Salts and crystal forms of omecamtiv mecarbil

Abstract

To provide free base crystalline forms, crystalline salts and amorphous salts of omecamtiv mecarbil exhibiting specific X-ray powder diffraction.SOLUTION: An omecamtiv mecarbil free base crystalline form III is provided which is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 9.50, 19.06 and 23.01±0.2° 2θ using Cu Kα radiation.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present disclosure relates to salts and crystal forms of omecamtiv mecarbil, pharmaceutical compositions thereof, and methods of using the same.

Background Art

[0002] The sarcomere is the basic unit of muscle contraction in the heart. The sarcomere is a highly ordered cytoskeletal structure composed of cardiac myosin, actin, and a series of regulatory proteins. The discovery and development of small molecule cardiac myosin activators lead to promising treatments for acute and chronic heart failure and dilated cardiomyopathy (DCM), as well as conditions associated with left and / or right ventricular systolic dysfunction or contractile reserve. Cardiac myosin is a cytoskeletal motor protein in cardiomyocytes. It is directly involved in converting chemical energy into mechanical force, resulting in myocardial contraction.

[0003] Current inotropes, such as beta-adrenergic receptor agonists or phosphodiesterase activity inhibitors, increase the concentration of intracellular calcium, thereby increasing the contractility of the sarcomere. However, the increase in calcium concentration increases the rate of myocardial contraction and shortens the systolic ejection time, which is associated with potentially life-threatening side effects. In contrast, cardiac myosin activators act by a mechanism that directly stimulates the activity of the cardiac myosin motor protein without increasing intracellular calcium concentration. They accelerate the rate-limiting step of the myosin enzyme cycle and shift it favorably towards the force-generating state. This mechanism does not increase the rate of cardiac contraction; instead, it lengthens the systolic ejection time and potentially provides a more oxygen-efficient way to increase myocardial contractility and cardiac output.

[0004] Omecamtiv mecarbil is the first in a class of direct activators of cardiac myosin, a motor protein that causes heart muscle contraction. It is being evaluated as a potential treatment for heart failure with both intravenous and oral formulations, with the goal of establishing new ongoing care for patients in both inpatient and outpatient settings. Omecamtiv mecarbil has the structure of

Chemical formula

[0005] There is a need for various novel salts and crystalline forms of omecamtiv mecarbil having various chemical and physical stabilities, as well as their formulations and uses.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Summary of the Invention

Means for Solving the Problems

[0007] This specification provides salts and crystal forms of omecamtiv mecarbil, including the free base crystal forms, crystal salts, and amorphous salt forms of omecamtiv mecarbil. In some embodiments, omecamtiv mecarbil free base crystal form III is provided herein. In some embodiments, omecamtiv mecarbil free base crystal form IV is provided herein. In some embodiments, omecamtiv mecarbil free base crystal form V is provided herein. In some embodiments, omecamtiv mecarbil free base crystal form VI is provided herein. In some embodiments, omecamtiv mecarbil free base crystal form VII is provided herein. In some embodiments, omecamtiv mecarbil amorphous hydrochloride is provided herein. In some embodiments, omecamtiv mecarbil ethanesulfonic acid crystal salt is provided herein. In some embodiments, omecamtiv mecarbil bisfumarate crystal salt form A is provided herein. In some embodiments, omecamtiv mecarbil bisfumarate crystal salt form B is provided herein. In some embodiments, omecamtiv mecarbil bisfumarate crystal salt form C is provided herein. In some embodiments, omecamtiv mecarbil monofumarate crystal salt form D is provided herein. In some embodiments, omecamtiv mecarbil bismaleate crystal salt is provided herein. In some embodiments, omecamtiv mecarbil bismalonate crystal salt is provided herein. In some embodiments, omecamtiv mecarbil mesylate crystal salt form A is provided herein. In some embodiments, omecamtiv mecarbil bismesylate crystal salt form B is provided herein. In some embodiments, omecamtiv mecarbil bisnaphthalene-2-sulfonic acid crystal salt is provided herein. In some embodiments, omecamtiv mecarbil mononapadisylate crystal salt is provided herein. In some embodiments, omecamtiv mecarbil nicotinate crystal salt is provided herein. In some embodiments, omecamtiv mecarbil oxalate crystal salt form A is provided herein.In some embodiments, omecamtiv mecarbil succinic acid crystalline salt Form B is provided herein. In some embodiments, omecamtiv mecarbil salicylic acid crystalline salt is provided herein. In some embodiments, omecamtiv mecarbil hemisuccinic acid crystalline salt is provided herein. In some embodiments, omecamtiv mecarbil bisulfate crystalline salt Form A is provided herein. In some embodiments, omecamtiv mecarbil bisulfate crystalline salt Form B is provided herein. In some embodiments, omecamtiv mecarbil bisulfate crystalline salt Form C is provided herein. In some embodiments, omecamtiv mecarbil sulfate crystalline salt Form D is provided herein. In some embodiments, omecamtiv mecarbil 2-hydroxyethanesulfonic acid crystalline salt is provided herein. In some embodiments, omecamtiv mecarbil bitartrate crystalline salt Form A is provided herein. In some embodiments, provided herein is omecamtiv mecarbil bitartrate crystalline salt Form B. In some embodiments, provided herein is omecamtiv mecarbil bitartrate crystalline salt Form C. In some embodiments, provided herein is omecamtiv mecarbil monotartrate crystalline salt Form D.

[0008] Also provided is a pharmaceutical composition comprising a salt or crystalline form of omecamtiv mecarbil disclosed herein and a pharmaceutically acceptable excipient.

[0009] Further provided is a method of treating heart failure in a subject in need thereof, the method comprising administering to the subject a salt or crystalline form of omecamtiv mecarbil disclosed herein in an amount effective to treat heart failure.

Brief Description of the Drawings

[0010]

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Mode for Carrying Out the Invention

[0011] The present disclosure provides salts and crystal forms of omecamtiv mecarbil.

[0012] Embodiments of the free base crystal form, crystal salts, and amorphous salts of omecamtiv mecarbil can be characterized by one or more of the parameters described in more detail below.

[0013] Free base crystal form of omecamtiv mecarbil The free base crystal form of omecamtiv mecarbil is provided herein. In some embodiments, the free base crystal form of omecamtiv mecarbil can be the non - ionic form of omecamtiv mecarbil. In some embodiments, the free base crystal forms III - VII of omecamtiv mecarbil can be anhydrous. The free base crystal forms I and II of omecamtiv mecarbil shown in Figure 13 were prepared and discussed in detail in Morrison et al., Organic Process Research & Development, 2015, 19, 1842 - 1848.

[0014] Free base crystal form III The free base crystalline form III of omecamtiv mecarbil is obtained as described in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at approximately 9.50, 19.06 and 23.01 ± 0.2° 2θ using CuKα irradiation. The free base crystalline form III can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 14.27, 15.25, 16.10, 17.78 and 23.87 ± 0.2° 2θ using CuKα irradiation. The free base crystalline form III can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 7.91, 20.65, 28.11, 31.01, 31.95 and 32.34 ± 0.2° 2θ using CuKα irradiation. The free base crystalline form III can optionally be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 1 described in the Examples. In some embodiments, the free base crystalline form III has an X-ray powder diffraction pattern substantially as shown in Figure 1, where "substantially" means that the reported peaks can vary by approximately ±0.2°. In the field of XRPD, it is well known that the relative peak heights of the spectrum depend on many factors such as sample preparation and the geometry of the instrument, but the peak positions are relatively unaffected by the details of the experiment.

[0015] A differential scanning calorimetry (DSC) thermogram of the free base crystalline form III was obtained as described in the Examples. The DSC curve shows an endothermic transition at approximately 186°C ± 3°C. Thus, in some embodiments, the free base crystalline form III can be characterized by a DSC thermogram having an endothermic decomposition starting in the range of approximately 175°C to approximately 190°C. For example, in some embodiments, the free base crystalline form III is characterized by DSC as shown in Figure 2.

[0016] The free base crystalline form III can also be characterized by thermogravimetric analysis (TGA). Thus, the free base crystalline form III can be characterized by a weight loss in the range of about 0% to about 1% with an onset temperature in the range of about 25 °C to about 100 °C. For example, the free base crystalline form III can be characterized by a weight loss of about 0% up to about 150 °C. In some embodiments, the free base crystalline form III has a thermogravimetric analysis substantially as shown in FIG. 3, where "substantially" means that the reported TGA characteristics can vary by about ±5 °C.

[0017] The free base crystalline form IV The free base crystalline form IV of omecamtiv mecarbil is obtained as described in the examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 5.18, 10.35, 14.84, 15.54, 18.10 and 19.92 ± 0.2 °2θ using CuKα irradiation. The free base crystalline form IV can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 14.21, 20.62, 20.77, 22.86, 24.05, 24.36, 27.81 and 29.42 ± 0.2 °2θ using CuKα irradiation. The free base crystalline form IV can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 7.42, 7.70, 21.70, 22.40, 23.09, 25.20, 25.72, 27.40, 28.18, 28.63, 28.98 and 30.51 ± 0.2 °2θ using CuKα irradiation. The free base crystalline form IV can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 2 described in the examples. In some embodiments, the free base crystalline form IV has an X-ray powder diffraction pattern substantially as shown in FIG. 4, where "substantially" means that the reported peaks can vary by about ±0.2 °C.

[0018] A differential scanning calorimetry (DSC) thermograph of the free base crystalline form IV was obtained as described in the Examples. The DSC curve shows an endothermic transition at about 185 °C ± 3 °C. Thus, in some embodiments, the free base crystalline form IV can be characterized by a DSC thermograph having an endothermic decomposition starting in the range of about 175 °C to about 190 °C. For example, in some embodiments, the free base crystalline form IV is characterized by DSC as shown in FIG. 5.

[0019] The free base crystalline form IV can also be characterized by thermogravimetric analysis (TGA). Thus, the free base crystalline form IV can be characterized by a weight loss in the range of about 0% to about 1% with a starting temperature in the range of about 25 °C to about 100 °C. For example, the free base crystalline form IV can be characterized by a weight loss of about 0% up to about 150 °C. In some embodiments, the free base crystalline form IV has a thermogravimetric analysis substantially as shown in FIG. 6, where "substantially" means that the reported TGA characteristics can vary by about ±5 °C.

[0020] Free base crystalline form V The free base crystalline form V of omecamtiv mecarbil is obtained as described in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 7.38, 8.56, 9.14 and 18.28 ± 0.2° 2θ using CuKα irradiation. The free base crystalline form V can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 8.93, 10.03, 10.73, 11.71, 13.69, 15.08, 16.85, 17.85, 18.86, 20.05, 20.72, 21.74, 23.56, 24.03, 26.23 and 27.62 ± 0.2° 2θ using CuKα irradiation. The free base crystalline form V can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 5.40, 16.04, 22.83, 25.45, 26.23, 27.62, 28.58, 29.85, 32.10 and 33.37 ± 0.2° 2θ using CuKα irradiation. The free base crystalline form V can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 3 described in the Examples. In some embodiments, the free base crystalline form V has an X-ray powder diffraction pattern substantially as shown in FIG. 7, where "substantially" means that the reported peaks can vary by about ± 0.2°.

[0021] A differential scanning calorimetry (DSC) thermogram of form V was obtained as described in the Examples. The DSC curve shows an endothermic transition at about 185 °C ± 3 °C. Thus, in some embodiments, the free base crystalline form V can be characterized by a DSC thermogram having an endothermic decomposition starting in the range of about 175 °C to about 190 °C. For example, in some embodiments, the free base crystalline form V is characterized by DSC as shown in FIG. 8.

[0022] The free base crystalline form V can also be characterized by thermogravimetric analysis (TGA). Accordingly, the free base crystalline form V can be characterized by a weight loss in the range of about 2% to about 6% with an onset temperature in the range of about 25 °C to about 100 °C. For example, the free base crystalline form V can be characterized by a weight loss of about 4.2% up to about 150 °C. In some embodiments, the free base crystalline form V has a thermogravimetric analysis substantially as shown in FIG. 9, where "substantially" means that the reported TGA characteristics can vary by about ±5 °C.

[0023] Free base crystalline form VI The free base crystalline form VI of omecamtiv mecarbil is obtained as described in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 9.07, 16.67, 18.18, 19.70, 20.89 and 21.28 ± 0.2° 2θ using CuKα irradiation. The free base crystalline form VI can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 15.88, 17.81, 18.80, 23.72, 24.26, 26.80, 27.59 and 29.82 ± 0.2° 2θ using CuKα irradiation. The free base crystalline form VI can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 14.28, 20.23, 26.19 and 28.90 ± 0.2° 2θ using CuKα irradiation. The free base crystalline form VI can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 4 described in the Examples. In some embodiments, the free base crystalline form VI has an X-ray powder diffraction pattern substantially as shown in FIG. 10, where "substantially" means that the reported peaks can vary by about ±0.2°.

[0024] The differential scanning calorimetry (DSC) thermograph of Form VI was obtained as described in the Examples. The DSC curve shows an endothermic transition at about 185 °C ± 3 °C. Thus, in some embodiments, the free base crystalline Form VI can be characterized by a DSC thermograph having an endothermic decomposition starting in the range of about 175 °C to about 190 °C. For example, in some embodiments, the free base crystalline Form VI is characterized by DSC as shown in FIG. 11.

[0025] Free base crystalline Form VII The free base crystalline Form VII of omecamtiv mecarbil was obtained as described in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 8.40, 8.71, 13.08, 15.66 and 19.61 ± 0.2° 2θ using CuKα irradiation. The free base crystalline Form VII can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 4.37, 16.83, 18.92, 20.32, 20.49, 22.26, 24.21 and 25.41 ± 0.2° 2θ using CuKα irradiation. The free base crystalline Form VII can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 7.84, 10.81, 21.61, 23.22, 23.46, 27.58, 29.53, 30.13 and 31.32 ± 0.2° 2θ using CuKα irradiation. The free base crystalline Form VII can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 5 described in the Examples. In some embodiments, the free base crystalline Form VII has an X-ray powder diffraction pattern substantially as shown in FIG. 12, where "substantially" means that the reported peaks can vary by about ± 0.2°.

[0026] Crystalline salts of omecamtiv mecarbil Various crystalline salts of ome-camtimemecarbil are provided herein. Specifically, salts are provided that are crystalline salts of ome-camtimemecarbil that are ethanesulfonate, fumarate, maleate, malonate, mesylate, naphthalene-2-sulfonate, napadisylate, nicotinate, oxalate, salicylate, succinate, sulfate, hydroxyethanesulfonate, or tartrate.

[0027] Ethanesulfonic acid crystalline salt The ethanesulfonic acid crystalline salt of ome-camtimemecarbil is obtained as described in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 8.61, 16.14, 16.76, 16.97, 20.73, 20.96, 25.95 and 26.30 ± 0.2° 2θ using CuKα irradiation. The ethanesulfonic acid crystalline salt can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 17.23, 18.35, 19.20, 20.27, 23.73, 25.24 and 27.09 ± 0.2° 2θ using CuKα irradiation. The ethanesulfonic acid crystalline salt can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 7 described in the Examples. In some embodiments, the ethanesulfonic acid crystalline salt has an X-ray powder diffraction pattern substantially as shown in FIG. 18, where "substantially" means that the reported peaks can vary by about ±0.2°. In some embodiments, the ethanesulfonic acid crystalline salt has a TG / DTA substantially as shown in FIG. 19.

[0028] Bis-fumaric acid crystalline form A The bisfumaric acid crystal salt Form A of omecamtiv mecarbil is obtained as described in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 5.64, 15.76, 22.03, and 23.87 ± 0.2° 2θ using CuKα irradiation. The bisfumaric acid crystal salt Form A can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 16.80, 21.55, 21.87, 23.61, 23.87, 26.01, and 27.20 ± 0.2° 2θ using CuKα irradiation. The bisfumaric acid crystal salt Form A can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 10.80, 12.04, 15.76, 16.40, 17.94, 18.32, 19.87, 20.61, 22.88, 27.86, 32.73, and 36.54 ± 0.2° 2θ using CuKα irradiation. The bisfumaric acid crystal salt Form A can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 8 described in the Examples. In some embodiments, the bisfumaric acid crystal salt Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 20, where "substantially" means that the reported peaks can vary by about ±0.2°.

[0029] The bisfumaric acid crystal salt Form A can also be characterized by thermogravimetric analysis (TGA). Thus, the bisfumaric acid crystal salt Form A can be characterized by a weight loss in the range of about 6% to about 10% having an onset temperature in the range of about 25°C to about 100°C. For example, the bisfumaric acid crystal salt Form A can be characterized by a weight loss of about 7.9% up to about 150°C. In some embodiments, the bisfumaric acid crystal salt Form A has a thermogravimetric analysis substantially as shown in FIG. 21, where "substantially" means that the reported TGA characteristics can vary by about ±5°C.

[0030] Bisfumaric acid crystal salt Form B The bisfumaric acid crystal salt Form B of omecamtiv mecarbil is obtained as described in the examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 5.68, 6.11, 13.13, 18.08 and 22.47 ± 0.2° 2θ using CuKα irradiation. The bisfumaric acid crystal salt Form B can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 9.69, 11.43, 12.92, 15.95, 20.81, 22.95, 26.04, 27.01 and 28.43 ± 0.2° 2θ using CuKα irradiation. The bisfumaric acid crystal salt Form B can optionally be further characterized by an X-ray powder diffraction pattern having further peaks at about 19.52, 24.53, 31.37, 32.32, 34.89, 35.89 and 37.16 ± 0.2° 2θ using CuKα irradiation. The bisfumaric acid crystal salt Form B can optionally be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 9 described in the examples. In some embodiments, the bisfumaric acid crystal salt Form B has an X-ray powder diffraction pattern substantially as shown in Figure 22, where "substantially" means that the reported peaks can vary by about ±0.2°.

[0031] The bisfumaric acid crystal salt Form B can also be characterized by thermogravimetric analysis (TGA). Thus, the bisfumaric acid Form B can be characterized by a weight loss in the range of about 4% to about 8% with an onset temperature in the range of about 25°C to about 100°C. For example, the bisfumaric acid crystal salt Form B can be characterized by a weight loss of about 5.6% up to about 150°C. In some embodiments, the bisfumaric acid crystal salt Form B has a thermogravimetric analysis substantially as shown in Figure 23, where "substantially" means that the reported TGA characteristics can vary by about ±5°C.

[0032] Bisfumaric acid crystal salt Form C The bisfumaric acid crystal salt form C of omecamtiv mecarbil is obtained as described in the examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 5.88, 18.79, 25.41 and 26.86 ± 0.2° 2θ using CuKα irradiation. The bisfumaric acid crystal salt form C can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 12.74, 13.56, 17.15, 17.63, 20.29, 21.47, 21.77, 22.21, 22.92, 23.58, 24.15, 25.41, 26.78 and 27.83 ± 0.2° 2θ using CuKα irradiation. The bisfumaric acid crystal salt form C can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 10 described in the examples. In some embodiments, the bisfumaric acid crystal salt form C has an X-ray powder diffraction pattern substantially as shown in FIG. 24, where "substantially" means that the reported peaks can vary by about ±0.2°.

[0033] The bisfumaric acid crystal salt form C can also be characterized by thermogravimetric analysis (TGA). Thus, the bisfumaric acid form C can be characterized by a weight loss in the range of about 6% to about 10% with an onset temperature in the range of about 25°C to about 100°C. For example, the bisfumaric acid crystal salt form C can be characterized by a weight loss of about 8.4% up to about 150°C. In some embodiments, the bisfumaric acid crystal salt form C has a thermogravimetric analysis substantially as shown in FIG. 25, where "substantially" means that the reported TGA characteristics can vary by about ±5°C. This weight loss was determined to be water by Karl Fischer (KF) analysis. The KF analysis indicates that the water content of the bisfumaric acid crystal salt form C can be about 8.4% corresponding to the trihydrate.

[0034] Monofumaric acid crystal salt form D The monofumaric acid crystal salt Form D of Omecamtiv mecarbil is obtained as described in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at approximately 8.01, 15.20 and 20.02 ± 0.2° 2θ using CuKα irradiation. The monofumaric acid crystal salt Form D can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 12.11, 12.67, 14.46, 16.01, 16.57, 17.04, 17.63, 20.51, 21.75, 22.86, 24.25, 24.97, 25.84, 26.17, 27.10, 27.97 and 29.21 ± 0.2° 2θ using CuKα irradiation. The monofumaric acid crystal salt Form D can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 11 described in the Examples. In some embodiments, the monofumaric acid crystal salt Form D has an X-ray powder diffraction pattern substantially as shown in Figure 26, where "substantially" means that the reported peaks can vary by approximately ±0.2°.

[0035] A differential scanning calorimetry (DSC) thermogram of the monofumaric acid crystal salt Form D was obtained as described in the Examples. The DSC curve shows an endothermic transition at approximately 125°C ± 3°C. Thus, in some embodiments, the monofumaric acid crystal salt Form D can be characterized by a DSC thermogram having an endothermic decomposition starting in the range of approximately 110°C to approximately 130°C. For example, in some embodiments, the monofumaric acid crystal salt Form D is characterized by DSC as shown in Figure 27.

[0036] Monofumaric acid crystalline form D can also be characterized by thermogravimetric analysis (TGA). Thus, monofumaric acid crystalline form D can be characterized by a weight loss in the range of about 5% to about 9% with an onset temperature in the range of about 25°C to about 100°C. For example, monofumaric acid crystalline form D can be characterized by a weight loss of about 6.7% up to about 150°C. In some embodiments, monofumaric acid crystalline form D has a thermogravimetric analysis substantially as shown in FIG. 28, where "substantially" means that the reported TGA characteristics can vary by about ±5°C.

[0037] Bismaleic acid crystalline salt The bismaleic acid crystalline salt of omecamtiv mecarbil is obtained as described in the examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 9.97, 15.31, 16.04 and 26.96 ± 0.2° 2θ using CuKα irradiation. The bismaleic acid crystalline salt can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 10.56, 13.25, 15.53, 16.38, 17.44, 17.70, 18.17, 19.00, 20.13, 21.47, 22.31, 22.44, 24.38, 24.64, 25.66, 26.66 and 27.83 ± 0.2° 2θ using CuKα irradiation. The bismaleic acid crystalline salt can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at 4.99, 14.83, 17.10, 22.02, 28.55, 30.76, 32.01, 34.39 and 34.51 ± 0.2° 2θ using CuKα irradiation. The bismaleic acid crystalline salt can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 13 described in the examples. In some embodiments, the bismaleic acid crystalline salt has an X-ray powder diffraction pattern substantially as shown in FIG. 30, where "substantially" means that the reported peaks can vary by about ±0.2°.

[0038] A differential scanning calorimetry (DSC) thermograph of the bis(maleic acid) crystal salt was obtained as described in the Examples. The DSC curve shows an endothermic transition at about 190°C ± 3°C. Thus, in some embodiments, the bis(maleic acid) crystal salt can be characterized by a DSC thermograph having an endothermic decomposition starting in the range of about 160°C to about 210°C. For example, in some embodiments, the bis(maleic acid) crystal salt is characterized by DSC as shown in Figure 31.

[0039] The bis(maleic acid) crystal salt can also be characterized by thermogravimetric analysis (TGA). Thus, the bis(maleic acid) crystal salt can be characterized by a weight loss in the range of about 0% to about 1% with a starting temperature in the range of about 25°C to about 150°C. For example, the bis(maleic acid) crystal salt can be characterized by a weight loss of about 0% up to about 150°C. In some embodiments, the bis(maleic acid) crystal salt has a thermogravimetric analysis substantially as shown in Figure 32, where "substantially" means that the reported TGA characteristics can vary by about ±5°C.

[0040] Bis(malonate) crystal salt The bis(malonic acid) crystal salt of omecamtiv mecarbil is obtained as described in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 4.74, 11.37, 14.25, 15.13, 18.29, 20.14, 23.87, 27.78, and 28.01 ± 0.2° 2θ using CuKα irradiation. The bis(malonic acid) crystal salt can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 9.30, 13.73, 16.45, 16.83, 18.08, 18.88, 19.54, 20.77, 21.21, 23.32, 24.67, 26.51, 27.59, and 28.90 ± 0.2° 2θ using CuKα irradiation. The bis(malonic acid) crystal salt can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 15.69, 25.72, 30.18, 33.70, 34.19 ± 0.2° 2θ using CuKα irradiation. The bis(malonic acid) crystal salt can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 14 described in the Examples. In some embodiments, the bis(malonic acid) crystal salt has an X-ray powder diffraction pattern substantially as shown in Figure 33, where "substantially" means that the reported peaks can vary by about ±0.2°.

[0041] The bis(malonic acid) crystal salt can also be characterized by thermogravimetric analysis (TGA). Thus, the bis(malonic acid) crystal salt can be characterized by a weight loss in the range of about 0% to about 1% with an onset temperature in the range of about 25°C to about 140°C. For example, the bis(malonic acid) crystal salt can be characterized by a weight loss of about 0% up to about 140°C. In some embodiments, the bis(malonic acid) crystal salt has a thermogravimetric analysis substantially as shown in Figure 34, where "substantially" means that the reported TGA characteristics can vary by about ±5°C.

[0042] Mesylate crystal form A The mesylate crystal salt form A of omecamtiv mecarbil is obtained as described in the examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 4.02, 4.87, 15.21, 15.86, 20.53 and 24.39 ± 0.2° 2θ using CuKα irradiation. The mesylate crystal salt form A can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 7.79, 11.61, 16.51, 17.57, 18.42, 19.26, 21.55, 23.17, 25.51, 26.38 and 27.63 ± 0.2° 2θ using CuKα irradiation. The mesylate crystal salt form A can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 15 described in the examples. In some embodiments, the mesylate crystal salt form A has an X-ray powder diffraction pattern substantially as shown in Figure 35, where "substantially" means that the reported peaks can vary by about ±0.2°.

[0043] The mesylate crystal salt form A can also be characterized by thermogravimetric analysis (TGA). Thus, the mesylate crystal salt form A can be characterized by a weight loss in the range of about 0% to about 2% with an onset temperature in the range of about 25°C to about 175°C. For example, the mesylate crystal salt form A can be characterized by a weight loss of about 1.0% up to about 200°C. In some embodiments, the mesylate crystal salt form A has a thermogravimetric analysis substantially as shown in Figure 36, where "substantially" means that the reported TGA characteristics can vary by about ±5°C.

[0044] Bis(mesylate) crystal salt form B The bis(mesylate) crystal form B of omecamtiv mecarbil is obtained as described in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 8.30, 8.94, 9.59, 12.15, 14.37, 19.82, 20.29, 22.04 and 25.02 ± 0.2° 2θ using CuKα irradiation. The bis(mesylate) crystal form B can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 11.66, 16.18, 16.64, 16.81, 17.07, 17.19, 17.41, 17.76, 19.24, 20.66, 21.62, 22.39, 23.95, 24.60, 25.59, 25.89, 27.14, 27.35, 27.41 and 29.45 ± 0.2° 2θ using CuKα irradiation. The bis(mesylate) crystal form B can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 10.78, 11.15, 14.93, 15.36, 15.57, 23.54, 26.14, 26.49, 27.89, 28.86, 29.89, 31.11, 32.47, 33.10, 33.51 and 34.56 ± 0.2° 2θ using CuKα irradiation. The bis(mesylate) crystal form B can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 16 described in the Examples. In some embodiments, the bis(mesylate) crystal form B has an X-ray powder diffraction pattern substantially as shown in Figure 37, where "substantially" means that the reported peaks can vary by about ±0.2°. In some embodiments, the bis(mesylate) crystal form B has a TG / DTA substantially as shown in Figure 38.

[0045] Bis(naphthalene-2-sulfonic acid) crystal salt The bisnaphthalene-2-sulfonic acid crystal salt is obtained as described in the examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 4.49, 18.20, 18.62, 21.38, 21.52 and 26.11 ± 0.2° 2θ using CuKα irradiation. The bisnaphthalene-2-sulfonic acid crystal salt can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 6.25, 6.65, 13.44, 14.39, 14.92, 16.28, 18.90, 19.53, 20.82, 22.02, 22.43, 22.80, 24.40, 25.16, 27.01, 29.67, 31.63 and 33.42 ± 0.2° 2θ using CuKα irradiation. The bisnaphthalene-2-sulfonic acid crystal salt can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 18 described in the examples. In some embodiments, the bisnaphthalene-2-sulfonic acid crystal salt has an X-ray powder diffraction pattern substantially as shown in FIG. 40, where "substantially" means that the reported peaks can vary by about ±0.2°. In some embodiments, the bisnaphthalene-2-sulfonic acid crystal salt has a TG / DTA substantially as shown in FIG. 41.

[0046] Mononapadisyl acid crystal salt The mononapadisylate crystal salt of omecamtiv mecarbil is obtained as described in the examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 12.27, 15.75, 16.5, 17.83, 19.94, 21.83 and 22.87 ± 0.2° 2θ using CuKα irradiation. The mononapadisylate crystal salt can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 13.41, 14.57, 15.14, 18.82, 23.49, 24.34 and 25.26 ± 0.2° 2θ using CuKα irradiation. The mononapadisylate crystal salt can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 19 described in the examples. In some embodiments, the mononapadisylate crystal salt has an X-ray powder diffraction pattern substantially as shown in Figure 42, where "substantially" means that the reported peaks can vary by about ±0.2°.

[0047] A differential scanning calorimetry (DSC) thermogram of the mononapadisylate crystal salt was obtained as described in the examples. The DSC curve shows an endothermic transition at about 100°C ± 3°C. Thus, in some embodiments, the mononapadisylate crystal salt can be characterized by a DSC thermogram having an endothermic decomposition starting in the range of about 80°C to about 115°C. For example, in some embodiments, the mononapadisylate crystal salt is characterized by DSC as shown in Figure 43.

[0048] The mononapadisylate crystal salt can also be characterized by thermogravimetric analysis (TGA). Thus, the mononapadisylate crystal salt can be characterized by a weight loss in the range of about 4% to about 8% having a starting temperature in the range of about 20°C to about 100°C. For example, the mononapadisylate crystal salt can be characterized by a weight loss of about 5.8% up to about 100°C. In some embodiments, the mononapadisylate crystal salt has a thermogravimetric analysis substantially as shown in Figure 44, where "substantially" means that the reported TGA characteristics can vary by about ±5°C.

[0049] Nicotinic acid crystal salt The nicotinic acid crystal salt of omecamtiv mecarbil is obtained as described in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 3.69, 8.55, 9.13, 16.70, 16.84, 18.30, 19.99, 20.76, 23.43, 24.83 and 25.95 ± 0.2° 2θ using CuKα irradiation. The nicotinic acid crystal salt can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 7.36, 10.01, 12.43, 14.74, 15.50, 17.62, 18.58, 19.59, 20.34, 21.32, 22.03, 22.91, 23.87, 24.92, 25.40, 26.85, 26.94, 27.32, 28.01 and 28.94 ± 0.2° 2θ using CuKα irradiation. The nicotinic acid crystal salt can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 20 described in the Examples. In some embodiments, the nicotinic acid crystal salt has an X-ray powder diffraction pattern substantially as shown in FIG. 45, where "substantially" means that the reported peaks can vary by about ±0.2°. In some embodiments, the nicotinic acid crystal salt has a TG / DTA substantially as shown in FIG. 46.

[0050] Oxalic acid crystal form A The oxalic acid crystal salt form A of omecomtibumecarb can be obtained as described in the examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 6.48, 13.01, and 23.82 ± 0.2° 2θ using CuKα irradiation. The oxalic acid crystal salt form A can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 10.36, 11.85, 14.79, 15.35, 17.11, 19.23, 19.91, 21.48, 22.07, 22.75, 25.70, 28.55, and 30.71 ± 0.2° 2θ using CuKα irradiation. The oxalic acid crystal salt form A can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 21 described in the examples. In some embodiments, the oxalic acid crystal salt form A has an X-ray powder diffraction pattern substantially as shown in FIG. 47, where "substantially" means that the reported peaks can vary by about ±0.2°.

[0051] A differential scanning calorimetry (DSC) thermogram of the oxalic acid crystal salt form A was obtained as described in the examples. The DSC curve shows an endothermic transition at about 209°C ± 3°C. Thus, in some embodiments, the oxalic acid crystal salt form A can be characterized by a DSC thermogram having an endothermic decomposition starting in the range of about 190°C to about 230°C. For example, in some embodiments, the oxalic acid crystal salt form A is characterized by DSC as shown in FIG. 48.

[0052] The oxalic acid crystal salt form A can also be characterized by thermogravimetric analysis (TGA). Thus, the oxalic acid crystal salt form A can be characterized by a weight loss in the range of about 0.5% to about 4.5% having a starting temperature in the range of about 25°C to about 100°C. For example, the oxalic acid crystal salt form A can be characterized by a weight loss of about 2.5% up to about 150°C. In some embodiments, the oxalic acid crystal salt form A has a thermogravimetric analysis substantially as shown in FIG. 49, where "substantially" means that the reported TGA characteristics can vary by about ±5°C.

[0053] Oxalic acid crystal form B The oxalic acid crystal form B of omecamtiv mecarbil can be obtained as described in the Examples and characterized by an X-ray powder diffraction pattern having peaks at about 7.38, 13.30 and 16.54 ± 0.2° 2θ using CuKα irradiation. The oxalic acid crystal form B can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 17.11, 17.95, 18.45, 21.25, 22.63, 24.82 and 25.77 ± 0.2° 2θ using CuKα irradiation. The oxalic acid crystal form B can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 14.76, 24.35, 28.61, 29.58, 30.49, 31.76, 34.46 and 37.35 ± 0.2° 2θ using CuKα irradiation. The oxalic acid crystal form B can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 22 described in the Examples. In some embodiments, the oxalic acid crystal form B has an X-ray powder diffraction pattern substantially as shown in FIG. 50, where "substantially" means that the reported peaks can vary by about ± 0.2°.

[0054] The oxalic acid crystal form B can also be characterized by thermogravimetric analysis (TGA). Thus, the oxalic acid crystal form B can be characterized by a weight loss in the range of about 0% to about 1% with an onset temperature in the range of about 25°C to about 100°C. For example, the oxalic acid crystal form B can be characterized by a weight loss of about 0% up to about 150°C. In some embodiments, the oxalic acid crystal form B has a thermogravimetric analysis substantially as shown in FIG. 51, where "substantially" means that the reported TGA characteristics can vary by about ± 5°C.

[0055] Salicylic acid crystal salt The salicylic acid crystal salt of omecamtiv mecarbil is obtained as described in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 8.36, 16.75, 17.56, 23.58 and 28.21 ± 0.2° 2θ using CuKα irradiation. The salicylic acid crystal salt can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 10.08, 11.30, 13.69, 17.77, 17.86, 18.67, 19.11, 20.22, 21.07, 25.23 and 27.40 ± 0.2° 2θ using CuKα irradiation. The salicylic acid crystal salt can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 9.78, 12.00, 13.80, 15.51, 19.27, 19.62, 20.02, 20.79, 22.19, 22.39, 22.75, 22.92, 24.99, 25.59, 26.79, 29.94 and 34.07 ± 0.2° 2θ using CuKα irradiation. The salicylic acid crystal salt can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 24 described in the Examples. In some embodiments, the salicylic acid crystal salt has an X-ray powder diffraction pattern substantially as shown in FIG. 53, where "substantially" means that the reported peaks can vary by about ±0.2°. In some embodiments, the salicylic acid crystal salt has a TG / DTA substantially as shown in FIG. 54.

[0056] Hemisuccinic acid crystal salt The hemisuccinic acid crystal salt of omecamtiv mecarbil is obtained as shown in the examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 6.32, 18.87, 19.32, 20.5, 21.24, 21.89, 23.49, 24.23 and 26.71 ± 0.2° 2θ using CuKα irradiation. The hemisuccinic acid crystal salt can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 12.93, 15.08, 16.97, 25.36, 27.39 and 28.32 ± 0.2° 2θ using CuKα irradiation. The hemisuccinic acid crystal salt can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 25 described in the examples. In some embodiments, the hemisuccinic acid crystal salt has an X-ray powder diffraction pattern substantially as shown in FIG. 55, where "substantially" means that the reported peaks can vary by about ±0.2°.

[0057] A differential scanning calorimetry (DSC) thermogram of the hemisuccinic acid crystal salt was obtained as described in the examples. The DSC curve shows an endothermic transition at about 171 °C ± 3 °C. Thus, in some embodiments, the hemisuccinic acid crystal salt can be characterized by a DSC thermogram having an endothermic decomposition starting in the range of about 155 °C to about 190 °C. For example, in some embodiments, the hemisuccinic acid crystal salt is characterized by DSC as shown in FIG. 56.

[0058] Bisulfate crystal form A The bisulfate crystal form A of omecamtiv mecarbil is obtained as described in the examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 5.39, 7.55, 14.35, 19.26 and 20.22 ± 0.2° 2θ using CuKα irradiation. The bisulfate crystal form A can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 16.17, 16.71, 16.92, 17.07, 18.60, 20.83, 21.38, 22.27, 22.77, 23.14, 23.42, 23.76, 24.32, 25.11, 25.74, 26.46, 27.71, 28.15 and 29.92 ± 0.2° 2θ using CuKα irradiation. The bisulfate crystal form A can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 26 described in the examples. In some embodiments, the bisulfate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 57, where "substantially" means that the reported peaks can vary by about ±0.2°.

[0059] Bisulfate crystal form B The bisulfate crystal form B of omecamtiv mecarbil is obtained as described in the examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 11.72 and 20.48 ± 0.2° 2θ using CuKα irradiation. The bisulfate crystal form B can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 12.17, 12.93, 17.79, 18.39, 18.76, 19.84, 23.60, 25.13, 25.63 and 30.12 ± 0.2° 2θ using CuKα irradiation. The bisulfate crystal form B can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 27 described in the examples. In some embodiments, the bisulfate crystal form B has an X-ray powder diffraction pattern substantially as shown in Figure 58, where "substantially" means that the reported peaks can vary by about ±0.2°.

[0060] Bisulfate crystal form B can also be characterized by thermogravimetric analysis (TGA). Thus, bisulfate form B can be characterized by a weight loss in the range of about 10% to about 14% with an onset temperature in the range of about 25 °C to about 100 °C. For example, bisulfate crystal form B can be characterized by a weight loss of about 12.2% up to about 150 °C. In some embodiments, bisulfate crystal form B has a thermogravimetric analysis substantially as shown in FIG. 59, where "substantially" means that the reported TGA characteristics can vary by about ±5 °C. This weight loss was determined to be water by Karl Fischer (KF) analysis. KF analysis indicates that the water content of bisulfate crystal form B can be about 12%, corresponding to the pentahydrate.

[0061] Bisulfate crystal form C The bisulfate crystal form C of omecamtiv mecarbil can be obtained as described in the examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 10.98, 11.49, 18.04 and 19.60 ± 0.2° 2θ using CuKα irradiation. Bisulfate crystal form C can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 10.39, 10.72, 12.52, 12.99, 17.11, 17.43, 20.94, 24.76, 25.25, 25.87 and 26.51 ± 0.2° 2θ using CuKα irradiation. Bisulfate crystal form C can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 28 described in the examples. In some embodiments, bisulfate crystal form C has an X-ray powder diffraction pattern substantially as shown in FIG. 60, where "substantially" means that the reported peaks can vary by about ±0.2°.

[0062] Bisulfate crystal form C can also be characterized by thermogravimetric analysis (TGA). Thus, bisulfate crystal form C can be characterized by a weight loss in the range of about 7% to about 11% with an onset temperature in the range of about 25 °C to about 60 °C. For example, bisulfate crystal form C can be characterized by a weight loss of about 9.0% up to about 150 °C. In some embodiments, bisulfate crystal form C has a thermogravimetric analysis substantially as shown in FIG. 61, where "substantially" means that the reported TGA characteristics can vary by about ±5 °C.

[0063] Sulfate crystal form D The sulfate crystal form D of omecamtiv mecarbil can be obtained as described in the examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 7.32, 8.02 and 20.44 ± 0.2° 2θ using CuKα irradiation. Sulfate crystal form D can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 13.57, 14.54, 16.29, 16.41, 16.91, 17.36, 18.70, 21.02, 21.77, 22.37, 22.90, 23.72, 24.28, 25.14, 25.88, 26.58, 27.25, 28.10 and 29.43 ± 0.2° 2θ using CuKα irradiation. Sulfate crystal form D can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 29 described in the examples. In some embodiments, sulfate crystal form D has an X-ray powder diffraction pattern substantially as shown in FIG. 62, where "substantially" means that the reported peaks can vary by about ±0.2°. In an embodiment, sulfate crystal form D has a TG / DTA substantially as shown in FIG. 63.

[0064] 2-Hydroxyethanesulfonic acid crystal salt The 2-hydroxyethanesulfonic acid crystal salt of omecamtiv mecarbil is obtained as described in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 9.95, 17.85, 19.93, 20.07, 20.46, 25.06 and 26.20 ± 0.2° 2θ using CuKα irradiation. The 2-hydroxyethanesulfonic acid crystal salt can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 6.26, 6.69, 14.99, 16.37, 19.61, 20.95, 29.98, 32.16 and 34.39 ± 0.2° 2θ using CuKα irradiation. The 2-hydroxyethanesulfonic acid crystal salt can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 31 described in the Examples. In some embodiments, the 2-hydroxyethanesulfonic acid crystal salt has an X-ray powder diffraction pattern substantially as shown in FIG. 65, where "substantially" means that the reported peaks can vary by about ±0.2°. In some embodiments, the 2-hydroxyethanesulfonic acid crystal salt has a TG / DTA substantially as shown in FIG. 66.

[0065] Bis-tartaric acid crystal form A The bis-tartaric acid crystal salt Form A of omecamtiv mecarbil is obtained as described in the examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 4.20, 7.49, 8.22, 11.88, 16.42 and 21.19 ± 0.2° 2θ using CuKα irradiation. The bis-tartaric acid crystal salt Form A can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 4.77, 7.67, 8.43, 9.49, 13.05, 13.26, 14.98, 15.14, 17.34, 17.47, 18.02, 18.23, 18.72, 19.20, 22.50, 24.53, 25.67, 26.30 and 28.14 ± 0.2° 2θ using CuKα irradiation. The bis-tartaric acid crystal salt Form A can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 32 described in the examples. In some embodiments, the bis-tartaric acid crystal salt Form A has an X-ray powder diffraction pattern substantially as shown in Figure 67, where "substantially" means that the reported peaks can vary by about ±0.2°.

[0066] The bis-tartaric acid crystal salt Form A can also be characterized by thermogravimetric analysis (TGA). Thus, the bis-tartaric acid crystal salt Form A can be characterized by a weight loss in the range of about 1% to about 5% having an onset temperature in the range of about 25°C to about 120°C. For example, the bis-tartaric acid crystal salt Form A can be characterized by a weight loss of about 3.2% up to about 150°C. In some embodiments, the bis-tartaric acid crystal salt Form A has a thermogravimetric analysis substantially as shown in Figure 68, where "substantially" means that the reported TGA characteristics can vary by about ±5°C.

[0067] Bis-tartaric acid crystal salt Form B The bis-tartrate form B of omecamtiv mecarbil is obtained as described in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 3.77, 5.69 and 10.07 ± 0.2° 2θ using CuKα irradiation. The bis-tartrate crystal form B can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 4.72, 6.95, 9.34, 11.18, 12.63, 15.18, 17.69, 22.35 and 25.46 ± 0.2° 2θ using CuKα irradiation. The bis-tartrate crystal form B can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 33 described in the Examples. In some embodiments, the bis-tartrate crystal form B has an X-ray powder diffraction pattern substantially as shown in Figure 69, where "substantially" means that the reported peaks can vary by about ±0.2°.

[0068] The bis-tartrate crystal form B can also be characterized by thermogravimetric analysis (TGA). Thus, the bis-tartrate crystal form B can be characterized by a weight loss in the range of about 3% to about 7% with an onset temperature in the range of about 20°C to about 100°C. For example, the bis-tartrate crystal form B can be characterized by a weight loss of about 5.4% up to about 150°C. In some embodiments, the bis-tartrate crystal form B has a thermogravimetric analysis substantially as shown in Figure 70, where "substantially" means that the reported TGA characteristics can vary by about ±5°C.

[0069] Bis-tartrate crystal form C The bis-tartaric acid crystal salt form C of omecamtiv mecarbil is obtained as described in the examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 3.57, 6.23, and 15.84 ± 0.2° 2θ using CuKα irradiation. The bis-tartaric acid crystal salt form C can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 3.86, 4.78, 7.04, 9.36, 13.08, 13.96, 16.88, 17.60, 18.20, 18.73, 20.40, 22.58, 25.44, 26.06, and 28.61 ± 0.2° 2θ using CuKα irradiation. The bis-tartaric acid crystal salt form C can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 34 described in the examples. In some embodiments, the bis-tartaric acid crystal salt form C has an X-ray powder diffraction pattern substantially as shown in Figure 71, where "substantially" means that the reported peaks can vary by about ±0.2°.

[0070] The bis-tartaric acid crystal salt form C can also be characterized by thermogravimetric analysis (TGA). Thus, the bis-tartaric acid crystal salt form C can be characterized by a weight loss in the range of about 12% to about 17% having an onset temperature in the range of about 20°C to about 100°C. For example, the bis-tartaric acid crystal salt form C can be characterized by a weight loss of about 14.6% up to about 150°C. In some embodiments, the bis-tartaric acid crystal salt form C has a thermogravimetric analysis substantially as shown in Figure 72, where "substantially" means that the reported TGA characteristics can vary by about ±5°C.

[0071] Mono-tartaric acid crystal salt form D The mono-tartrate crystal salt form D of omecamtiv mecarbil is obtained as described in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at about 9.77 and 15.40 ± 0.2° 2θ using CuKα irradiation. The mono-tartrate crystal salt form D can optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at about 10.87, 13.79, 17.36, 17.74, 18.58, 18.87, 21.78, 25.43 and 26.24 ± 0.2° 2θ using CuKα irradiation. The mono-tartrate crystal salt form D can be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 35 described in the Examples. In some embodiments, the mono-tartrate crystal salt form D has an X-ray powder diffraction pattern substantially as shown in FIG. 73, where "substantially" means that the reported peaks can vary by about ±0.2°.

[0072] The mono-tartrate crystal salt form D can also be characterized by thermogravimetric analysis (TGA). Thus, the mono-tartrate form D can be characterized by a weight loss in the range of about 4% to about 8% having an onset temperature in the range of about 20°C to about 75°C. For example, the mono-tartrate crystal salt form D can be characterized by a weight loss of about 6.4% up to about 150°C. In some embodiments, the mono-tartrate crystal salt form D has a thermogravimetric analysis substantially as shown in FIG. 74, where "substantially" means that the reported TGA characteristics can vary by about ±5°C. This weight loss was determined to be water by Karl Fischer (KF) analysis. The KF analysis indicates that the water content of the mono-tartrate crystal salt form D can be about 6.9% corresponding to the dihydrate.

[0073] Amorphous hydrochloride Also provided herein is the amorphous hydrochloride of omecamtiv mecarbil, and confirmation of its amorphous nature is provided by its X-ray powder diffraction pattern as shown in FIG. 14.

[0074] A differential scanning calorimetry (DSC) thermograph of the amorphous hydrochloride was obtained as described in the Examples. The DSC curve shows an endothermic transition at about 171 °C ± 3 °C. Thus, in some embodiments, the amorphous hydrochloride can be characterized by a DSC thermograph having an endothermic decomposition starting in the range of about 155 °C to about 190 °C. For example, in some embodiments, the amorphous hydrochloride is characterized by DSC as shown in Figure 15.

[0075] The amorphous hydrochloride can also be characterized by thermogravimetric analysis (TGA). Thus, the amorphous hydrochloride can be characterized by a weight loss in the range of about 6% to about 10% with a starting temperature in the range of about 20 °C to about 60 °C. For example, the amorphous hydrochloride can be characterized by a weight loss of about 7.9% up to about 150 °C. In some embodiments, the amorphous hydrochloride has a thermogravimetric analysis substantially as shown in Figure 16, where "substantially" means that the reported TGA characteristics can vary by about ±5 °C. In some embodiments, the amorphous hydrochloride has a moisture sorption profile substantially as shown in Figure 17.

[0076] Pharmaceutical composition Also provided herein are pharmaceutical compositions comprising a salt or crystalline form of omecamtiv mecarbil as disclosed herein and a pharmaceutically acceptable excipient.

[0077] The phrase "pharmaceutically acceptable" as used herein refers, within the scope of sound medical judgment, to ligands, materials, compositions, and / or dosage forms that, without undue toxicity, irritation, allergic response, or other problems or complications, are suitable for use in contact with the tissues of humans and animals and represent a reasonable benefit / risk ratio. The compositions described herein can be formulated for any form of administration. In various cases, the composition is for oral administration. In various cases, the composition is a tablet.

[0078] In some embodiments, the pharmaceutical composition can include a pharmaceutically acceptable carrier. As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. As used herein, the term "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. that are compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include the following: (1) sugars such as lactose, glucose, sucrose; (2) starches such as corn starch, potato starch, and substituted or unsubstituted β-cyclodextrin; (3) cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic compatible substances used in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions provided herein are non-pyrogenic, i.e., they do not induce a significant increase in temperature when administered to a patient.

[0079] Wetting agents, emulsifying agents, and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants may also be present in the composition as excipients.

[0080] Examples of pharmaceutically acceptable antioxidants as excipients include the following: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0081] The pharmaceutical composition may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. By containing various antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid phenol, etc., the prevention of the action of microorganisms may be ensured. Also, it may be desirable to include a tonicity regulator such as sugar in the composition. Furthermore, the absorption of the injectable drug may be made to last for a long time by containing agents that slow absorption such as aluminum monostearate and gelatin.

[0082] In some cases, it is desirable to delay the absorption of the compound from subcutaneous or intramuscular injection in order to sustain the effect of one or more compounds provided herein for a long time. For example, the delayed absorption of a parenterally administered compound can be achieved by dissolving or suspending the compound in an oil vehicle.

[0083] The composition should be stable under the conditions of manufacture and storage and must be protected from the contaminating action of microorganisms such as bacteria and fungi. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it is preferred to include in the composition isotonic agents such as sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride. Sustained absorption of the injectable composition can be achieved by including in the composition an agent that delays absorption such as aluminum monostearate and gelatin.

[0084] Sterile injectable solutions can be prepared by incorporating the required amount of the active compound in an appropriate solvent, optionally with one or a combination of the ingredients enumerated above, followed by filter sterilization. Generally, dispersions are prepared by incorporating the active compound in a sterile vehicle which contains a basic dispersion medium and the desired other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, a preferred method of preparation is lyophilization (freeze-drying) which yields a powder that is obtained from its previously sterile-filtered solution by adding any additional desired ingredients to the active ingredient.

[0085] Injectable depot formulations can be prepared by forming microcapsule or nanocapsule matrices of the compounds provided herein in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be adjusted depending on the ratio of the drug to the polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectables can also be prepared by encapsulating the drug in liposomes, microemulsions or nanoemulsions that are compatible with body tissues.

[0086] In one embodiment, the therapeutic crystalline salt is prepared with a carrier that protects the therapeutic compound from rapid elimination from the body, such as a controlled release formulation that includes an implant and a microencapsulation delivery system. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Such formulations can be prepared using standard techniques or obtained commercially, for example, from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes that target selected cells having monoclonal antibodies against cell antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those of skill in the art, such as those described in U.S. Patent No. 4,522,811, which is hereby incorporated by reference in its entirety.

[0087] The pharmaceutical composition can be contained in a container, pack, or dispenser, together with instructions for administration.

[0088] Controlled release composition In various cases, the pharmaceutical formulations described herein can uniformly release omecamtiv mecarbil at a pace controlled by the diffusion of omecamtiv mecarbil through a gel layer formed by the hydration of a release control agent in the tablet. In some embodiments, in combination with other embodiments above or below, the release-modulating matrix tablets of the present invention exhibit minimal pH-dependent release in vitro. In some embodiments, in combination with other embodiments above or below, complete release of omecamtiv mecarbil is achieved within 24 hours in dissolution media of both pH 2 and 6.8, likely reducing variability between and within subjects and the effects of food. The release-modulating matrix tablet dosage form of the present invention has been found to be superior to the former immediate-release dosage form in minimizing the plasma peak-trough ratio. As a result, the release-modulating matrix tablets of the present invention reduce fluctuations in plasma concentration, reduce side effects, and improve safety and efficacy. In addition, the release-modulating matrix tablets of the present invention are expected to improve patient compliance by reducing the dosing frequency. Furthermore, the release-modulating matrix tablets of the present invention are physically and chemically stable and do not result in changes in physical attributes, assay, impurities, or dissolution profile after storage at 40 °C / 75% RH for 6 months.

[0089] There is provided a pharmaceutical formulation comprising a salt or crystalline form of omecamtiv mecarbil, a release control agent, a pH adjuster, a filler, and a lubricant as disclosed herein.

[0090] As used herein, the term "release control agent" refers to an agent that facilitates the release of the active ingredient from the composition in a controlled manner. In some embodiments, in combination with other embodiments above or below, the release control agent forms a gel when hydrated. Examples of controlled release agents include pullulan, dextrin, sodium and calcium acids, polyacrylic acid, polymethacrylic acid, polymethyl vinyl ether-co-maleic anhydride, polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxymethyl methacrylate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, methylcellulose, maltodextrin, xanthan gum, tragacanth gum, agar, gellan gum, kayaragum, alginic acid, pectin, pregelatinized starch, polyvinyl alcohol, carboxymethyl ethyl cellulose phthalic acid cellulose acetate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethyl ethyl cellulose phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl alcohol phthalate, polyvinyl acetate phthalate, polyvinyl acetal phthalate, copolymer of vinyl acetate / maleic anhydride, copolymer of styrene / maleic acid monoester, copolymer of methyl acrylate / methacrylic acid, copolymer of styrene / acrylic acid, copolymer of methyl acrylate / methacrylic acid / octyl acrylate, copolymer of methacrylic acid / methyl methacrylate, benzylaminomethyl cellulose, diethylaminomethyl cellulose, piperidylethyl hydroxyethyl cellulose, cellulose acetate dimethylaminoacetate, copolymer of vinyldiethylamine / vinyl acetate, copolymer of vinylbenzylamine / vinyl acetate, polyvinyl acetal diethylaminoacetate, copolymer of vinyl piperidyl acetoacetal / vinyl acetate, polydiethylaminomethylstyrene, copolymer of methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate and polydimethylaminoethyl methacrylate, copolymer of 2-methyl-5-vinylpyridine / methyl methacrylate / methacrylic acid,Copolymers of 2-methyl-5-vinylpyridine / methyl acrylate / methacrylic acid, copolymers of 2-vinyl-5-ethylpyridine / methacrylic acid / methyl acrylate, copolymers of 2-vinylpyridine / methacrylic acid / acrylonitrile, carboxymethyl piperidyl dextrin, carboxy-methylbenzylamino cellulose, N-vinylglycine / styrene copolymers, chitosan, poly(vinyl alcohol), maleic anhydride copolymers, poly(vinyl pyrrolidone), starch and starch-based polymers, poly(2-ethyl-2-oxazoline), poly(ethyleneimine), polyurethane hydrogels, welan gum, ramson gum, polyvinyl acetate, ethyl cellulose, eudragit RL, RS, NE 30D, Kollicoat EMM 30D, or combinations thereof.

[0091] In some embodiments, in combination with the above or other embodiments below, the release control agent is a polymer.

[0092] In some embodiments, in combination with the above or below other embodiments, the release control agent is pullulan, dextrin, sodium and calcium acids, polyacrylic acid, polymethacrylic acid, polymethyl vinyl ether-co-maleic anhydride, polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxymethyl methacrylate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, methyl cellulose, maltodextrin, xanthan gum, tragacanth gum, agar, gellan gum, kaya gum, alginic acid, pectin, pregelatinized starch, polyvinyl alcohol, carboxymethyl ethyl cellulose phthalic acid cellulose, cellulose acetate succinate, methyl cellulose phthalate, hydroxymethyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl alcohol phthalate, polyvinyl acetate phthalate, polyvinyl acetal phthalate, vinyl acetate / maleic anhydride copolymer, styrene / maleic acid monoester copolymer, methyl acrylate / methacrylic acid copolymer, styrene / acrylic acid copolymer, methyl acrylate / methacrylic acid / octyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, benzylaminomethyl cellulose, diethylaminomethyl cellulose, piperidylethyl hydroxyethyl cellulose, cellulose acetate dimethylaminoacetate, vinyldiethylamine / vinyl acetate copolymer, vinylbenzylamine / vinyl acetate copolymer, polyvinyl acetal diethylaminoacetate, vinyl piperidyl acetoacetal / vinyl acetate copolymer, polydiethylaminomethylstyrene, methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate and polydimethylaminoethyl methacrylate copolymer, 2-methyl-5-vinylpyridine / methyl methacrylate / methacrylic acid copolymer, 2-methyl-5-vinylpyridine / methyl acrylate / methacrylic acid copolymer, 2-vinyl-5-ethylpyridine / methacrylic acid / methyl acrylate copolymer,It is selected from a copolymer of 2-vinylpyridine / methacrylic acid / acrylonitrile, carboxymethyl piperidyl dextran, carboxy-methylbenzylamino cellulose, a copolymer of N-vinylglycine / styrene, chitosan, poly(vinyl alcohol), maleic anhydride copolymer, poly(vinyl pyrrolidone), starch and starch-based polymers, poly(2-ethyl-2-oxazoline), poly(ethyleneimine), polyurethane hydrogel, welan gum, ramasan gum, polyvinyl acetate, ethyl cellulose, eudragit RL, RS, NE 30D, and Kollicoat EMM 30D, or any combination thereof.,

[0093] As used herein, the term "pH adjuster" refers to an agent that can adjust the pH to a desired range. In some embodiments, in combination with other embodiments above or below, the pH adjuster is an acidifying agent. In some embodiments, in combination with other embodiments above or below, the pH adjuster is present in an amount sufficient to lower the pH. Examples of pH adjusters include maleic acid, citric acid, tartaric acid, pamoic acid, fumaric acid, salicylic acid, 2,6-diaminohexanoic acid, camphorsulfonic acid, glycerophosphoric acid, 2-hydroxyethanesulfonic acid, isethionic acid, succinic acid, carbonic acid, p-toluenesulfonic acid, aspartic acid, 8-chlorotheophylline, benzenesulfonic acid, malic acid, orotic acid, oxalic acid, benzoic acid, 2-naphthalenesulfonic acid, stearic acid, adipic acid, p-aminosalicylic acid, 5-aminosalicylic acid, ascorbic acid, sulfuric acid, cyclamic acid, sodium lauryl sulfate, glucoheptonic acid, glucuronic acid, glycine, mandelic acid, 1,5-naphthalenedisulfonic acid, nicotinic acid, oleic acid, 2-oxoglutaric acid, pyridoxal 5-phosphate, undecanoic acid, p-acetamidobenzoic acid, o-acetamidobenzoic acid, m-acetamidobenzoic acid, N-acetyl-L-aspartic acid, borneol acid, dehydrocholic acid, malonic acid, edetic acid, ethylenediaminetetraacetic acid, ethyl sulfate, hydroxyphenylbenzoylbenzoic acid, glutamic acid, glycyrrhizic acid, 4-hexylresorcinol, hippuric acid, p-phenolsulfonic acid, 4-hydroxybenzoic acid, 3-hydroxybenzoic acid, 3-hydroxy-2-naphthoic acid, 1-hydroxy-2-naphthoic acid, lactobionic acid, 3'-adenylic acid, 5'-adenylic acid, mucic acid, galactaric acid, pantothenic acid, pectic acid, polygalacturonic acid, 5-sulfosalicylic acid, 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-propanesulfonic acid, terephthalic acid, and combinations thereof. In some embodiments, in combination with other embodiments above or below, examples of pH adjusters include, for example, maleic acid, citric acid, malic acid, fumaric acid, sulfuric acid, tartaric acid, lactic acid, salicylic acid, aspartic acid, aminosalicylic acid, malonic acid, glutamic acid, and combinations thereof.In some embodiments, in combination with the above or below other embodiments, the pH adjuster includes fumaric acid, tartaric acid, glutamic acid, or a combination thereof.

[0094] In some embodiments, in combination with the above or below other embodiments, as the pH adjuster, maleic acid, citric acid, tartaric acid, pamoic acid, fumaric acid, salicylic acid, 2,6-diaminohexanoic acid, camphorsulfonic acid, glycerophosphoric acid, 2-hydroxyethanesulfonic acid, isethionic acid, succinic acid, carbonic acid, p-toluenesulfonic acid, aspartic acid, 8-chlorotheophylline, benzenesulfonic acid, malic acid, orotic acid, oxalic acid, benzoic acid, 2-naphthalenesulfonic acid, stearic acid, adipic acid, p-aminosalicylic acid, 5-aminosalicylic acid, ascorbic acid, sulfuric acid, cyclamic acid, sodium lauryl sulfate, glucoheptonic acid, glucuronic acid, glycine, mandelic acid, 1,5-naphthalenedisulfonic acid, nicotinic acid, oleic acid, 2-oxoglutaric acid, pyridoxal 5-phosphate, undecanoic acid, p-acetamidobenzoic acid, o-acetamidobenzoic acid, m-acetamidobenzoic acid, N-acetyl-L-aspartic acid, borneol acid, dehydrocholic acid, malonic acid, edetic acid, ethylenediaminetetraacetic acid, ethyl sulfate, hydroxyphenylbenzoylbenzoic acid, glutamic acid, glycyrrhizic acid, 4-hexylresorcinol, hippuric acid, p-phenolsulfonic acid, 4-hydroxybenzoic acid, 3-hydroxybenzoic acid, 3-hydroxy-2-naphthoic acid, 1-hydroxy-2-naphthoic acid, lactobionic acid, 3'-adenylic acid, 5'-adenylic acid, mucic acid, galactaric acid, pantothenic acid, pectic acid, polygalacturonic acid, 5-sulfosalicylic acid, 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-propanesulfonic acid, terephthalic acid, 1-hydroxy-2-naphthoic acid, and combinations thereof may be mentioned.

[0095] In some embodiments, in combination with the above or below other embodiments, the pH adjuster is selected from, for example, maleic acid, citric acid, malic acid, fumaric acid, sulfuric acid, tartaric acid, lactic acid, salicylic acid, aspartic acid, aminosalicylic acid, malonic acid, glutamic acid, and combinations thereof.

[0096] In some embodiments, in combination with the above or below other embodiments, fumaric acid has lower hygroscopicity than citric acid and higher compatibility with omecamtiv mecarbil dihydrochloride hydrate, so it is used as a pH adjuster. When stored at about 40 °C / 75% RH for about 6 months, there is little or no change in the active form, and there is no change in the appearance of the tablets, and a final product of good quality can be obtained. Furthermore, fumaric acid is more acidic (about twice) than citric acid. Therefore, it is more efficient to use fumaric acid to adjust the microenvironmental pH and enhance the release of omecamtiv mecarbil in a neutral environment. That is, it is active at a weight ratio of about 1:1 rather than about 2:1. Fumaric acid also has a very slow dissolution rate. As a result, fumaric acid remains in the tablets longer, better maintains a low microenvironmental pH, and releases omecamtiv mecarbil more completely within about 24 hours.

[0097] As used herein, the term "filler" refers to one or more substances that can be added to the components of a pharmaceutical composition to increase the bulk weight of the material to be formulated (e.g., tableted) in order to achieve the desired weight. Fillers include, but are not limited to, starch, lactose, mannitol (such as Pearlitol TM SD 200, etc.), cellulose derivatives, calcium phosphate, sugars, and the like.

[0098] Different grades of lactose include lactose monohydrate, lactose DT (direct compression), lactose anhydrous, Flowlac TM (available from Meggle products), Pharmatose TM(Available from the DMV), etc., but not limited thereto. Different grades of starch include corn starch, potato starch, rice starch, wheat starch, pregelatinized starch (commercially available as PCS PC10 from Signet Chemical Corporation), Starch 1500 from Colorcon, Starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starch (commercially available as National 78-1551 from Essex Grain Products), etc., but not limited thereto. Different cellulose compounds that can be used include crystalline cellulose and powdered cellulose. Examples of crystalline cellulose products include CEOLUS TM KG801, Avicel TM PH101, PH102, PH301, PH302 and PH-F20, microcrystalline cellulose 114 and microcrystalline cellulose 112, but not limited thereto. Other useful fillers include sugar alcohols such as carmellose, mannitol, sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate, but not limited thereto.

[0099] In some embodiments, in combination with the above or other embodiments below, the filler is selected from starch, lactose, mannitol (such as Pearlitol TM SD 200, etc.), cellulose derivatives, calcium phosphate, and sugars.

[0100] In some embodiments, in combination with the above or other embodiments below, the filler is lactose anhydrous or lactose monohydrate. In some embodiments, in combination with the above or other embodiments below, the filler is Lactose DT, Flowlac TM or Pharmatose TM .

[0101] In some embodiments, in combination with the above or other embodiments below, the filler is corn starch, potato starch, rice starch, wheat starch, pregelatinized starch (such as Starch 1500 or Starch 1500 LM grade (low moisture content grade)) or fully pregelatinized starch.

[0102] In some embodiments, in combination with the above or other embodiments below, the filler is CEOLUS TM KG801, Avicel TM PH101, PH102, PH301, PH302 and PH-F20, microcrystalline cellulose such as microcrystalline cellulose 114 or microcrystalline cellulose 112.

[0103] In some embodiments, in combination with the above or other embodiments below, the filler is carmellose, mannitol, sorbitol, xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate or tribasic calcium phosphate.

[0104] As used herein, the term "lubricant" refers to one or more substances that can be added to the components of the composition to reduce the adhesion of the solid preparation to the equipment used in the manufacture of the unit dosage form. Lubricants include stearic acid, hydrogenated vegetable oil, hydrogenated soybean oil and hydrogenated soybean oil-caster wax, stearyl alcohol, leucine, polyethylene glycol, magnesium stearate, glyceryl monostearate, glyceryl behenate, ethylene oxide polymer, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, and mixtures thereof.

[0105] In some embodiments, in combination with the above or other embodiments below, the lubricant is stearic acid, hydrogenated vegetable oil, hydrogenated soybean oil, carnauba wax, stearyl alcohol, leucine, polyethylene glycol, magnesium stearate, glyceryl monostearate, glyceryl behenate, ethylene oxide polymer, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, or any mixture thereof.

[0106] Swelling core formulation Disclosed herein is a pharmaceutical formulation comprising a drug layer containing omecamtiv mecarbil as a salt or crystalline form disclosed herein, a swelling layer, and a semipermeable membrane coating having at least one delivery port.

[0107] Furthermore, omecamtiv mecarbil as a salt or crystalline form disclosed herein, a drug layer polymer, and a lubricant comprising a drug layer; a swelling layer polymer, a permeant, a diluent, and a lubricant comprising a swelling layer; and an insoluble polymer and a pore-forming polymer comprising a semipermeable membrane coating having at least one delivery port is provided.

[0108] In some embodiments, in combination with the above or other embodiments below, the pharmaceutical formulation is a drug layer containing 10 - 20 (w / w%) omecamtiv mecarbil salt or crystalline form, 40 - 60 (w / w%) polyethylene oxide, and 0 - 2% (w / w%) lubricant; a swelling layer containing 12 - 30 (w / w%) polyethylene oxide, 2 - 10 (w / w%) permeant, 1 - 8 (w / w%) microcrystalline cellulose, and 0.1 - 2% (w / w%) lubricant; and A semipermeable membrane coating having at least one delivery port containing 5 to 15 (w / w%) cellulose acetate and 0.3 to 5 (w / w%) polyethylene glycol comprising.

[0109] In some embodiments, in combination with the above or other embodiments below, the pharmaceutical formulation is A drug layer containing 14 to 17 (w / w%) omecamtiv mecarbil salt or crystalline form, 48 to 55 (w / w%) polyethylene oxide, and 0.1 to 0.5% (w / w%) lubricant; A swelling layer containing 18 to 25 (w / w%) polyethylene oxide, 4 to 9 (w / w%) osmotic agent, 3 to 6 (w / w%) microcrystalline cellulose, and 0.1 to 0.5 (w / w%) lubricant; and A semipermeable membrane coating having at least one delivery port containing 8 to 10 (w / w%) cellulose acetate and 0.5 to 3 (w / w%) polyethylene glycol comprising.

[0110] In some embodiments, in combination with the above or other embodiments below, the pharmaceutical formulation is A drug layer containing 10 to 20 (w / w%) omecamtiv mecarbil salt or crystalline form, 40 to 60 (w / w%) polyethylene oxide, and 0 to 2% (w / w%) magnesium stearate; A swelling layer containing 12 to 30 (w / w%) polyethylene oxide, 2 to 10 (w / w%) sodium chloride, 1 to 8 (w / w%) microcrystalline cellulose, and 0.1 to 2 (w / w%) magnesium stearate; and A semipermeable membrane coating having at least one delivery port containing 5 to 15 (w / w%) cellulose acetate and 0.3 to 5 (w / w%) polyethylene glycol 3350 comprising.

[0111] In some embodiments, in combination with the above or other embodiments below, the pharmaceutical formulation is 15 to 16 (w / w%) omecamtiv mecarbil salt or crystalline form, 50 to 52 (w / w%) PolyOx TMA drug layer containing WSR N-80 and 0.1 to 0.5% (w / w%) magnesium stearate; 20 to 23 (w / w%) PolyOx TM A swelling layer containing a WSR aggregating agent, 4 to 9% (w / w%) sodium chloride, 3 to 6% (w / w%) Avicel PH 200, and 0.1 to 0.5% (w / w%) lubricant; and A semipermeable membrane coating having at least one delivery port containing 8 to 10% (w / w%) cellulose acetate and 0.5 to 3% (w / w%) polyethylene glycol 3350 comprising.

[0112] In some embodiments, in combination with the above or other embodiments below, the pharmaceutical formulation is 15 to 16% (w / w%) omecamtiv mecarbil salt or crystalline form, 50 to 52% (w / w%) PolyOx TM A drug layer containing WSR N-80 and 0.1 to 0.5% (w / w%) magnesium stearate; 20 to 23 (w / w%) PolyOx TM A swelling layer containing a WSR aggregating agent, 4 to 9% (w / w%) sodium chloride, 3 to 6% (w / w%) Avicel PH 200, and 0.1 to 0.5% (w / w%) lubricant; and A semipermeable membrane coating having at least one delivery port containing 8 to 9% (w / w%) cellulose acetate and 2 to 3% (w / w%) polyethylene glycol 3350 comprising.

[0113] In some embodiments, in combination with the above or other embodiments below, the pharmaceutical formulation is 15 to 16% (w / w%) omecamtiv mecarbil salt or crystalline form, 50 to 52% (w / w%) PolyOx TM A drug layer containing WSR N-80 and 0.1 to 0.5% (w / w%) magnesium stearate; 20 to 23 (w / w%) PolyOx TM A swelling layer containing a WSR aggregating agent, 4 to 9% (w / w%) sodium chloride, 3 to 6% (w / w%) Avicel PH 200, and 0.1 to 0.5% (w / w%) lubricant; and A semipermeable membrane coating having at least one delivery port containing 9 to 10 (w / w%) cellulose acetate and 0.5 to 2 (w / w%) polyethylene glycol 3350 comprises.

[0114] Method of use The omecamtiv mecarbil salts or crystalline forms disclosed herein, or the pharmaceutical compositions described herein, can be used for the treatment or prevention of diseases associated with heart failure, such as, but not limited to, acute (or decompensated) congestive heart failure and chronic congestive heart failure; particularly systolic heart failure.

[0115] Also provided herein is a method for treating or preventing heart failure in a subject in need thereof, comprising administering to the subject one or more of the omecamtiv mecarbil salts or crystalline forms disclosed herein, or one or more of the pharmaceutical compositions described herein, in an amount effective to treat or prevent heart failure. Further provided is a method of using the disclosed omecamtiv mecarbil salts and crystalline forms, or compositions thereof, for the treatment or prevention of diseases associated with heart failure, such as, but not limited to, acute (or decompensated) congestive heart failure and chronic congestive heart failure; particularly systolic heart failure.

[0116] Also provided herein is the use of the omecamtiv mecarbil salts or crystalline forms disclosed herein, or the pharmaceutical compositions described herein, in the manufacture of a medicament for the treatment or prevention of heart failure. In some embodiments, the present disclosure provides the use of the omecamtiv mecarbil salts or crystalline forms disclosed herein, or the pharmaceutical compositions described herein, in the manufacture of a medicament for the treatment of diseases associated with acute (or decompensated) congestive heart failure and chronic congestive heart failure; particularly systolic heart failure.

[0117] "Treatment" or "treating" includes one or more of the following: a) inhibiting a disease or disorder; b) delaying or halting the onset of clinical symptoms of a disease or disorder; and / or c) alleviating a disease or disorder, i.e., causing a reduction in clinical symptoms. The term includes both complete and partial reduction of a condition or disorder, as well as complete or partial reduction of clinical symptoms of a disease or disorder. Thus, the salts or crystalline forms of omecamtiv mecarbil described herein, or the pharmaceutical compositions described herein, can prevent the worsening of an existing disease or disorder, assist in the management of a disease or disorder, or reduce or eliminate a disease or disorder. "Prevention", i.e., not causing the clinical symptoms of a disease or disorder, includes, for example, the prophylactic administration of a pharmaceutical formulation described herein to a subject (i.e., an animal, preferably a mammal, most preferably a human) considered to be in need of prophylactic treatment, such as for chronic heart failure.

Example

[0118] Method X-ray powder diffraction Procedure A: XRPD analysis was performed on a PANalytical X’pert pro, scanning the sample from 3 to 35° 2θ. The material was gently milled to release aggregates and mounted on a multiwell plate with a Kapton or Mylar polymer film to support the sample. The multiwell plate was then placed in the diffractometer and run and analyzed in transmission mode (step size 0.0130° 2θ) using CuK irradiation (α1 λ = 1.54060 Å; α2 = 1.54443 Å; β = 1.39225 Å; α1:α2 ratio = 0.5) with a 40 kV / 40 mA generator setting:

[0119] Procedure B: XRPD analysis was performed using a PANalytical X’pert pro, scanning the sample at 3 - 40° 2θ. The material was mounted on a zero - background sample holder and then placed on a diffractometer on a spin stage rotating once per second. Using CuK radiation (α1λ = 1.54060 Å; α2 = 1.54443 Å; β = 1.39225 Å; α1:α2 ratio = 0.5), it was run and analyzed in transmission mode (step size 0.0167° 2θ) using a 45 kV / 40 mA generator setting:

[0120] Procedure C: Using CuKα irradiation (40 kV, 40 mA), an automated XYZ stage, a laser video microscope for automatic sample positioning, and a HiStar two - dimensional area detector, an X - ray powder diffraction pattern was collected using a Bruker AXS C2 GADDS diffractometer. The X - ray optical system consisted of a single GObel multilayer mirror coupled with a 0.3 mm pinhole collimator. The beam divergence, i.e., the effective size of the X - ray beam on the sample, was approximately 4 mm. A θ - θ continuous scanning mode was used at a sample - detector distance of 20 cm giving an effective 2θ range of 3.2° - 29.7°. Usually, the sample was exposed to the X - ray beam for 120 seconds. Ambient conditions. Samples carried out under ambient conditions were prepared as flat specimens using the received powders with and without grinding. Approximately 1 - 2 mg of the sample was lightly pressed on a slide glass to obtain a flat surface.

[0121] Differential Scanning Calorimetry (DSC) Procedure A: Thermal properties were characterized using a DSC Q1000 or DSC Q100 type, TA Instruments, differential scanning calorimeter, and a Q500, TA Instruments, thermogravimetric analyzer. Data analysis was performed using Universal Analysis 2000, TA Instruments. For differential scanning calorimetry and thermogravimetric analysis, heating rates of 1, 10, and 100 °C / min were used over various temperature ranges. For DSC analysis, samples in the range of 1 - 5 mg were prepared in crimped, hermetically sealed, or open aluminum pans.

[0122] Procedure B: DSC data were collected using a TA Instruments Q2000 equipped with a 50-position autosampler. The instrument was calibrated using certified indium for energy and temperature calibration. Generally, 0.5 - 3 mg of each sample was heated from 25 °C to 350 °C at 10 °C / min in an aluminum pan with a pinhole. A nitrogen purge of 50 ml / min was maintained over the sample. The instrument control software was Thermal Advantage v4.6.6, and the data were analyzed using Universal Analysis v4.3A.

[0123] Thermogravimetric / differential thermal analysis (TG / DTA) Approximately 5 mg of the material was weighed into an open aluminum pan, loaded into a simultaneous thermogravimetric / differential thermal analyzer (TG / DTA), and held at room temperature. The sample was then heated from 20 °C to 300 °C at a rate of 10 °C / min, during which the change in sample weight was recorded along with any differential thermal events (DTA). Nitrogen was used as the purge gas at a flow rate of 300 cm 3 / min.

[0124] Thermogravimetric analysis Procedure A: Thermograms were collected using a TA Instruments Q500 thermogravimetric analyzer. The sample was loaded into a platinum pan (1 - 10 mg) and heated from ambient temperature to 300 °C at 10 °C / min.

[0125] Procedure B: TGA data were collected using a TA Instruments Q500 TGA equipped with a 16-position autosampler. The instrument was temperature calibrated using certified alumel. Generally, 5 - 30 mg of each sample was loaded into a platinum crucible and an aluminum DSC pan whose tare weight had been previously measured, and heated from ambient temperature to 350 °C at 10 °C / min. A nitrogen purge of 60 ml / min was maintained over the sample. The instrument control software was Thermal Advantage v4.6.6, and the data were analyzed using Universal Analysis v4.3A.

[0126] Water sorption The moisture balance was collected using a Dynamic Vapor Sorption (DVS) analyzer. The relative humidity (RH) was set to 0, 5, 15, 25, 35, 45, 55, 65, 75, 85, and 95% RH for two sorption / desorption cycles at 25 °C. The equilibration criterion was set to 0.001 wt%. Approximately 10 mg of sample was used.

[0127] Solubility Excess solid was added to water, buffer at pH 1.0 or pH 4.5 to form a suspension, and dispersed at room temperature for at least 24 hours. The suspension was filtered. The filtrate was analyzed by HPLC-UV and the solution concentration of the crystalline form was measured by comparing with a standard curve.

[0128] Experimental Section Free base crystalline form III: Prepared by Procedure A - 429 mg of omecamtiv mecarbil was added to 20 mL of 2-propanol and 20 mL of water, then heated to 50 °C to dissolve, and then precipitated with 200 mL of water.

[0129] Procedure B - During solubility screening, prepared from seven different solvents (2-BuOAc slurry, cumene slurry, isopropyl acetate slurry, MTBE slurry, heptane slurry, tBuOAc slurry, or toluene slurry). 10 mg of the free base was placed in a vial, and 50 μL aliquots of the solvent were added to the vial, first 300 μL, then 100 μL (up to 1 mL). Between each addition, the dissolution of the mixture was checked, and if dissolution was not evident, the mixture was heated to approximately 50 °C and checked again. This procedure was continued until dissolution was observed or 100 volumes of solvent had been added. If dissolution did not occur, the solid was filtered and XRPD was collected. If dissolution occurred, the cap was removed and the solvent was evaporated, and XRPD of the remaining solid was collected. Then, 60 mg of lyophilized free base was added to the solvent and the free base crystalline form III was regenerated from the cumene, isopropyl acetate, MTBE, or tBuOAc slurry by gently heating to approximately 40 °C.

[0130] Omecamtiv mecarbil free base crystalline form III was characterized by an XRPD pattern comprising the peaks in Table 1.

[0131]

Table 1

[0132] Free base crystalline form IV: Prepared by precipitating 46 mg of omecamtiv mecarbil from 2 mL of THF with 2 mL of n-butyl ether.

[0133] Omecamtiv mecarbil free base crystalline form IV was characterized by an XRPD pattern comprising the peaks in Table 2.

[0134]

Table 2

[0135] Free base crystalline form V: Prepared by Procedure A - adding 50 mg of omecamtiv mecarbil to 2 mL of THF at 60 °C, filtering, and then crashing and cooling the sample in an acetone / dry ice bath.

[0136] Procedure B - During solubility screening, free base crystalline form V was prepared from a 1,4-dioxane slurry. 10 mg of the free base was placed in a vial, and 50 μL aliquots of solvent were added to the vial, first 300 μL and then 100 μL (up to 1 mL). Between each addition, the dissolution of the mixture was checked, and if dissolution was not apparent, the mixture was heated to about 50 °C and checked again. This procedure was continued until dissolution was observed or 100 volumes of solvent had been added. If dissolution did not occur, the solid was filtered and XRPD was collected. If dissolution occurred, the cap was removed and the solvent was evaporated, and XRPD of the remaining solid was collected.

[0137] Omecamtiv mecarbil free base crystalline form V was characterized by an XRPD pattern comprising the peaks in Table 3.

[0138]

Table 3

[0139] Free base crystalline form VI: Prepared by heating free base crystalline form V to 150 °C.

[0140] Omecamtiv mecarbil free base crystalline form VI was characterized by an XRPD pattern including the peaks in Table 4.

[0141]

Table 4

[0142] Free base crystalline form VII: Prepared from an aqueous slurry during solubility screening. 10 mg of the free base was placed in a vial, and 50 μL aliquots of water were added to the vial, first 300 μL and then 100 μL (up to 1 mL). Between each addition, the dissolution of the mixture was checked, and if dissolution was not evident, the mixture was heated to about 50 °C and checked again. This procedure was continued until dissolution was observed or 100 volumes of solvent had been added. The solid was filtered and XRPD was collected.

[0143] Omecamtiv mecarbil free base crystalline form VII was characterized by an XRPD pattern including the peaks in Table 5.

[0144]

Table 5

[0145] The XRPD peaks specific to each of the free base crystalline forms III - VII disclosed herein are shown in Table 6.

[0146]

Table 6

[0147] Amorphous hydrochloride: 0.505 g of bis hydrochloride monohydrate Form A was dissolved in 20 mL of water, rapidly frozen with liquid nitrogen, and lyophilized to prepare amorphous bis hydrochloride. As a result of chloride analysis, 14.6% Cl, which corresponds to bis hydrochloride, was obtained. Thermal analysis showed a weight loss of approximately 7.9% due to water loss during heating and a Tg of approximately 149 °C. The water vapor sorption test showed that this amorphous form is hygroscopic and converts to crystalline bis hydrochloride monohydrate Form A.

[0148] Ethanesulfonic acid crystalline salt: Prepared in the primary salt screening. A 2 mL aliquot of acetone was added to approximately 40 mg of the free base. 1.05 equivalents of ethanesulfonate as a 1 M solution in THF was added, and the sample was subjected to temperature cycling for 3 - 5 days.

[0149] The ethanesulfonic acid crystalline salt of omecamtiv mecarbil was characterized by an XRPD pattern containing the peaks in Table 7.

[0150]

Table 7

[0151] Bis fumaric acid crystalline salt Form A: Prepared by dissolving 1 equivalent of the free base (4.104 g) and 2.1 equivalents of fumaric acid (as 84 mL of 95% EtOH / aqueous solution) in 20 mL of 90% THF aqueous solution, and then distilling at 50 °C under house vacuum. An additional 92 mL of water and seeds of monofumarate Form A were added to induce precipitation.

[0152] The bis fumaric acid crystalline salt Form A of omecamtiv mecarbil was characterized by an XRPD pattern containing the peaks in Table 8.

[0153]

Table 8

[0154] Bis-fumaric acid crystalline salt form B: Prepared during the DVS cycle of bis-fumarate form A.

[0155] Bis-fumaric acid crystalline salt form B of omecamtiv mecarbil was characterized by an XRPD pattern including the peaks in Table 9.

[0156] [Table 9]

[0157] Bis-fumaric acid crystalline salt form C: Prepared at room temperature from a slurry of bis-fumarate forms A and B in 2 mL of water. The water solubility was measured to be 13.7 mg / mL (pH 3.1).

[0158] Bis-fumaric acid crystalline salt form C of omecamtiv mecarbil was characterized by an XRPD pattern including the peaks in Table 10.

[0159] [Table 10]

[0160] Monofumaric acid crystalline salt form D: First, during high-throughput screening, 0.3 mL of a 0.05 M methanol solution of the free base and 0.3 mL of a 0.05 M methanol solution of fumaric acid were added to a glass plate, then the solvent was evaporated, then 0.4 mL of a solvent (water, 0.001 M aqueous HCl, acetone, acetonitrile or hexane) was added, heated at 50 °C for 4 hours, and then evaporated.

[0161] Monofumaric acid crystalline salt form D of omecamtiv mecarbil was characterized by an XRPD pattern including the peaks in Table 11.

[0162] [Table 11]

[0163] The XRPD peaks specific to each of the fumaric acid crystal forms A - D disclosed in this specification are shown in Table 12.

[0164] [Table 12]

[0165] Bis - maleic acid crystal form A: Procedure A: First, during high - throughput screening, 0.2 mL of a 0.124 M methanol solution of the free base and 0.2 mL of a 0.25 M methanol solution of maleic acid were added to a glass plate, then the solvent was evaporated, then 0.2 mL of a solvent (water, 0.001 M aqueous HCl, or acetone) was added, heated at 50 °C for 4 hours, and then evaporated. The salt was scaled up by adding 100 mg of the free base and 5 mL of methanol to an 8 - mL vial and gently heating to dissolve. Maleic acid (2 mL of a 0.25 M solution in acetone) was added at room temperature. The precipitate was isolated by filtration.

[0166] Procedure B - 3.011 g of the free base (1 equivalent) and 1.828 g of maleic acid (solution in 8 mL of MeOH; 2.1 equivalents) were dissolved in 45 mL of methanol at 60 °C and then cooled to precipitate bis - maleic acid crystal form A. The water solubility was measured to be 3.8 mg / mL (pH 3.7).

[0167] Procedure C - Bis - maleic acid crystal form A was also prepared during primary salt screening. 2 - mL aliquots of 2 - propanol, THF, acetonitrile, isopropyl acetate, or acetone were added to approximately 40 mg of the free base. 1.05 equivalents of maleic acid were added as a 1 M solution in THF, and the sample was subjected to temperature cycling for 3 - 5 days.

[0168] The bis - maleic acid crystal form A of omecamtiv mecarbil was characterized by an XRPD pattern containing the peaks in Table 13.

[0169] [Table 13]

[0170]

Table 14

[0171] Bismalonate crystal salt: Prepared by dissolving 200.7 mg of free base (1 equivalent) and malonic acid (2.1 equivalents) in methanol in 525 μL of methanol in 5 mL of methanol at 50 °C, then adding 0.5 mL of IPAc to precipitate, and then subjecting to 2 heat cycles at 40 °C / room temperature. The water solubility was determined to be greater than 62 mg / mL (pH 3.69).

[0172] The bismalonate crystal salt of omecamtiv mecarbil was characterized by an XRPD pattern including the peaks in Table 14.

[0173]

Table 15

[0174] Mesylate crystal form A: Prepared by dissolving 200.7 mg of free base (1 equivalent) and methanesulfonic acid (2.1 equivalents) in 68.1 μL of methanol in 5 mL of methanol at 50 °C, and adding 2 mL of IPAc and 5 mL of acetone to precipitate. The water solubility was determined to be greater than 72 mg / mL (pH 1.39).

[0175] The mesylate crystal form A of omecamtiv mecarbil was characterized by an XRPD pattern including the peaks in Table 15.

[0176]

Table 16

[0177] Bis(mesylate) crystal form B: Prepared by primary salt screening. A 2 mL aliquot of 2-propanol was added to approximately 40 mg of the free base. 1.05 equivalents of methanesulfonic acid was added as a 1 M solution in THF, and the sample was subjected to temperature cycling for 3 - 5 days, then tert-butyl methyl ether was added as an antisolvent. The solubility in pH 1 and 4.5 buffers was determined to exceed 23 mg / mL.

[0178] The bis(mesylate) crystal form B of omecamtiv mecarbil was characterized by an XRPD pattern including the peaks in Table 16.

[0179] [Table 17]

[0180] [Table 18]

[0181] The XRPD peaks specific to each of the mesylate crystal forms A and B disclosed herein are shown in Table 17.

[0182] [Table 19]

[0183] Bisnaphthalene-2-sulfonic acid crystal salt was prepared. In the primary (small-scale) screening, 2 mL aliquots of 2-propanol, THF, acetonitrile, isopropyl acetate, acetone or toluene were added to 40 mg of the free base, 1.05 equivalents of the sodium salt of naphthalene-2-sulfonic acid and 1.0 equivalent of 1 M hydrochloric acid were added, and then the temperature cycle was applied for 3 - 5 days. The salt was analyzed by XRPD. In the secondary screening (scale-up), 1.05 equivalents of naphthalene-2-sulfonate and 2 M hydrochloric acid in THF were added to 700 mg of the free base in 7 mL of 2-propanol, then the temperature cycle (room temperature - 40 °C) was carried out for 3 days, filtered, and dried at ambient temperature in a vacuum oven. The salt was analyzed by XRPD, IR, HPLC, 1H NMR, PLM, TG / DTA, DSC, DVS, VH-XRPD, stability test, thermodynamic solubility test, disproportionation test and hydration test. The solubility in pH 1 and 4.5 buffers was determined to exceed 10 mg / mL.

[0184] The bisnaphthalene-2-sulfonic acid crystal salt of omecamtiv mecarbil was characterized by an XRPD pattern including the peaks in Table 18.

[0185]

Table 20

[0186] Mononapadisylate crystal salt: During high-throughput screening, 0.2 mL of a 0.124 M methanol solution of the free base and 0.2 mL of a 0.25 M methanol solution of 1,5-naphthalene-disulfonic acid were added to a glass plate, then the solvent was evaporated, then 0.2 mL of solvent (acetonitrile or 0.001 M aqueous HCl) was added, heated at 50 °C for 4 hours, and then evaporated. The salt was scaled up by adding 100 mg of the free base and 3 mL of methanol to an 8 mL vial and gently heating to dissolve. 1,5-Naphthalene-disulfonic acid (2 mL of a 0.25 M solution) was added at room temperature. After evaporation and filtration, the solid was collected. The water solubility was measured to be 0.3 mg / mL (pH 2.35).

[0187] The mononapadisylate crystal salt of ome-camtib mecabil was characterized by an XRPD pattern comprising the peaks of Table 19.

[0188] [Table 21]

[0189] Nicotinate crystal salt: Prepared in primary salt screening. A 2 mL aliquot of acetone was added to approximately 40 mg of the free base. 1.05 equivalents of nicotinic acid were added, and the sample was subjected to temperature cycling for 3 - 5 days and then evaporated.

[0190] The nicotinate crystal salt of ome-camtib mecabil was characterized by an XRPD pattern comprising the peaks of Table 20.

[0191] [Table 22]

[0192] Oxalate crystal form A: During procedure A - high-throughput screening, 0.3 mL of a 0.05 M methanol solution of the free base and 0.3 mL of a 0.05 M methanol solution of oxalic acid were added to a glass plate, then the solvent was evaporated, then 0.4 mL of a solvent (water, 0.001 M aqueous HCl, acetone, acetonitrile or hexane) was added, heated at 50 °C for 4 hours, and then evaporated.

[0193] Procedure B - 47 mg of the free base was dissolved in approximately 10 mL of methanol, then 145 μL of a 102 mg / mL oxalic acid solution was added, and the sample was prepared by placing it in an N2 box. The solid was then slurried with water / ethanol at room temperature.

[0194] The oxalate crystal form A of ome-camtib mecabil was characterized by an XRPD pattern comprising the peaks of Table 21.

[0195]

Table 23

[0196] Oxalic acid crystal form B: Prepared during the water vapor sorption analysis of oxalic acid crystal form A.

[0197] The oxalic acid crystal form B of omecamtiv mecarbil was characterized by an XRPD pattern that included the peaks in Table 22.

[0198]

Table 24

[0199] The XRPD peaks specific to each of the oxalic acid crystal forms A and B disclosed herein are shown in Table 23.

[0200]

Table 25

[0201] Salicylic acid crystal salt: Prepared in the primary salt screening. A 2 mL aliquot of 2-propanol or toluene was added to approximately 40 mg of the free base. 1.05 equivalents of salicylic acid was added as a 1 M solution in THF, and the sample was subjected to temperature cycling for 3 - 5 days, and then 2-propanol or toluene was evaporated.

[0202] The salicylic acid crystal salt of omecamtiv mecarbil was characterized by an XRPD pattern that included the peaks in Table 24.

[0203]

Table 26

[0204] Hemisuccinate crystal salt: During high-throughput screening, 0.3 mL of a 0.05 M methanol solution of the free base and 0.3 mL of a 0.05 M methanol solution of succinic acid were added to a glass plate, then the solvent was evaporated, then 0.4 mL of a solvent (water, 0.001 M aqueous HCl solution, acetone, acetonitrile or hexane) was added, heated at 50 °C for 4 hours, and then evaporated. The water solubility was measured to be 7.4 mg / mL (pH 4.7).

[0205] The hemisuccinate crystal salt of omecamtiv mecarbil was characterized by an XRPD pattern including the peaks in Table 25.

[0206] [Table 27]

[0207] Bisulfate crystal form A: During procedure A - high-throughput screening, 0.2 mL of a 0.124 M methanol solution of the free base and 0.2 mL of a 0.25 M methanol solution of sulfuric acid were added to a glass plate, then the solvent was evaporated, then 0.2 mL of a solvent (THF or 0.001 M aqueous HCl solution) was added, heated at 50 °C for 4 hours, and then evaporated. The salt was scaled up by adding 100 mg of the free base and 4 mL of methanol to an 8 mL vial and gently heating to dissolve. Sulfuric acid (2 mL of a 0.25 M solution) was added at room temperature. After evaporation to dryness, the solid was collected.

[0208] Procedure B: Prepared by dissolving 200.7 mg of the free base (1 equivalent) and 1.05 mL of 1 M sulfuric acid (2.1 equivalents) in 5 mL of methanol at 50 °C and then cooling to precipitate.

[0209] Procedure C - Form D was formed by exposing to storage conditions of 40 °C / 75% RH for 3 days. The water solubility was measured to be 16 mg / mL (pH 1.5).

[0210] The bisulfate crystal form A of omecamtiv mecarbil was characterized by an XRPD pattern including the peaks in Table 26.

[0211]

Table 28

[0212]

Table 29

[0213] Bisulfate crystal form B: Prepared by dissolving 150 mg of the free base in 20 mL of acetone, adding 22 μL of 17.6 M sulfuric acid, and then sonicating. The isolated solid was slurried with water at room temperature. The water solubility was measured to be 9 mg / mL (pH 3.5).

[0214] The bisulfate crystal form B of omecamtiv mecarbil was characterized by an XRPD pattern including the peaks in Table 27.

[0215]

Table 30

[0216] Bisulfate crystal form C: Prepared by heating bisulfate form B in TGA.

[0217] The bisulfate crystal form C of omecamtiv mecarbil was characterized by an XRPD pattern including the peaks in Table 28.

[0218]

Table 31

[0219] Sulfate crystal form D: Prepared in the primary salt screening. To prepare form D, a 2 mL aliquot of acetone was added to approximately 40 mg of the free base. 1.05 equivalents of sulfuric acid were added as a 1 M solution in THF, and the sample was subjected to temperature cycling for 3 - 5 days.

[0220] The sulfate crystalline salt form D of omecamtiv mecarbil was characterized by an XRPD pattern containing the peaks in Table 29.

[0221]

Table 32

[0222] The XRPD peaks specific to each of the sulfate crystalline salt forms A - D disclosed herein are shown in Table 30.

[0223]

Table 33

[0224] 2 - hydroxyethanesulfonic acid crystalline salt: Prepared in primary salt screening. A 2 mL aliquot of THF, acetonitrile or isopropyl acetate was added to approximately 40 mg of the free base. 1.05 equivalents of 2 - hydroxyethanesulfonic acid as a solid and 1 equivalent of 1 M hydrochloric acid were added, and the sample was subjected to temperature cycling for 3 - 5 days.

[0225] The 2 - hydroxyethanesulfonic acid crystalline salt of omecamtiv mecarbil was characterized by an XRPD pattern containing the peaks in Table 31.

[0226]

Table 34

[0227] Bis - tartaric acid crystalline salt form A: Prepared by dissolving 200.7 mg (1 equivalent) of the free base and 525 μL of tartaric acid (30.02 g in 100 mL of methanol, 2.1 equivalents) in 20 mL of methanol and subjecting it to 2 heat cycles at 40 °C / RT. The water solubility was measured to be >53 mg / mL (pH 3.28).

[0228] The bis-tartrate crystal form A of omecamtiv mecarbil was characterized by an XRPD pattern including the peaks in Table 32.

[0229] [Table 35]

[0230] Bis-tartrate crystal form B: Prepared by dissolving 1.004 g of omecamtiv mecarbil and 0.788 g of L-tartaric acid (2.1 equivalents) in 50 mL of MeOH at 50 °C and then cooling to precipitate.

[0231] The bis-tartrate crystal form B of omecamtiv mecarbil was characterized by an XRPD pattern including the peaks in Table 33.

[0232] [Table 36]

[0233] Bis-tartrate crystal form C: Prepared from the water slurry of bis-tartrate form B.

[0234] The bis-tartrate crystal form C of omecamtiv mecarbil was characterized by an XRPD pattern including the peaks in Table 34.

[0235] [Table 37]

[0236] Mono-tartrate crystal form D: Prepared by mixing 1.004 g of omecamtiv mecarbil and 0.375 g of L-tartaric acid (1 equivalent) in 10 mL of THF containing 5% H2O at 50 °C and then cooling to precipitate.

[0237] The mono-tartrate crystal form D of omecamtiv mecarbil was characterized by an XRPD pattern including the peaks in Table 35.

[0238]

Table 38

[0239] The XRPD peaks specific to each of the tartaric acid crystal forms A to D disclosed in this specification are shown in Table 36.

[0240]

Table 39

Claims

1. Omecamtiv mecarbil free base crystal form III, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 9.50, 19.06 and 23.01 ± 0.2° 2θ using CuKα irradiation.

2. Omecamtiv mecarbil according to claim 1, further characterized by XRPD pattern peaks at 14.27, 15.25, 16.10, 17.78 and 23.87 ± 0.2° 2θ using CuKα irradiation.

3. Omecamtiv mecarbil according to claim 2, further characterized by XRPD pattern peaks at 7.91, 20.65, 28.11, 31.01, 31.95 and 32.34 ± 0.2° 2θ using CuKα irradiation.

4. Omecamtiv mecarbil according to any one of claims 1 to 3, having an XRPD pattern substantially as shown in Figure 1.

5. Omecamtiv mecarbil according to any one of claims 1 to 4, having an endothermic transition at 175°C to 190°C as measured by differential scanning calorimetry.

6. Omecamtiv mecarbil according to claim 5, wherein said endothermic transition is at 186°C ± 3°C.

7. Omecamtiv mecarbil according to any one of claims 1 to 6, having a thermogravimetric analysis (TGA) substantially as shown in Figure 3.

8. Omecamtiv mecarbil free base crystal form IV, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.18, 10.35, 14.84, 15.54, 18.10 and 19.92 ± 0.2° 2θ using CuKα irradiation.

9. Omecamtiv mecarbil according to claim 8, further characterized by XRPD pattern peaks at 14.21, 20.62, 20.77, 22.86, 24.05, 24.36, 27.81 and 29.42 ± 0.2° 2θ using CuKα irradiation.

10. Omecamtiv mecarbil according to claim 9, further characterized by XRPD pattern peaks at 7.42, 7.70, 21.70, 22.40, 23.09, 25.20, 25.72, 27.40, 28.18, 28.63, 28.98 and 30.51 ± 0.2° 2θ using CuKα irradiation.

11. Omecamtiv mecarbil according to any one of claims 8 to 10, having an XRPD pattern substantially as shown in Figure 4.

12. The omega cam tib mecalvir according to any one of claims 8 to 11, having an endothermic transition at 175°C to about 190°C in a measurement by differential scanning calorimetry.

13. The omega cam tib mecalvir according to claim 12, wherein the endothermic transition is at 185°C ± 3°C.

14. The omega cam tib mecalvir according to any one of claims 8 to 13, having thermogravimetric analysis (TGA) as shown in FIG.

6.

15. Omega cam tib mecalvir free base crystal form V characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 7.38, 8.56, 9.14 and 18.28 ± 0.2° 2θ using CuKα irradiation.

16. The omega cam tib mecalvir according to claim 15, further characterized by XRPD pattern peaks at 8.93, 10.03, 10.73, 11.71, 13.69, 15.08, 16.85, 17.85, 18.86, 20.05, 20.72, 21.74, 23.56, 24.03, 26.23 and 27.62 ± 0.2° 2θ using CuKα irradiation.

17. The omega cam tib mecalvir according to claim 16, further characterized by XRPD pattern peaks at 5.40, 16.04, 22.83, 25.45, 26.23, 27.62, 28.58, 29.85, 32.10 and 33.37 ± 0.2° 2θ using CuKα irradiation.

18. The omega cam tib mecalvir according to any one of claims 15 to 17, having an XRPD pattern substantially as shown in FIG.

7.

19. The omega cam tib mecalvir according to any one of claims 15 to 18, having an endothermic transition at 175°C to 190°C in a measurement by differential scanning calorimetry.

20. The omega cam tib mecalvir according to claim 19, wherein the endothermic transition is at 185°C ± 3°C.

21. The omega cam tib mecalvir according to any one of claims 15 to 20, having thermogravimetric analysis (TGA) as shown in FIG.

9.

22. Omega cam tib mecalvir free base crystal form VI characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 9.07, 16.67, 18.18, 19.70, 20.89 and 21.28 ± 0.2° 2θ using CuKα irradiation.

23. Omecamtiv mecarbil according to claim 22, further characterized by XRPD pattern peaks at 15.88, 17.81, 18.80, 23.72, 24.26, 26.80, 27.59 and 29.82 ± 0.2° 2θ using CuKα irradiation.

24. Omecamtiv mecarbil according to claim 23, further characterized by XRPD pattern peaks at 14.28, 20.23, 26.19 and 28.90 ± 0.2° 2θ using CuKα irradiation.

25. Omecamtiv mecarbil according to any one of claims 22 to 24, having an XRPD pattern substantially as shown in FIG.

10.

26. Omecamtiv mecarbil according to any one of claims 22 to 25, having an endothermic transition at 175°C to 190°C as measured by differential scanning calorimetry.

27. Omecamtiv mecarbil according to claim 26, wherein the endothermic transition is at 185°C ± 3°C.

28. Omecamtiv mecarbil free base crystalline form VII, characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 8.40, 8.71, 13.08, 15.66 and 19.61 ± 0.2° 2θ using CuKα irradiation.

29. Omecamtiv mecarbil according to claim 28, further characterized by XRPD pattern peaks at 4.37, 16.83, 18.92, 20.32, 20.49, 22.26, 24.21 and 25.41 ± 0.2° 2θ using CuKα irradiation.

30. Omecamtiv mecarbil according to claim 29, further characterized by XRPD pattern peaks at 7.84, 10.81, 21.61, 23.22, 23.46, 27.58, 29.53, 30.13 and 31.32 ± 0.2° 2θ using CuKα irradiation.

31. Omecamtiv mecarbil according to any one of claims 28 to 30, having an XRPD pattern substantially as shown in FIG.

12.

32. Omecamtiv mecarbil ethanesulfonic acid crystal salt, characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 8.61, 16.14, 16.76, 16.97, 20.73, 20.96, 25.95 and 26.30 ± 0.2° 2θ using CuKα irradiation.

33. Omecamtiv mecarbil as claimed in claim 32, further characterized by XRPD pattern peaks at 17.23, 18.35, 19.20, 20.27, 23.73, 25.24, and 27.09 ± 0.2° 2θ using CuKα irradiation.

34. Omecamtiv mecarbil as claimed in claim 32 or 33, having an XRPD pattern substantially as shown in FIG.

18.

35. Omecamtiv mecarbil bisfumarate crystal salt, Form A, characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 5.64, 15.76, 22.03 and 23.87 ± 0.2° 2θ using CuKα irradiation.

36. Omecamtiv mecarbil as claimed in claim 35, further characterized by XRPD pattern peaks at 16.80, 21.55, 21.87, 23.61, 23.87, 26.01 and 27.20 ± 0.2° 2θ using CuKα irradiation.

37. Omecamtiv mecarbil as claimed in claim 36, further characterized by XRPD pattern peaks at 10.80, 12.04, 15.76, 16.40, 17.94, 18.32, 19.87, 20.61, 22.88, 27.86, 32.73 and 36.54 ± 0.2° 2θ using CuKα irradiation.

38. Omecamtiv mecarbil as claimed in any one of claims 35 to 37, having an XRPD pattern substantially as shown in FIG.

20.

39. Omecamtiv mecarbil as claimed in any one of claims 35 to 38, having a thermogravimetric analysis (TGA) as shown in FIG.

21.

40. Omecamtiv mecarbil bisfumarate crystal salt, Form B, characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 5.68, 6.11, 13.13, 18.08 and 22.47 ± 0.2° 2θ using CuKα irradiation.

41. Omecamtiv mecarbil as claimed in claim 40, further characterized by XRPD pattern peaks at 9.69, 11.43, 12.92, 15.95, 20.81, 22.95, 26.04, 27.01 and 28.43 ± 0.2° 2θ using CuKα irradiation.

42. Omega-cimbucalvir as claimed in claim 41, further characterized by XRPD pattern peaks at 19.52, 24.53, 31.37, 32.32, 34.89, 35.89 and 37.16 ± 0.2° 2θ using CuKα irradiation.

43. Omega-cimbucalvir as claimed in any one of claims 40 to 42, having an XRPD pattern substantially as shown in Figure 22.

44. Omega-cimbucalvir as claimed in any one of claims 40 to 43, having thermogravimetric analysis (TGA) as shown in Figure 23.

45. Omega-cimbucalvir bisfumarate crystal salt, Form C, characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 5.88, 18.79, 25.41 and 26.86 ± 0.2° 2θ using CuKα irradiation.

46. Omega-cimbucalvir as claimed in claim 45, further characterized by XRPD pattern peaks at 12.74, 13.56, 17.15, 17.63, 20.29, 21.47, 21.77, 22.21, 22.92, 23.58, 24.15, 25.41, 26.78 and 27.83 ± 0.2° 2θ using CuKα irradiation.

47. Omega-cimbucalvir as claimed in claim 45 or 46, having an XRPD pattern substantially as shown in Figure 24.

48. Omega-cimbucalvir as claimed in any one of claims 45 to 47, having thermogravimetric analysis (TGA) as shown in Figure 25.

49. Omega-cimbucalvir monofumarate crystal salt, Form D, characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 8.01, 15.20 and 20.02 ± 0.2° 2θ using CuKα irradiation.

50. Omega-cimbucalvir as claimed in claim 49, further characterized by XRPD pattern peaks at 12.11, 12.67, 14.46, 16.01, 16.57, 17.04, 17.63, 20.51, 21.75, 22.86, 24.25, 24.97, 25.84, 26.17, 27.10, 27.97 and 29.21 ± 0.2° 2θ using CuKα irradiation.

51. Omega-cimbucalvir as claimed in claim 49 or 50, having an XRPD pattern substantially as shown in Figure 26.

52. The omega cam tib mecal bill according to any one of claims 49 to 51, having an endothermic transition at 110°C to 130°C in a measurement by differential scanning calorimetry.

53. The omega cam tib mecal bill according to claim 52, wherein the endothermic transition is at 125°C ± 3°C.

54. The omega cam tib mecal bill according to any one of claims 49 to 53, having thermogravimetric analysis (TGA) as shown in FIG.

28.

55. The omega cam tib mecal bill bismaleate crystal salt characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 9.97, 15.31, 16.04, and 26.96 ± 0.2° 2θ using CuKα irradiation.

56. The omega cam tib mecal bill according to claim 55, further characterized by XRPD pattern peaks at 10.56, 13.25, 15.53, 16.38, 17.44, 17.70, 18.17, 19.00, 20.13, 21.47, 22.31, 22.44, 24.38, 24.64, 25.66, 26.66, and 27.83 ± 0.2° 2θ using CuKα irradiation.

57. The omega cam tib mecal bill according to claim 56, further characterized by XRPD pattern peaks at 4.99, 14.83, 17.10, 22.02, 28.55, 30.76, 32.01, 34.39, and 34.51 ± 0.2° 2θ using CuKα irradiation.

58. The omega cam tib mecal bill according to any one of claims 55 to 57, having an XRPD pattern substantially as shown in FIG.

30.

59. The omega cam tib mecal bill according to any one of claims 55 to 58, having an endothermic transition at 160°C to 210°C in a measurement by differential scanning calorimetry.

60. The omega cam tib mecal bill according to claim 59, wherein the endothermic transition is at 190°C ± 3°C.

61. The omega cam tib mecal bill according to any one of claims 55 to 60, having thermogravimetric analysis (TGA) as shown in FIG.

32.

62. The omega cam tib mecal bill bismalonate crystal salt characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 4.74, 11.37, 14.25, 15.13, 18.29, 20.14, 23.87, 27.78, and 28.01 ± 0.2° 2θ using CuKα irradiation.

63. The omecamtiv mecarbil according to claim 62, further characterized by XRPD pattern peaks at 9.30, 13.73, 16.45, 16.83, 18.08, 18.88, 19.54, 20.77, 21.21, 23.32, 24.67, 26.51, 27.59 and 28.90 ± 0.2° 2θ using CuKα irradiation.

64. The omecamtiv mecarbil according to claim 63, further characterized by XRPD pattern peaks at 15.69, 25.72, 30.18, 33.70 and 34.19 ± 0.2° 2θ using CuKα irradiation.

65. The omecamtiv mecarbil according to any one of claims 62 to 64, having an XRPD pattern substantially as shown in Figure 33.

66. The omecamtiv mecarbil according to any one of claims 62 to 65, having thermogravimetric analysis (TGA) as shown in Figure 34.

67. The omecamtiv mecarbil mesylate crystal salt, Form A, characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 4.02, 4.87, 15.21, 15.86, 20.53 and 24.39 ± 0.2° 2θ using CuKα irradiation.

68. The omecamtiv mecarbil according to claim 67, further characterized by XRPD pattern peaks at 7.79, 11.61, 16.51, 17.57, 18.42, 19.26, 21.55, 23.17, 25.51, 26.38 and 27.63 ± 0.2° 2θ using CuKα irradiation.

69. The omecamtiv mecarbil according to claim 67 or 68, having an XRPD pattern substantially as shown in Figure 35.

70. The omecamtiv mecarbil according to any one of claims 67 to 69, having thermogravimetric analysis (TGA) as shown in Figure 36.

71. The omecamtiv mecarbil bis(mesylate) crystal salt, Form B, characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 8.30, 8.94, 9.59, 12.15, 14.37, 19.82, 20.29, 22.04 and 25.02 ± 0.2° 2θ using CuKα irradiation.

72. The omecamtiv mecarbil according to claim 71, further characterized by XRPD pattern peaks at 11.66, 16.18, 16.64, 16.81, 17.07, 17.19, 17.41, 17.76, 19.24, 20.66, 21.62, 22.39, 23.95, 24.60, 25.59, 25.89, 27.14, 27.35, 27.41 and 29.45 ± 0.2° 2θ using CuKα irradiation.

73. The omecamtiv mecarbil according to claim 72, further characterized by XRPD pattern peaks at 10.78, 11.15, 14.93, 15.36, 15.57, 23.54, 26.14, 26.49, 27.89, 28.86, 29.89, 31.11, 32.47, 33.10, 33.51 and 34.56 ± 0.2° 2θ using CuKα irradiation.

74. The omecamtiv mecarbil according to any one of claims 71 to 73, having an XRPD pattern substantially as shown in FIG.

37.

75. An omecamtiv mecarbil bisnaphthalene sulfonic acid-2-sulfonate crystal salt characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 4.49, 18.20, 18.62, 21.38, 21.52 and 26.11 ± 0.2° 2θ using CuKα irradiation.

76. The omecamtiv mecarbil according to claim 75, further characterized by XRPD pattern peaks at 6.25, 6.65, 13.44, 14.39, 14.92, 16.28, 18.90, 19.53, 20.82, 22.02, 22.43, 22.80, 24.40, 25.16, 27.01, 29.67, 31.63 and 33.42 ± 0.2° 2θ using CuKα irradiation.

77. The omecamtiv mecarbil according to claim 75 or 76, having an XRPD pattern substantially as shown in FIG.

40.

78. An omecamtiv mecarbil mononapadisylate crystal salt characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 12.27, 15.75, 16.5, 17.83, 19.94, 21.83 and 22.87 ± 0.2° 2θ using CuKα irradiation.

79. Omega Methylcobalamin, as further characterized by XRPD pattern peaks at 10.84, 13.41, 14.57, 15.14, 18.82, 23.49, 24.34 and 25.26 ± 0.2° 2θ using CuKα irradiation.

80. Omega Methylcobalamin according to claim 78 or 79, having an XRPD pattern substantially as shown in Figure 42.

81. Omega Methylcobalamin according to any one of claims 78 to 80, having differential scanning calorimetry (DSC) as shown in Figure 43.

82. Omega Methylcobalamin according to any one of claims 78 to 81, having thermogravimetric analysis (TGA) as shown in Figure 44.

83. Omega Methylcobalamin nicotinate crystal salt, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 3.69, 8.55, 9.13, 16.70, 16.84, 18.30, 19.99, 20.76, 23.43, 24.83 and 25.95 ± 0.2° 2θ using CuKα irradiation.

84. Omega Methylcobalamin according to claim 83, as further characterized by XRPD pattern peaks at 7.36, 10.01, 12.43, 14.74, 15.50, 17.62, 18.58, 19.59, 20.34, 21.32, 22.03, 22.91, 23.87, 24.92, 25.40, 26.85, 26.94, 27.32, 28.01 and 28.94 ± 0.2° 2θ using CuKα irradiation.

85. Omega Methylcobalamin according to claim 83 or 84, having an XRPD pattern substantially as shown in Figure 45.

86. Omega Methylcobalamin oxalate crystal salt, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.48, 13.01 and 23.82 ± 0.2° 2θ using CuKα irradiation.

87. Omega Methylcobalamin according to claim 86, as further characterized by XRPD pattern peaks at 10.36, 11.85, 14.79, 15.35, 17.11, 19.23, 19.91, 21.48, 22.07, 22.75, 25.70, 28.55 and 30.71 ± 0.2° 2θ using CuKα irradiation.

88. The omega-camtil bucarmil having an XRPD pattern substantially as shown in Figure 47, according to Claim 86 or 87.

89. The omega-camtil bucarmil according to any one of Claims 86 to 88, having an endothermic transition at 190°C to 230°C as measured by differential scanning calorimetry.

90. The omega-camtil bucarmil according to Claim 89, wherein the endothermic transition is at 209°C ± 3°C.

91. The omega-camtil bucarmil according to any one of Claims 86 to 87, having thermogravimetric analysis (TGA) as shown in Figure 49.

92. The omega-camtil bucarmil oxalic acid crystal salt, Form B, characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 7.38, 13.30, and 16.54 ± 0.2° 2θ using CuKα irradiation.

93. The omega-camtil bucarmil according to Claim 92, further characterized by XRPD pattern peaks at 17.11, 17.95, 18.45, 21.25, 22.63, 24.82, and 25.77 ± 0.2° 2θ using CuKα irradiation.

94. The omega-camtil bucarmil according to Claim 93, further characterized by XRPD pattern peaks at 14.76, 24.35, 28.61, 29.58, 30.49, 31.76, 34.46, and 37.35 ± 0.2° 2θ using CuKα irradiation.

95. The omega-camtil bucarmil according to any one of Claims 92 to 94, having an XRPD pattern substantially as shown in Figure 50.

96. The omega-camtil bucarmil according to any one of Claims 92 to 95, having thermogravimetric analysis (TGA) as shown in Figure 51.

97. The omega-camtil bucarmil salicylic acid crystal salt characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 8.36, 16.75, 17.56, 23.58, and 28.21 ± 0.2° 2θ using CuKα irradiation.

98. The omega-camtil bucarmil according to Claim 97, further characterized by XRPD pattern peaks at 10.08, 11,30, 13.69, 17.77, 17.86, 18.67, 19.11, 20.22, 21.07, 25.23, and 27.40 ± 0.2° 2θ using CuKα irradiation.

99. Omecamtiv mecarbil as claimed in claim 98, further characterized by XRPD pattern peaks at 9.78, 12.00, 13.80, 15.51, 19.27, 19.62, 20.02, 20.79, 22.19, 22.39, 22.75, 22.92, 24.99, 25.59, 26.79, 29.94 and 34.07 ± 0.2° 2θ using CuKα irradiation.

100. Omecamtiv mecarbil as claimed in any one of claims 97 to 99, having an XRPD pattern substantially as shown in Figure 53.

101. Omecamtiv mecarbil hemisuccinate crystal salt characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 6.32, 18.87, 19.32, 20.5, 21.24, 21.89, 23.49, 24.23 and 26.71 ± 0.2° 2θ using CuKα irradiation.

102. Omecamtiv mecarbil as claimed in claim 101, further characterized by XRPD pattern peaks at 12.93, 15.08, 16.97, 25.36, 27.39 and 28.32 ± 0.2° 2θ using CuKα irradiation.

103. Omecamtiv mecarbil as claimed in claim 101 or 102, having an XRPD pattern substantially as shown in Figure 55.

104. Omecamtiv mecarbil as claimed in any one of claims 101 to 103, having an endothermic transition at 155°C to 190°C as measured by differential scanning calorimetry.

105. Omecamtiv mecarbil as claimed in claim 104, wherein said endothermic transition is at 171°C ± 3°C.

106. Omecamtiv mecarbil bisulfate crystal salt, Form A, characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 5.39, 7.55, 14.35, 19.26 and 20.22 ± 0.2° 2θ using CuKα irradiation.

107. Omecamtiv mecarbil as claimed in claim 106, further characterized by XRPD pattern peaks at 16.17, 16.71, 16.92, 17.07, 18.60, 20.83, 21.38, 22.27, 22.77, 23.14, 23.42, 23.76, 24.32, 25.11, 25.74, 26.46, 27.71, 28.15 and 29.92 ± 0.2° 2θ using CuKα irradiation.

108. The omecamtiv mecarbil according to claim 106 or 107, having an XRPD pattern substantially as shown in FIG.

57.

109. The omecamtiv mecarbil bisulfate crystal salt, Form B, characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 11.72 and 20.48 ± 0.2° 2θ using CuKα irradiation.

110. The omecamtiv mecarbil according to claim 109, further characterized by XRPD pattern peaks at 12.17, 12.93, 17.79, 18.39, 18.76, 19.84, 23.60, 25.13, 25.63 and 30.12 ± 0.2° 2θ using CuKα irradiation.

111. The omecamtiv mecarbil according to claim 109 or 110, having an XRPD pattern substantially as shown in FIG.

58.

112. The omecamtiv mecarbil according to any one of claims 109 to 111, having a thermogravimetric analysis (TGA) as shown in FIG.

59.

113. The omecamtiv mecarbil bisulfate crystal salt, Form C, characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 10.98, 11.49, 18.04 and 19.60 ± 0.2° 2θ using CuKα irradiation.

114. The omecamtiv mecarbil according to claim 113, further characterized by XRPD pattern peaks at 10.39, 10.72, 12.52, 12.99, 17.11, 17.43, 20.94, 24.76, 25.25, 25.87 and 26.51 ± 0.2° 2θ using CuKα irradiation.

115. The omecamtiv mecarbil according to claim 113 or 114, having an XRPD pattern substantially as shown in FIG.

60.

116. The omecamtiv mecarbil according to any one of claims 113 to 115, having a thermogravimetric analysis (TGA) as shown in FIG.

61.

117. The omecamtiv mecarbil sulfate crystal salt, Form D, characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 7.32, 8.02 and 20.44 ± 0.2° 2θ using CuKα irradiation.

118. The omecamtiv mecarbil according to claim 117, further characterized by XRPD pattern peaks at 13.57, 14.54, 16.29, 16.41, 16.91, 17.36, 18.70, 21.02, 21.77, 22.37, 22.90, 23.72, 24.28, 25.14, 25.88, 26.58, 27.25, 28.10 and 29.43 ± 0.2° 2θ using CuKα irradiation.

119. The omecamtiv mecarbil according to claim 117 or 118, having an XRPD pattern substantially as shown in FIG.

62.

120. The omecamtiv mecarbil 2-hydroxyethanesulfonic acid crystal salt characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 9.95, 17.85, 19.93, 20.07, 20.46, 25.06 and 26.20 ± 0.2° 2θ using CuKα irradiation.

121. The omecamtiv mecarbil according to claim 120, further characterized by XRPD pattern peaks at 6.26, 6.69, 14.99, 16.37, 19.61, 20.95, 29.98, 32.16 and 34.39 ± 0.2° 2θ using CuKα irradiation.

122. The omecamtiv mecarbil according to claim 120 or 121, having an XRPD pattern substantially as shown in FIG.

65.

123. The omecamtiv mecarbil bis-tartaric acid crystal salt, form A, characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 4.20, 7.49, 8.22, 11.88, 16.42 and 21.19 ± 0.2° 2θ using CuKα irradiation.

124. The omecamtiv mecarbil according to claim 123, further characterized by XRPD pattern peaks at 4.77, 7.67, 8.43, 9.49, 13.05, 13.26, 14.98, 15.14, 17.34, 17.47, 18.02, 18.23, 18.72, 19.20, 22.50, 24.53, 25.67, 26.30 and 28.14 ± 0.2° 2θ using CuKα irradiation.

125. The omecamtiv mecarbil according to claim 123 or 124, having an XRPD pattern substantially as shown in FIG.

67.

126. Omecamtiv mecarbil according to any one of claims 123 to 125, having thermogravimetric analysis (TGA) as shown in FIG.

68. **Claim 127** Omecamtiv mecarbil bis tartrate crystal salt, Form B, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 3.77, 5.69 and 10.07 ± 0.2° 2θ using CuKα irradiation. **Claim 128** Omecamtiv mecarbil according to claim 127, further characterized by XRPD pattern peaks at 4.72, 6.95, 9.34, 11.18, 12.63, 15.18, 17.69, 22.35 and 25.46 ± 0.2° 2θ using CuKα irradiation. **Claim 129** Omecamtiv mecarbil according to claim 127 or 128, having an XRPD pattern substantially as shown in FIG.

69. **Claim 130** Omecamtiv mecarbil according to any one of claims 127 to 129, having thermogravimetric analysis (TGA) as shown in FIG.

70. **Claim 131** Omecamtiv mecarbil bis tartrate crystal salt, Form C, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 3.57, 6.23 and 15.84 ± 0.2° 2θ using CuKα irradiation. **Claim 132** Omecamtiv mecarbil according to claim 131, further characterized by XRPD pattern peaks at 3.86, 4.78, 7.04, 9.36, 13.08, 13.96, 16.88, 17.60, 18.20, 18.73, 20.40, 22.58, 25.44, 26.06 and 28.61 ± 0.2° 2θ using CuKα irradiation. **Claim 133** Omecamtiv mecarbil according to claim 131 or 132, having an XRPD pattern substantially as shown in FIG.

71. **Claim 134** Omecamtiv mecarbil according to any one of claims 131 to 133, having thermogravimetric analysis (TGA) substantially as shown in FIG.

72. **Claim 135** Omecamtiv mecarbil monotartrate crystal salt, Form D, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 9.77 and 15.40 ± 0.2° 2θ using CuKα irradiation. **Claim 136** Omega camtib mecabil, as further characterized by XRPD pattern peaks at 10.87, 13.79, 17.36, 17.74, 18.58, 18.87, 21.78, 25.43 and 26.24 ± 0.2° 2θ using CuKα irradiation, as claimed in claim 135.

137. Omega camtib mecabil as claimed in claim 135 or 136, having an XRPD pattern substantially as shown in Figure 73.

138. Omega camtib mecabil as claimed in any one of claims 135 to 137, having thermogravimetric analysis (TGA) as shown in Figure 74.

139. Omega camtib mecabil amorphous hydrochloride.

140. Omega camtib mecabil as claimed in claim 139, having a differential scanning calorimetry (DSC) transition substantially as shown in Figure 15.

141. Omega camtib mecabil as claimed in claim 139 or 140, having TGA substantially as shown in Figure 16.

142. Omega camtib mecabil as claimed in any one of claims 139 to 141, having a moisture sorption profile substantially as shown in Figure 17.

143. A pharmaceutical composition comprising omega camtib mecabil as claimed in any one of claims 1 to 142 and a pharmaceutically acceptable excipient.

144. A method for treating heart failure in a subject in need thereof, comprising administering to the subject an effective amount of omega camtib mecabil as claimed in any one of claims 1 to 142, or the pharmaceutical composition as claimed in claim 143, for the treatment of heart failure.

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