The X-ray powder diffraction (XRPD) pattern of Form V of Compound 1 is shown in Figure 4A; 13 The C solid-state NMR spectrum is shown in Figure 4B; the thermal analysis profile of Form V of Compound 1 determined by DSC and TGA measurements is shown in Figures 4C and 4D, respectively. Characteristic XRPD peaks of Form V and 13 The C solid-state nuclear magnetic resonance peaks are shown in Tables 10 and 11, respectively. [Table 11] [Table 12] In one embodiment of the present invention, Form V of Compound 1 is characterized by the XRPD pattern of Figure 4A. In another embodiment of the present invention, Form V of Compound 1 has the XRPD characteristics shown in Table 10. In another embodiment of the present invention, Form V of Compound 1 is characterized by at least three XRPD peaks at 2θ angles selected from 5.6°, 10.5°, 12.9°, and 22.8°.

[0024] In another embodiment of the present invention, Form V of Compound 1 is characterized by XRPD peaks at 2θ angles selected from 5.6°, 10.5°, 12.9°, 17.9°, 18.7°, 20.1°, 20.8°, and 22.8°. In one embodiment of the present invention, Form V of Compound 1 is shown in FIG. 13 Characterized by C solid-state NMR spectroscopy. In another embodiment of the present invention, Form V of Compound 1 is 13 C solid-state NMR characteristics. In another embodiment of the present invention, Form V of Compound 1 has a NMR spectrum at a chemical shift selected from 155.4 ppm, 116.4 ppm, 74.6 ppm, 71.5 ppm, and 29.6 ppm. 13 It is characterized by a C solid-state nuclear magnetic resonance peak. In another embodiment of the present invention, Form V of Compound 1 has a NMR spectrum at a chemical shift selected from 169.3, 155.4 ppm, 150.4 ppm, 116.4 ppm, 108.0 ppm, 74.6 ppm, 71.5 ppm, 67.7 ppm, 29.6 ppm, and 26.0 ppm. 13 It is characterized by a C solid-state nuclear magnetic resonance peak.

[0025] In one embodiment of the present invention, Form V of Compound 1 is characterized by the thermal analysis profile determined by DSC shown in Figure 4C. There are multiple thermal events: an initial endotherm with an onset at 107°C and a peak temperature of 119°C, followed by an exotherm with an onset at 154°C (peak temperature 164°C), and finally an endotherm with an onset at 194°C and a peak temperature of 196°C. In another embodiment of the present invention, Form V of Compound 1 is characterized by the thermal analysis profile determined by TGA shown in Figure 4D. The total loss upon heating from 25°C to 140°C is 3.0%.

[0026] Methods for Preparing the Compounds of the Invention Specific conditions for preparing solid forms of Compound 1 of the present invention are described in the Examples. Generally, the compounds of the present invention can be obtained by dissolving Compound 1 in a suitable solvent ("dissolving step"), preferably at a temperature above room temperature, more preferably at about 45°C to about 80°C. The heated solution is then cooled ("cooling step") to obtain a solid / liquid containing the compound of the present invention. In some embodiments, the heated solution may be filtered before cooling. In other embodiments, the heated solution may be concentrated ("concentrating step") before or during the cooling step. In still other embodiments, the heated solution may be treated with a co-solvent ("co-solvent treatment step"). In some embodiments, the co-solvent (if used) may be added during the cooling step. In still other embodiments, the cooling step comprises a stepwise cooling gradient. In still other embodiments, seed crystals or a seed slurry ("seeding step") are added before or during the cooling step. It should be understood that any combination of the above can be used to obtain the compounds of the present invention and mixtures thereof. After cooling, the resulting solid may be collected, washed with a suitable solvent, and dried to obtain the compounds of the present invention or mixtures thereof. In one embodiment, Form I can be obtained using a reactive crystallization method involving a pH swing. Compound 1 is dissolved in a basic aqueous solution (NaOH or ammonia). The pH is adjusted with an acid (HCl or citric acid) and seed crystals of Form I are added. As the solid phase of the slurry grows, the pH is slowly neutralized with the acid. The solid is collected, washed with an appropriate solvent, and dried.

[0027] Methods of Therapeutic Use The compounds disclosed herein effectively activate soluble guanylate cyclase.Activation or enhancement of soluble guanylate cyclase is an attractive means for preventing and treating certain diseases and disorders.Non-limiting examples of such diseases or disorders include those described in WO2014 / 039434 and WO2020 / 011804. In another embodiment, the present invention relates to methods of treating diseases and disorders, including: cardiovascular and related diseases, including hypertension, atherosclerosis, peripheral artery disease, restenosis, stroke, heart failure, coronary artery spasm, cerebral vasospasm, ischemia / reperfusion injury, thromboembolic pulmonary hypertension, pulmonary arterial hypertension, stable angina, unstable angina, and thromboembolic disorders; Inflammatory diseases, including psoriasis, multiple sclerosis, arthritis, asthma, and chronic obstructive pulmonary disease; hepatic fibrosis, including but not limited to cirrhosis of any etiology or fibrosis of specific regions of the liver, such as periportal fibrosis, which may be caused by immune damage, hemodynamic effects, and / or other causes; Renal fibrotic disorders, including but not limited to glomerulosclerosis, focal glomerulosclerosis, mesangial fibrosis, interstitial fibrosis due to immune damage, hemodynamic effects, diabetes (type I and type II), diabetic nephropathy, IgA nephropathy, lupus nephropathy, membranous nephropathy, hypertension, hemolytic uremic syndrome, glomerulonephritides, interstitial nephritis, tubulointerstitial nephritis of immunological and non-immunological causes; Pulmonary fibrotic disorders, both diffuse and focal, of immunological and non-immunological causes, including but not limited to idiopathic pulmonary fibrosis, pulmonary fibrosis due to exposure to toxins, chemicals, and drugs, and cystic fibrosis; ischemic heart disease (coronary artery disease) and transient and / or persistent reduction in blood flow in one or more coronary vessels, including that which may be associated with coronary arterial or venous interventions following cardiac surgery and / or the use of cardiopulmonary bypass, as well as cardiac fibrotic disorders of immunological and non-immunological origin, including myocarditis resulting from viral and non-viral causes, and immunologically related myocardial damage that may result from cross-reactivity with other antigens to which the body is exposed; Other diseases mediated at least in part by decreased or reduced soluble guanylate cyclase activity, such as kidney disease, diabetes, urinary system disorders including overactive bladder, benign prostatic hyperplasia, and erectile dysfunction, and neurological disorders including Alzheimer's disease, Parkinson's disease, and neuropathic pain.

[0028] In another embodiment, the present invention relates to the use of the compounds of the present invention to treat, alleviate, or slow the progression of chronic kidney disease (CKD), including fast progressors of CKD; non-alcoholic steatohepatitis (NASH); all-cause cirrhosis; clinically significant portal hypertension (CSPH), and systemic sclerosis (sclerosis). According to one embodiment, the present invention relates to a method for treating, preventing or slowing the progression of non-alcoholic steatohepatitis (NASH) in a patient in need thereof, which method comprises administering to the patient a pharmaceutical composition or pharmaceutical dosage form as defined above and below.

[0029] In one embodiment, the compounds of the present invention can be used to treat NASH associated with fibrosis, eg, F1-F4. In another embodiment, the compounds of the present invention can be used to treat cirrhosis of the liver with or without clinically significant portal hypertension. In another embodiment, the present invention relates to the treatment of patients with compensated NASH cirrhosis accompanied by clinically significant portal hypertension (CSPH). Portal vein pressure is the blood pressure in the hepatic portal vein and is typically 5-10 mmHg. Elevated portal vein pressure, called portal hypertension, leads to numerous sequelae, including ascites and hepatic encephalopathy. In one embodiment of the present invention, CSPH is defined as a hepatic venous pressure gradient (HVPG) of 10 mm / Hg or greater. Accordingly, another embodiment of the present invention relates to the treatment of patients with compensated NASH cirrhosis whose venous pressure gradient (HVPG) is 10 mm / Hg or greater.

[0030] In another embodiment, the present invention relates to the treatment of portal hypertension in patients with cirrhosis of any etiology (all-cause cirrhosis), including but not limited to NASH, alcoholic liver disease (ALD), hepatitis C, hepatitis B, and chronic primary biliary liver disease (primary sclerosing cholangitis, primary biliary cirrhosis). In another aspect, the present invention relates to a method for treating non-alcoholic steatohepatitis (NASH, NAS≧4), in particular NASH associated with liver fibrosis, such as NASH associated with liver fibrosis stages 2 and 3, in a patient in need thereof, characterized in that it comprises administering to the patient a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API), preferably a pharmaceutical composition according to the invention.

[0031] In one embodiment, the invention relates to the use of a compound of the invention for the preparation of a medicament for treating, preventing, or delaying the progression of non-alcoholic steatohepatitis (NASH) or one or more other conditions or diseases selected from the group of conditions or diseases outlined above in this section entitled "Methods of Therapeutic Use." In one embodiment, the invention relates to a compound of the invention for use in the treatment, prevention, or delay of progression of non-alcoholic steatohepatitis (NASH) or one or more other conditions or diseases selected from the group of conditions or diseases outlined above in this section entitled "Methods of Therapeutic Use." Another aspect of the present invention relates to a compound of the present invention for use in the manufacture of a medicament for the treatment of a condition or disease selected from the group of conditions or diseases outlined above in this section entitled "Methods of Therapeutic Use". The effect of administering the pharmaceutical composition to patients with NASH and / or liver fibrosis can be observed by a change, particularly a decrease, in biomarkers related to hepatitis and / or liver function, such as, for example, ALT (alanine aminotransferase), AST (aspartate aminotransferase), AP (alkaline phosphatase), γ-GT (γ-glutamyltransferase), CK-18 (cytokeratin 18) fragment, or HVPG (hepatic venous pressure gradient).

[0032] Furthermore, the effect of administering the pharmaceutical composition to patients with NASH and / or liver fibrosis can be observed, for example, by an improvement in the degree or stage of steatosis, fibrosis, liver stiffness, or health-related quality of life. For therapeutic use, the compound of the present invention can be administered by any conventional method in any conventional pharmaceutical dosage form of pharmaceutical composition.Conventional dosage forms typically contain a pharmaceutically acceptable carrier suitable for the specific dosage form selected.Administration routes include, but are not limited to, intravenous, intramuscular, subcutaneous, intrasynovial, infusion, sublingual, transdermal, oral, topical, or inhalation.Preferred administration modes are oral and intravenous. A preferred oral dose of the compound of the present invention is 0.1 to 100 mg, or 1 to 25 mg, or 1 to 10 mg, or 1 to 5 mg. In another embodiment, a preferred oral dose of the compound of the present invention is selected from 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, and 10 mg. In one embodiment, the compounds of the invention may be administered once daily, twice daily, or three or more times daily, hi another embodiment, the compounds of the invention may be administered once weekly, twice weekly, or three or more times weekly.

[0033] The compounds of the present invention can be administered alone or in combination with other active ingredients, such as adjuvants that enhance the stability of the inhibitor, in certain embodiments, facilitate administration of pharmaceutical compositions containing them, improve dissolution or dispersion, increase inhibitory activity, or provide adjunctive therapy. In one embodiment, for example, multiple compounds of the present invention can be administered. Advantageously, such combination therapy utilizes lower dosages of conventional therapeutic agents, thus avoiding potential toxic and adverse side effects that may occur when these agents are used as monotherapy. The compounds of the present invention can be physically combined with conventional therapeutic agents or other adjuvants into a single pharmaceutical composition. The compounds can then be advantageously administered together in a single dosage form. In some embodiments, pharmaceutical compositions containing such combinations of compounds contain at least about 5% (wt / w), and more preferably at least about 20% (wt / wt), of the compound of Formula (I) or combinations thereof. The optimal ratio (wt / w) of the compounds of the present invention can vary and is within the skill of those in the art. Alternatively, the compounds of the present invention and conventional therapeutic agents or other adjuvants can be administered separately (sequentially or concurrently). Separate administration allows for greater flexibility in dosing regimens.

[0034] As described above, dosage forms of the compounds of the present invention can contain pharmaceutically acceptable carriers and adjuvants known to those skilled in the art and suitable for the dosage form. Examples of such carriers and adjuvants include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes, and cellulose-based materials. Preferred dosage forms include tablets, capsules, caplets, liquids, solutions, suspensions, emulsions, lozenges, syrups, reconstitutable powders, granules, suppositories, and transdermal patches. Methods for preparing such dosage forms are known (see, for example, H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). Those skilled in the art can select the dosage level and required amount of the compounds of the present invention from available methods and techniques suitable for a particular patient. In some embodiments, the dosage level ranges from about 1 to 1,000 mg per dose for a 70 kg patient. Although a single dose per day may be sufficient, up to five doses per day may be administered. Oral administration may require up to 2000 mg / day. Those skilled in the art will recognize that lower or higher doses may be required depending on certain factors. For example, the specific dosage and treatment regimen will depend on factors such as the patient's general medical profile, the severity and course of the patient's disorder or its pharmacokinetics, and the judgment of the treating physician.

[0035] In one embodiment, for example, multiple compounds of the present invention can be administered. Advantageously, such combination therapy utilizes lower dosages of conventional therapeutic agents, thus avoiding potential toxic and adverse side effects when these agents are used as monotherapy. The compounds of the present invention can be physically combined with conventional therapeutic agents or other adjuncts into a single pharmaceutical composition. Advantageously, the compounds can then be administered together in a single dosage form. In some embodiments, pharmaceutical compositions containing such combinations of compounds contain at least about 5% (wt / wt), and more preferably at least about 20% (wt / wt), of the compound of Formula (I) or a combination thereof. The optimal ratio (wt / wt) of the compounds of the present invention can vary and is within the skill of those in the art. Alternatively, the compounds of the present invention and the conventional therapeutic agents or other adjuncts can be administered separately (sequentially or concurrently). Separate administration allows for greater flexibility in dosing schedules. [Example]

[0036] An amorphous form of Compound 1 ("Amorphous Compound 1") is prepared as described in Example 114 of WO 2014 / 039434. The solvent is removed from the resulting eluate under reduced pressure to provide amorphous Compound 1 as a solid. A typical XRPD pattern obtained for amorphous Compound 1 is shown in Figure 5. Example 1a Preparation of Form I of Compound 1 The amorphous form of Compound 1 (1.2 g) is treated with MeOH (12 g) and heated to 60° C. with stirring. The resulting slurry is treated with water (1 mL) and THF (8 mL). The mixture is stirred at 60° C. for an additional hour, cooled to 20° C. over 4 hours, and stirred at 20° C. overnight. The solid is collected by filtration and dried to give Form I of Compound 1 (1.03 g).

[0037] Example 1b Preparation of Form I of Compound 1 The amorphous form of compound 1 was treated with concentrated hydrochloric acid in THF and water (THF / HO 97 / 3) to obtain the HCl salt of compound 1. The HCl salt of compound 1 (4.45 kg) was treated with 2 equivalents of aqueous NaOH (1.15 kg of 50% aqueous NaOH) to obtain the sodium salt of compound 1 as a clear solution. The solution was polish filtered, and the pH of the filtrate was adjusted with dilute aqueous HCl to a pH of 8.6-9.0. Then, seed crystals of Form 1 of compound 1 (0.004 kg), obtained as described above, were added to the solution to initiate crystallization. The seeded mixture was treated with additional dilute HCl until the pH of the mixture reached approximately 7.2-7.9. The reaction mixture was cooled to 20 °C, aged for several hours, and filtered using a centrifuge. The solid was washed with water (110 kg) followed by acetone (6.8 kg). The solid is then dried under vacuum with a stream of nitrogen at about 40° C. to give Form I (4.08 kg).

[0038] Example 1c Preparation of Form I of Compound 1 The amorphous form of Compound 1 (7 g) is suspended in EtOH (56 mL) and water (31 mL). To this is added 7 g of ammonia solution (25% w / w) over 5 minutes to form a clear, pale yellow solution. The solution is heated to 50°C with stirring and held for 15 minutes. Citric acid (11 g of a 50% w / w solution) is added over 45 minutes until a pH in the range of 8.0 to 7.2 is reached. Seed crystals of Form 1 (7 mg, prepared as described above) are added to the solution, and the mixture is held for 15 minutes. An additional 2.65 g of citric acid solution (50% w / w) is then added over 120 minutes until a pH of approximately 6.0 is reached. The resulting slurry is cooled to 25°C over 60 minutes. The solid is collected by filtration, washed with 50 mL of HO, and dried to give Form I of Compound 1 (6.723 g).

[0039] Example 2a Preparation of Form III of Compound 1 Amorphous Compound 1 (10 mg) is added to a pan for dynamic vapor sorption analysis. The solid is exposed to gradients of 40% to 95%, 0%, 95%, and 0% at 25°C. After gradient exposure is complete, Form III is isolated. Example 2b Preparation of Form III of Compound 1 The amorphous form of Compound 1 (100 mg) is treated with water (1.0 mL). The mixture is agitated at room temperature using a magnetic stir bar and the solid is collected to give Form III.

[0040] Example 3a Preparation of Form IV of Compound 1 Form I of Compound 1 (1 g) was dissolved in 5 mL of 70% water-acetonitrile (ACN) to form a saturated solution. The solution was stirred at room temperature for 72 hours using a magnetic stir bar. The resulting crystals were collected as Form IV. The stoichiometry of Form IV (Compound 1:ACN:HO, 1:1:1) was determined by single-crystal X-ray diffraction. Example 3b Preparation of Form IV of Compound 1 Compound 1 Form I (1 g) was treated with 5 mL of 70% water in acetonitrile (ACN). The mixture was stirred at room temperature using a magnetic stir bar for 48 hours. The resulting crystals were collected as Form IV.

[0041] Example 4a Preparation of Form V of Compound 1 Form IV crystals (prepared as described above) are placed on the bench and air-dried at room temperature for 24 hours to yield Form V. The stoichiometry of Form V (compound 1:HO, 1:1) was determined by single crystal X-ray. Example 4b Preparation of Form V of Compound 1 Form I of Compound 1 (2 g) is treated with 10 mL of 70% water in acetonitrile (ACN) and seeded with Form IV from Example 3b. The mixture is stirred at room temperature for 24 hours using a magnetic stir bar. The solid is then isolated by filtration and dried overnight under reduced pressure at 60°C to obtain Form V.

Claims

1. Compound 1: 【Chemistry 1】 1 A solid crystalline form of: i) at least three XRPD peaks at 2θ angles selected from 4.1°, 8.2°, 11.9°, 17.0°, 21.8°, 22.6°, and 26.2°; or at chemical shifts selected from 166.3 ppm, 146.1 ppm, 65.2 ppm, 52.7 ppm, and 44.2 ppm 13 C solid state nuclear magnetic resonance peak Form I, characterized by: ii) at least three XRPD peaks at 2θ angles selected from 7.7°, 11.5°, 12.5°, 16.6°, and 22.9°; or at chemical shifts selected from 168.4 ppm, 167.4 ppm, 151.5 ppm, 60.6 ppm, 51.4 ppm, 47.7 ppm, and 42.7 ppm 13 C solid state nuclear magnetic resonance peak Form III, characterized by: iii) at least three XRPD peaks at 2θ angles selected from 5.7°, 10.0°, 17.4°, 22.6°, and 28.3°; or at chemical shifts selected from 169.8 ppm, 107.8 ppm, 30.6 ppm, and 2.6 ppm 13 C solid state nuclear magnetic resonance peak Form IV, characterized by: iv) at least three XRPD peaks at 2θ angles selected from 5.6°, 10.5°, 12.9°, and 22.8°; or at chemical shifts selected from 155.4 ppm, 116.4 ppm, 74.6 ppm, 71.5 ppm, and 29.6 ppm 13 C solid state nuclear magnetic resonance peak Form V is characterized by A solid crystalline form of Compound 1 selected from the group consisting of:

2. an XRPD peak at a 2θ angle selected from 4.1°, 8.2°, 11.9°, 17.0°, 21.8°, 22.6°, and 26.2°; or at chemical shifts selected from 166.3 ppm, 152.9 ppm, 146.1 ppm, 140.6 ppm, 65.2 ppm, 52.7 ppm, 44.2 ppm, 31.5 ppm, and 29.3 ppm 13 C solid state nuclear magnetic resonance peak Form I, a solid crystalline form of Compound 1 according to claim 1, further characterized by:

3. an XRPD peak at a 2θ angle selected from 7.7°, 11.5°, 12.5°, 16.6°, and 22.9°; or At chemical shifts selected from 168.4 ppm, 167.4 ppm, 151.5 ppm, 143.9 ppm, 142.8 ppm, 137.8 ppm, 113.2 ppm, 110.8 ppm, 73.0 ppm, 65.2 ppm, 61.7 ppm, 60.6 ppm, 51.4 ppm, 47.7 ppm, 42.7 ppm, 42.0 ppm, and 41.7 ppm 13 C solid state nuclear magnetic resonance peak 2. Form III, a solid crystalline form of Compound 1 according to claim 1, further characterized by:

4. an XRPD peak at a 2θ angle selected from 5.7°, 10.0°, 12.5°, 13.1, 17.4°, 22.6°, 26.3°, 27.3°, and 28.3°; or at chemical shifts selected from 169.8 ppm, 139.1 ppm, 107.8 ppm, 75.1 ppm, 30.6 ppm, and 2.6 ppm 13 C solid state nuclear magnetic resonance peak 10. Form IV, a solid crystalline form of Compound 1 according to claim 1, further characterized by:

5. XRPD peaks at 2θ angles selected from 5.6°, 10.5°, 12.9°, 17.9°, 18.7°, 20.1°, 20.8°, and 22.8° Form V, a solid crystalline form of Compound 1 according to claim 1, further characterized by:

6. A pharmaceutical composition comprising any of Form I, Form III, or Form V according to claims 1 to 3 and 5, and optionally including one or more inert carriers and / or diluents.

7. A pharmaceutical composition comprising Form I according to claim 2, and optionally containing one or more inert carriers and / or diluents.

8. 5. A pharmaceutical composition comprising Form III according to claim 4, and optionally containing one or more inert carriers and / or diluents.

9. A pharmaceutical composition comprising Form V of claim 5, and optionally containing one or more inert carriers and / or diluents.

10. A method for treating and / or preventing a disease or disorder responsive to treatment with an activator of sGC, comprising administering to a patient in need thereof a pharmaceutically effective amount of Form I, Form III, or Form V as described in claim 1.

11. 11. The method according to claim 10, wherein the disease or disorder responsive to treatment with an activator of sGC is selected from the group consisting of chronic kidney disease, diabetic kidney disease, non-alcoholic steatohepatitis (NASH), cirrhosis, portal hypertension, and systemic sclerosis (scleroderma).

12. 10. Use of a compound according to claim 1 for the preparation of a medicament for treating, preventing or delaying the progression of a disease or disorder that responds to treatment with an activator of sGC.

13. 10. Use of the pharmaceutical composition according to claim 6 for preparing a medicament for treating, preventing or delaying the progression of a disease or disorder that responds to treatment with an activator of sGC.

14. 15. The use according to claim 13 or 14, wherein the disease or disorder responsive to treatment with an activator of sGC is selected from the group consisting of chronic kidney disease, diabetic kidney disease, non-alcoholic steatohepatitis (NASH), liver cirrhosis, portal hypertension, and systemic sclerosis (scleroderma).

15. 10. A process for preparing Form I of compound 1 of claim 1, comprising: (i) adding an aqueous base to a suspension of Compound 1, ethanol, and water to provide a solution; (ii) heating the solution of step (i) to 50°C; (iii) treating the solution of step (ii) with an acid until a pH in the range of 8.0 to 7.2 is reached; (iv) adding seed crystals of Form I of Compound 1 to the solution of step (iii) to provide a seeded mixture; (v) treating the seeded mixture of step (iv) with acid until a pH of 6.0 is reached; (vi) cooling the mixture of step (v); (vii) isolating the solid from the mixture of step (vi) to obtain Form I of Compound 1; A method comprising:

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