Salt form of complement component c5a receptor

Abstract

To provide a salt form of a complement component 5a receptor.SOLUTION: Provided is a besylate salt of a complement component 5a receptor having the formula of Compound 1.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 932,658, filed November 8, 2019, the entire disclosure of which is incorporated herein by reference.

[0002] Declaration of Rights to Inventions Made Under United States Research and Development Grants Not applicable

[0003] Reference to a "Sequence Listing," table, or computer program listing provided on a compact disc Not applicable [Background technology]

[0004] The complement system plays a central role in the clearance of immune complexes and immune responses against infectious agents, foreign antigens, virus-infected cells, and tumor cells. Inappropriate or excessive activation of the complement system can lead to severe inflammation and consequent tissue destruction, which can have harmful and potentially life-threatening consequences. Clinically, these consequences are manifested in a variety of disorders, including septic shock, myocardial and intestinal ischemia-reperfusion injury, graft rejection, organ failure, nephritis, pathological inflammation, and autoimmune diseases.

[0005] The complement system is composed of a group of proteins that are normally present in an inactive state in serum. Complement activation involves three distinct pathways: the classical pathway, the alternative pathway, and the lectin pathway (VM Holers, Clinical Immunology: Principles and Practice, edited by RR Rich, Mosby Press, 1996, pp. 363-391). (1) The classical pathway is a calcium / magnesium-dependent cascade that is normally activated by the formation of an antigen-antibody complex. The classical pathway can also be activated antibody-independently by the binding of C-reactive protein complexed with a ligand and by many pathogens, including gram-negative bacteria. (2) The alternative pathway is a magnesium-dependent cascade that is activated by the attachment and activation of C3 on susceptible surfaces (e.g., cell wall polysaccharides of yeast and bacteria, as well as certain biopolymers). (3) The lectin pathway involves the initial binding of mannose-binding lectin and subsequent activation of C2 and C4, which are common to the classical pathway (Matsushita, M. et al., J. Exp. Med. 176:1497-1502 (1992); Suankratay, C. et al., J. Immunol. 160:3006-3013 (1998)).

[0006] Activation of the complement pathway generates biologically active fragments of complement proteins, such as C3a, C4a, and C5a anaphylatoxins and the C5b-9 membrane attack complex (MAC), all of which mediate the inflammatory response by affecting leukocyte chemotaxis, activating macrophages, neutrophils, platelets, mast cells, and endothelial cells, and increasing vascular permeability, cell lysis, and tissue injury.

[0007] Complement C5a is one of the most potent proinflammatory mediators of the complement system. (The anaphylactic C5a peptide is 100-fold more potent per mole than C3a in inducing inflammatory responses.) C5a is the activated form of C5 (molecular weight 190 kD). C5a is present in human serum at a concentration of approximately 80 μg / ml (Kohler, PF et al., J. Immunol. 99:1211-1216 (1967)). It consists of two polypeptide chains, the α-chain and the β-chain, with molecular weights of approximately 115 kD and 75 kD, respectively (Tack, BF et al., Biochemistry 18:1490-1497 (1979)). C5 is biosynthesized as a single-chain precursor molecule, which is enzymatically cleaved into a two-chain structure during processing and secretion. After cleavage, these two chains are linked by at least one disulfide bond as well as non-covalent bonds (Ooi, YM et al., J. Immunol. 124:2494-2498 (1980)).

[0008] Recent studies have identified compound 1, which is (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide. [ka] has been identified as useful for treating C5a-mediated diseases. Despite the disclosure of this compound, efficient delivery of biologically relevant amounts of Compound 1 remains challenging. Also, no salt forms of this compound have been reported.

[0009] Salt forms may improve the therapeutic efficacy of this compound by improving important biological characteristics such as solubility, dissolution rate, and bioavailability. Thus, there is a need to provide salt forms of Compound 1 that can provide advantageous pharmacokinetic properties. The present disclosure addresses these needs and also offers related advantages. Summary of the Invention

[0010] The present disclosure provides compound 1, (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide. [ka] The salt form of

[0011] In one aspect, provided herein is a besylate salt of Compound 1. In one embodiment, the besylate salt of Compound 1 is a single crystalline form substantially free of other crystalline or amorphous forms. In one embodiment, the single crystalline form is besylate Form I of Compound 1. In one embodiment, the single crystalline form is besylate Form II of Compound 1.

[0012] In one aspect, provided herein is a tosylate salt of Compound 1. In one embodiment, the tosylate salt of Compound 1 is a single crystalline form substantially free of other crystalline or amorphous forms. In one embodiment, the single crystalline form is tosylate Form I of Compound 1.

[0013] In one aspect, provided herein is a napadisylate salt of Compound 1. In one embodiment, the napadisylate salt of Compound 1 is a single crystalline form substantially free of other crystalline or amorphous forms. In one embodiment, the single crystalline form is napadisylate Form I of Compound 1.

[0014] In one aspect, provided herein is a napsylate salt of Compound 1. In one embodiment, the napsylate salt of Compound 1 is a single crystalline form substantially free of other crystalline or amorphous forms. In one embodiment, the single crystalline form is napsylate Form I of Compound 1.

[0015] In one aspect, provided herein is a camsylate salt of Compound 1. In one embodiment, the camsylate salt of Compound 1 is a single crystalline form substantially free of other crystalline or amorphous forms. In one embodiment, the single crystalline form is camsylate Form I of Compound 1.

[0016] In one aspect, provided herein is an edisylate salt of Compound 1. In one embodiment, the edisylate salt of Compound 1 is a single crystalline form substantially free of other crystalline or amorphous forms. In one embodiment, the single crystalline form is edisylate Form I of Compound 1.

[0017] Each of these salt forms presented may have further characteristics as described herein.

[0018] In another aspect, provided herein are pharmaceutical compositions of Compound 1 in the salt form described herein.

[0019] In a further aspect, provided herein is a method for treating an individual suffering from or susceptible to a disease or disorder associated with activation of the C5a receptor by a condition, the method comprising administering to the individual an effective amount of Compound 1 in the form of a salt as described herein. [Brief explanation of the drawings]

[0020] [Figure 1] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of besylate salt Form I of Compound 1.

[0021] [Figure 2] FIG. 2 shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermograms of Compound 1 in besylate Form I.

[0022] [Figure 3] FIG. 3 shows a dynamic vapor sorption (DVS) plot of besylate Form I of Compound 1.

[0023] [Figure 4] Figure 4 shows a representative scanning electron microscopy (SEM) image of Compound 1 in besylate Form I. The magnification is 5,000x.

[0024] [Figure 5] Figure 5 shows a representative polarized light microscopy (PLM) image of Compound 1 in besylate Form I. The magnification is 20x.

[0025] [Figure 6] FIG. 6 shows the X-ray powder diffraction (XRPD) pattern of Compound 1 in besylate Form II.

[0026] [Figure 7] FIG. 7 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermograms of Compound 1 in besylate Form II.

[0027] [Figure 8] FIG. 8 is an X-ray powder diffraction (XRPD) pattern of tosylate salt Form I of Compound 1.

[0028] [Figure 9] FIG. 9 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermograms of Compound 1 in tosylate salt Form I.

[0029] [Figure 10] FIG. 10 shows a dynamic vapor sorption (DVS) plot of tosylate salt Form I of Compound 1.

[0030] [Figure 11] 11 shows a representative scanning electron microscopy (SEM) image of Compound 1 in tosylate salt Form I. The magnification is 1,000x.

[0031] [Figure 12]12 shows a representative polarized light microscopy (PLM) image of Compound 1 in tosylate Form I. The magnification is 10x.

[0032] [Figure 13] FIG. 13 is an X-ray powder diffraction (XRPD) pattern of napadisylate salt Form I of Compound 1.

[0033] [Figure 14] FIG. 14 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermograms of napadisylate salt Form I of Compound 1.

[0034] [Figure 15] FIG. 15 depicts a dynamic vapor sorption (DVS) plot of napadisylate Form I of Compound 1.

[0035] [Figure 16] 16 shows a representative scanning electron microscopy (SEM) image of Compound 1 in napadisylate Form I. The magnification is 2,500x.

[0036] [Figure 17] 17 shows a representative polarized light microscopy (PLM) image of Compound 1 in napadisylate Form I. The magnification is 20x.

[0037] [Figure 18] FIG. 18 is an X-ray powder diffraction (XRPD) pattern of napsylate salt Form I of Compound 1.

[0038] [Figure 19] FIG. 19 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermograms of napsylate salt Form I of Compound 1.

[0039] [Figure 20] FIG. 20 depicts a dynamic vapor sorption (DVS) plot of napsylate salt Form I of Compound 1.

[0040] [Figure 21] 21 shows a representative scanning electron microscopy (SEM) image of Compound 1 in napsylate salt Form I. The magnification is 5,000x.

[0041] [Figure 22] 22 shows a representative polarized light microscopy (PLM) image of Compound 1 in napsylate salt Form I. The magnification is 10x.

[0042] [Figure 23] FIG. 23 is an X-ray powder diffraction (XRPD) pattern of camsylate salt Form I of Compound 1.

[0043] [Figure 24] FIG. 24 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermograms of camsylate salt Form I of Compound 1.

[0044] [Figure 25] FIG. 25 shows a dynamic vapor sorption (DVS) plot of camsylate salt Form I of Compound 1.

[0045] [Figure 26] 26 shows a representative scanning electron microscopy (SEM) image of Compound 1 in camsylate Form I. The magnification is 5,000x.

[0046] [Figure 27] 27 shows a representative polarized light microscopy (PLM) image of Compound 1 in camsylate Form I. The magnification is 10x.

[0047] [Figure 28] FIG. 28 depicts an X-ray powder diffraction (XRPD) pattern of edisylate salt Form I of Compound 1.

[0048] [Figure 29] FIG. 29 depicts a differential scanning calorimetry (DSC) thermogram of edisylate salt Form I of Compound 1.

[0049] [Figure 30] 30 shows a plot of plasma concentration over time in rats administered a liquid suspension formulation containing the crystalline form of Compound 1 (dotted line) and an equal amount of liquid suspension formulations containing various salt forms of Compound 1: napsylate (filled circles), camsylate (open triangles), napadisylate (open squares), tosylate (filled diamonds), besylate (filled squares), and edisylate (open circles). Additional formulation details are provided in Example 8.

[0050] [Figure 31] 31 shows a plot of plasma concentration over time in rats administered a liquid suspension formulation containing the crystalline form of Compound 1 (dotted line) and an equal amount of liquid suspension formulations containing various salt forms of Compound 1: napsylate (filled circles), camsylate (open triangles), napadisylate (open squares), tosylate (filled diamonds), besylate (filled squares), and edisylate (open circles). Additional formulation details are provided in Example 9. DETAILED DESCRIPTION OF THE INVENTION

[0051] Overview The present disclosure presents salt forms of Compound 1. These forms are advantageous in that they enhance the solubility and bioavailability of the compound, thereby providing the opportunity to prepare pharmaceutical formulations and the like that can deliver biologically relevant amounts of Compound 1 without the need to administer excessive amounts of liquid or an excessive number of capsules.

[0052] II definition The terms "about" and "approximately," when used herein to modify a numerical value, indicate a close range around the stated value. When "X" is the value, "about X" or "approximately X" indicates a value of 0.9X to 1.1X, more preferably 0.95X to 1.05X. Any reference to "about X" or "approximately X" specifically indicates values ​​of at least X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, "about X" and "approximately X" are intended to teach and provide a description that supports claim limitations such as "0.98X."

[0053] "Compound 1" is a compound having the IUPAC name (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide and the structure shown below. [ka]

[0054] "Substantially free" refers to an amount of another form of 10% or less, preferably 8%, 5%, 4%, 3%, 2%, 1%, 0.5%, or less of another form.

[0055] The neutral form of Compound 1 can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of Compound 1 differs from the various salt forms with respect to certain physical properties, such as (but not limited to) solubility in polar solvents, but otherwise these salts are equivalent to the parent form of Compound 1 for the purposes of this disclosure.

[0056] The term "treating" or "treatment" encompasses both disease-modifying and symptomatic treatment, either of which may be prophylactic (i.e., treatment before the onset of symptoms to prevent, delay, or reduce the severity of symptoms) or therapeutic (i.e., treatment after the onset of symptoms to reduce the severity and / or duration of symptoms).

[0057] As used herein, a condition is considered "C5a receptor modulation responsive" if modulation of C5a receptor activity results in a decrease in the inappropriate activity of the C5a receptor.

[0058] The term "individual" refers to mammals, including primates (particularly humans), companion animals (e.g., dogs, cats, horses, etc.), and livestock (e.g., cows, pigs, sheep, etc.) that receive a dose as described herein. In one embodiment, the term "individual" refers to a human.

[0059] III. Detailed Description of the Embodiments Presented herein are salt forms of Compound 1, pharmaceutical compositions containing the compound, methods for their use, and methods for preparing these salt forms.

[0060] A. Compound 1 in salt form The present disclosure provides various salt forms of Compound 1, including the besylate, tosylate, napadisylate, napsylate, camsylate, and edisylate salts. In certain embodiments, single crystalline forms of the besylate, tosylate, napadisylate, napsylate, camsylate, or edisylate salts are provided. In certain embodiments, the single crystalline forms of these described salts are substantially free of other crystalline or amorphous forms.

[0061] In one embodiment, the besylate salt of Compound 1 has the formula: [ka]

[0062] In one embodiment, the tosylate salt of Compound 1 has the formula: [ka]

[0063] In one embodiment, the napadisylate salt of Compound 1 has the formula: [ka]

[0064] In one embodiment, the napsylate salt of Compound 1 has the formula: [ka]

[0065] In one embodiment, the camsylate salt of Compound 1 has the formula: [ka]

[0066] In one embodiment, the edisylate salt of Compound 1 has the formula: [ka]

[0067] Certain salts disclosed herein may exist in one or more polymorphic forms, and individual polymorphic forms of the salts may be identified as Form I, Form II, etc.

[0068] i. Compound 1 besylate (Form I) In one embodiment, provided herein is Compound 1 in besylate Form I, substantially free of other crystalline or amorphous forms of Compound 1: [ka]

[0069] In one embodiment, the besylate Form I of Compound 1 is characterized by an X-ray powder diffraction pattern comprising peaks at 10.9, 13.3, 16.2, 17.6, and 21.8 degrees 2θ (±0.2 degrees 2θ). In one embodiment, the besylate Form I of Compound 1 is further characterized by an X-ray powder diffraction pattern comprising peaks at 6.6, 7.6, 14.5, 16.2, and 28.2 degrees 2θ (±0.2 degrees 2θ). In one embodiment, the besylate Form I of Compound 1 is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 1.

[0070] Differential scanning calorimetry (DSC) may also be used to characterize the besylate Form I of Compound 1 described herein. In one embodiment, the besylate Form I of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 207.2°C. In one embodiment, the besylate Form I of Compound 1 is characterized by an onset melting temperature of about 200.6°C as determined by the differential scanning calorimetry (DSC) thermogram. In one embodiment, the besylate Form I of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 2.

[0071] Thermogravimetric analysis (TGA) is another technique that can be used to characterize the besylate Form I of Compound 1 described herein. In one embodiment, the besylate Form I of Compound 1 is characterized by a weight loss of about 0.14% when heated to about 202.9°C, as measured by thermogravimetric analysis (TGA). In one embodiment, the besylate Form I of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 2.

[0072] Dynamic Vapor Sorption (DVS) is another method that can be used to characterize the besylate Form I of Compound 1 described herein. In one embodiment, the besylate Form I of Compound 1 is characterized by a weight gain of about 0.5% after DVS cycling from about 0% relative humidity (RH) to about 75% RH at 25° C. In one embodiment, the besylate Form I of Compound 1 is characterized by a weight gain of about 0.73% after DVS cycling from about 5% relative humidity (RH) to about 95% RH at 25° C. In one embodiment, the besylate Form I of Compound 1 is characterized by a dynamic vapor sorption (DVS) plot substantially in accordance with FIG. 3.

[0073] Microscopy can also be used to characterize the besylate Form I of Compound 1 described herein. In some embodiments, scanning electron microscopy (SEM) is used. In some embodiments, the besylate Form I of Compound 1 is characterized by an SEM image having predominantly prismatic or irregularly shaped particles. In some embodiments, the particles are about 1 μm to about 73 μm as measured by SEM. In some embodiments, the besylate Form I of Compound 1 is characterized by a scanning electron microscopy (SEM) image substantially consistent with FIG. 4.

[0074] Polarized light microscopy (PLM) is another technique that can be used to characterize the besylate Form I of Compound 1 described herein. In one embodiment, the besylate Form I of Compound 1 is characterized by particles ranging in size from about 2.5 μm to about 83 μm as measured by polarized light microscopy (PLM). In one embodiment, the besylate Form I of Compound 1 is characterized by a polarized light microscopy (PLM) profile substantially as shown in FIG. 5.

[0075] ii. Besylate salt of Compound 1 (Form II) In one embodiment, provided herein is Compound 1 in besylate Form II, which is substantially free of other crystalline or amorphous forms of Compound 1. [ka]

[0076] In one embodiment, the besylate Form II of Compound 1 is characterized by an X-ray powder diffraction pattern comprising peaks at 3.6, 7.1, 12.3, 12.8, and 16.7 degrees 2θ (±0.2 degrees 2θ). In one embodiment, the besylate Form II of Compound 1 is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 6.

[0077] Differential scanning calorimetry (DSC) may also be used to characterize the besylate Form II of Compound 1 described herein. In one embodiment, the besylate Form II of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 187.2°C. In one embodiment, the besylate Form II of Compound 1 is characterized by an onset melting temperature of about 180.5°C as determined by the differential scanning calorimetry (DSC) thermogram. In one embodiment, the besylate Form II of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 7.

[0078] Thermogravimetric analysis (TGA) is another technique that can be used to characterize the besylate Form II of Compound 1 described herein. In one embodiment, the besylate Form II of Compound 1 is characterized by a weight loss of about 0.095% when heated to about 189.5° C., as measured by thermogravimetric analysis (TGA). In one embodiment, the besylate Form II of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG. 7.

[0079] iii. Tosylate salt of Compound 1 (Form I) In one embodiment, provided herein is Compound 1 in tosylate Form I, substantially free of other crystalline or amorphous forms of Compound 1. [ka]

[0080] In certain embodiments, tosylate Form I of Compound 1 is characterized by an X-ray powder diffraction pattern comprising peaks at 7.6, 10.8, 13.1, 16.5, 19.7, and 21.6 degrees 2θ (±0.2 degrees 2θ). In certain embodiments, tosylate Form I of Compound 1 is further characterized by an X-ray powder diffraction pattern comprising peaks at 6.6, 15.3, 16.0, and 27.8 degrees 2θ (±0.2 degrees 2θ). In certain embodiments, tosylate Form I of Compound 1 is characterized by an X-ray powder diffraction pattern substantially in accordance with FIG. 8.

[0081] Differential scanning calorimetry (DSC) can also be used to characterize tosylate Form I of Compound 1 described herein. In some embodiments, tosylate Form I of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 209.8°C. In some embodiments, tosylate Form I of Compound 1 is characterized by an onset melting temperature of about 206.1°C as determined by the differential scanning calorimetry (DSC) thermogram. In some embodiments, tosylate Form I of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 9.

[0082] Thermogravimetric analysis (TGA) is another technique that can be used to characterize the tosylate Form I of Compound 1 described herein. In one embodiment, the tosylate Form I of Compound 1 is characterized by a weight loss of about 0.19% when heated to about 204.2°C, as measured by thermogravimetric analysis (TGA). In one embodiment, the tosylate Form I of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 9.

[0083] Dynamic Vapor Sorption (DVS) is another method that can be used to characterize tosylate Form I of Compound 1 described herein. In some embodiments, tosylate Form I of Compound 1 is characterized by a weight gain of about 0.58% after DVS cycling from about 0% relative humidity (RH) to about 75% RH at 25° C. In some embodiments, tosylate Form I of Compound 1 is characterized by a weight gain of about 0.83% after DVS cycling from about 5% relative humidity (RH) to about 95% RH at 25° C. In some embodiments, tosylate Form I of Compound 1 is characterized by a dynamic vapor sorption (DVS) plot substantially in accordance with FIG. 10.

[0084] Microscopy can also be used to characterize tosylate Form I of Compound 1 described herein. In some embodiments, scanning electron microscopy (SEM) is used. In some embodiments, tosylate Form I of Compound 1 is characterized by an SEM image having predominantly flat, rod-shaped, or equidimensional particles. In some embodiments, the particles are about 1 μm to about 500 μm as measured by SEM. In some embodiments, tosylate Form I of Compound 1 is characterized by a scanning electron microscopy (SEM) image substantially in accordance with FIG. 11.

[0085] Polarized light microscopy (PLM) is another technique that can be used to characterize tosylate salt Form I of Compound 1 described herein. In some embodiments, tosylate salt Form I of Compound 1 is characterized by particles with a size range of about 2.5 μm to about 440 μm as measured by polarized light microscopy (PLM). In some embodiments, tosylate salt Form I of Compound 1 is characterized by a polarized light microscopy (PLM) profile substantially as shown in FIG. 12.

[0086] iv. Napadisylate salt of Compound 1 (Form I) In one embodiment, provided herein is napadisylate Form I of Compound 1, substantially free of other crystalline or amorphous forms of Compound 1. [ka]

[0087] In certain embodiments, napadisylate Form I of Compound 1 is characterized by an X-ray powder diffraction pattern comprising peaks at 6.5, 7.0, 12.4, 14.7, 15.2, and 18.0 degrees 2θ (±0.2 degrees 2θ). In certain embodiments, napadisylate Form I of Compound 1 is further characterized by an X-ray powder diffraction pattern comprising peaks at 9.6, 11.2, 18.6, and 20.4 degrees 2θ (±0.2 degrees 2θ). In certain embodiments, napadisylate Form I of Compound 1 is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 13.

[0088] Differential scanning calorimetry (DSC) may also be used to characterize napadisylate Form I of Compound 1 described herein. In some embodiments, napadisylate Form I of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 232.8°C. In some embodiments, napadisylate Form I of Compound 1 is characterized by an onset melting temperature of about 222.7°C as determined by a differential scanning calorimetry (DSC) thermogram. In some embodiments, napadisylate Form I of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 14.

[0089] Thermogravimetric analysis (TGA) is another technique that can be used to characterize the napadisylate Form I of Compound 1 described herein. In one embodiment, the napadisylate Form I of Compound 1 is characterized by a weight loss of about 2.0% when heated to about 233.1° C., as measured by thermogravimetric analysis (TGA). In one embodiment, the napadisylate Form I of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG. 14.

[0090] Dynamic vapor sorption (DVS) is another method that can be used to characterize napadisylate Form I of Compound 1 described herein. In some embodiments, napadisylate Form I of Compound 1 is characterized by a weight gain of about 0.6% after dynamic vapor sorption (DVS) cycling from about 0% relative humidity (RH) to about 55% RH at 25° C. In some embodiments, napadisylate Form I of Compound 1 is characterized by a weight gain of about 1.42% after dynamic vapor sorption (DVS) cycling from about 5% relative humidity (RH) to about 95% RH at 25° C. In some embodiments, napadisylate Form I of Compound 1 is characterized by a dynamic vapor sorption (DVS) plot substantially in accordance with FIG. 15.

[0091] Microscopy can also be used to characterize napadisylate Form I of Compound 1 described herein. In some embodiments, scanning electron microscopy (SEM) is used. In some embodiments, napadisylate Form I of Compound 1 is characterized by an SEM image having predominantly flat, rod-shaped, or equidimensional particles. In some embodiments, the particles are about 1 μm to about 150 μm as measured by SEM. In some embodiments, napadisylate Form I of Compound 1 is characterized by a scanning electron microscopy (SEM) image substantially in accordance with FIG. 16.

[0092] Polarized light microscopy (PLM) is another technique that can be used to characterize napadisylate Form I of Compound 1 described herein. In some embodiments, napadisylate Form I of Compound 1 is characterized by particles with a size ranging from about 1.3 μm to about 75 μm as measured by polarized light microscopy (PLM). In some embodiments, napadisylate Form I of Compound 1 is characterized by a polarized light microscopy (PLM) profile substantially as shown in FIG.

[0093] v. Napsylate salt of Compound 1 (Form I) In one embodiment, provided herein is Compound 1 in napsylate Form I, substantially free of other crystalline or amorphous forms of Compound 1. [ka]

[0094] In certain embodiments, napsylate salt Form I of Compound 1 is characterized by an X-ray powder diffraction pattern comprising peaks at 6.5, 7.7, 10.4, 12.9, and 16.1 degrees 2θ (±0.2 degrees 2θ). In certain embodiments, napsylate salt Form I of Compound 1 is further characterized by an X-ray powder diffraction pattern comprising peaks at 15.4, 15.5, 17.8, and 20.8 degrees 2θ (±0.2 degrees 2θ). In certain embodiments, napsylate salt Form I of Compound 1 is characterized by an X-ray powder diffraction pattern substantially in accordance with FIG. 18.

[0095] Differential scanning calorimetry (DSC) can also be used to characterize napsylate Form I of Compound 1 described herein. In some embodiments, napsylate Form I of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 218.3°C. In some embodiments, napsylate Form I of Compound 1 is characterized by an onset melting temperature of about 211.7°C as determined by a differential scanning calorimetry (DSC) thermogram. In some embodiments, napsylate Form I of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 19.

[0096] Thermogravimetric analysis (TGA) is another technique that can be used to characterize the napsylate Form I of Compound 1 described herein. In one embodiment, the napsylate Form I of Compound 1 is characterized by a weight loss of about 0.49% when heated to about 217° C., as measured by thermogravimetric analysis (TGA). In one embodiment, the napsylate Form I of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG. 19.

[0097] Dynamic Vapor Sorption (DVS) is another method that can be used to characterize napsylate Form I of Compound 1 described herein. In some embodiments, napsylate Form I of Compound 1 is characterized by a weight gain of about 0.2% after DVS cycling from about 0% relative humidity (RH) to about 55% RH at 25° C. In some embodiments, napsylate Form I of Compound 1 is characterized by a weight gain of about 0.65% after DVS cycling from about 5% relative humidity (RH) to about 95% RH at 25° C. In some embodiments, napsylate Form I of Compound 1 is characterized by a dynamic vapor sorption (DVS) plot substantially in accordance with FIG. 20.

[0098] Microscopy can also be used to characterize napsylate Form I of Compound 1 described herein. In some embodiments, scanning electron microscopy (SEM) is used. In some embodiments, napsylate Form I of Compound 1 is characterized by an SEM image having predominantly flat, rod-shaped, and equidimensional particles. In some embodiments, the particles are about 1 μm to about 150 μm as measured by SEM. In some embodiments, napsylate Form I of Compound 1 is characterized by a scanning electron microscopy (SEM) image substantially in accordance with FIG. 21.

[0099] Polarized light microscopy (PLM) is another technique that can be used to characterize napsylate salt Form I of Compound 1 described herein. In some embodiments, napsylate salt Form I of Compound 1 is characterized by particles with a size ranging from about 5 to 470 μm as measured by polarized light microscopy (PLM). In some embodiments, napsylate salt Form I of Compound 1 is characterized by a polarized light microscopy (PLM) profile substantially as shown in FIG. 22.

[0100] vi. Camsylate salt of Compound 1 (Form I) In one embodiment, provided herein is Compound 1 in camsylate Form I, which is substantially free of other crystalline or amorphous forms of Compound 1. [ka]

[0101] In some embodiments, camsylate Form I of Compound 1 is characterized by an X-ray powder diffraction pattern comprising peaks at 6.3, 7.9, 10.8, 12.2, and 16.1 degrees 2θ (±0.2 degrees 2θ). In some embodiments, camsylate Form I of Compound 1 is further characterized by an X-ray powder diffraction pattern comprising peaks at 7.4, 8.5, 13.6, 17.0, and 18.5 degrees 2θ (±0.2 degrees 2θ). In some embodiments, camsylate Form I of Compound 1 is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 23.

[0102] Differential scanning calorimetry (DSC) can also be used to characterize camsylate Form I of Compound 1 described herein. In some embodiments, camsylate Form I of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 209.8°C. In some embodiments, camsylate Form I of Compound 1 is characterized by an onset melting temperature of about 202.8°C as determined by a differential scanning calorimetry (DSC) thermogram. In some embodiments, camsylate Form I of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 24.

[0103] Thermogravimetric analysis (TGA) is another technique that can be used to characterize the camsylate Form I of Compound 1 described herein. In one embodiment, the camsylate Form I of Compound 1 is characterized by a weight loss of about 0.23% when heated to about 205.0° C., as measured by thermogravimetric analysis (TGA). In one embodiment, the camsylate Form I of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG. 24.

[0104] Dynamic Vapor Sorption (DVS) is another method that can be used to characterize camsylate Form I of Compound 1 described herein. In some embodiments, camsylate Form I of Compound 1 is characterized by a weight gain of about 0.35% after DVS cycling from about 0% relative humidity (RH) to about 65% RH at 25° C. In some embodiments, camsylate Form I of Compound 1 is characterized by a weight gain of about 0.96% after DVS cycling from about 5% relative humidity (RH) to about 95% RH at 25° C. In some embodiments, camsylate Form I of Compound 1 is characterized by a dynamic vapor sorption (DVS) plot substantially in accordance with FIG. 25.

[0105] Microscopy can also be used to characterize camsylate Form I of Compound 1 described herein. In some embodiments, scanning electron microscopy (SEM) is used. In some embodiments, camsylate Form I of Compound 1 is characterized by an SEM image having predominantly thick, flat, and rod-shaped particles. In some embodiments, the particles are about slightly less than 1 μm to about 77 μm as measured by SEM. In some embodiments, camsylate Form I of Compound 1 is characterized by a scanning electron microscopy (SEM) image substantially in accordance with FIG. 26.

[0106] Polarized light microscopy (PLM) is another technique that can be used to characterize camsylate salt Form I of Compound 1 described herein. In some embodiments, camsylate salt Form I of Compound 1 is characterized by particles with a size ranging from about 2.5 μm to about 84 μm as measured by polarized light microscopy (PLM). In some embodiments, camsylate salt Form I of Compound 1 is characterized by a polarized light microscopy (PLM) profile substantially as shown in FIG. 27.

[0107] vii. Edisylate salt of Compound 1 (Form I) In one embodiment, provided herein is Compound 1 in edisylate Form I, substantially free of other crystalline or amorphous forms of Compound 1. [ka]

[0108] In certain embodiments, edisylate salt Form I of Compound 1 is characterized by an X-ray powder diffraction pattern comprising peaks at 3.4, 5.6, 12.9, 15.3, 18.1, and 20.8 degrees 2θ (±0.2 degrees 2θ). In certain embodiments, edisylate salt Form I of Compound 1 is further characterized by an X-ray powder diffraction pattern comprising peaks at 7.3, 10.7, 14.5, 15.6, 19.1, and 19.7 degrees 2θ (±0.2 degrees 2θ). In certain embodiments, edisylate salt Form I of Compound 1 is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 28.

[0109] Differential scanning calorimetry (DSC) can also be used to characterize edisylate salt Form I of Compound 1 described herein. In some embodiments, edisylate salt Form I of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 213.3°C. In some embodiments, edisylate salt Form I of Compound 1 is characterized by an onset melting temperature of about 205.2°C as determined by the differential scanning calorimetry (DSC) thermogram. In some embodiments, edisylate salt Form I of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 29.

[0110] B. Pharmaceutical Compositions Presented herein are liquid pharmaceutical compositions comprising the salt forms of Compound 1 described herein or prepared using the salt forms of Compound 1 described herein. The pharmaceutical compositions include one or more pharmaceutically acceptable excipients.

[0111] The pharmaceutical compositions containing the salt forms of Compound 1 described herein may be in a form suitable for oral use, such as tablets, troches, lozenges, liquid formulations, aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsifying formulations such as those described in U.S. Patent Application Publication No. 2002-0012680, hard or soft capsules, syrups, elixirs, liquids, buccal patches, oral gels, chewing gums, chewable tablets, effervescent powders, and effervescent tablets. Compositions for oral use may be prepared according to any method known in the art of pharmaceutical composition manufacture, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives to provide a medicament with a clean and palatable taste. Tablets contain Compound 1 in a salt form mixed with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture. These excipients may be inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as PVP, cellulose, PEG, starch, gelatin, or gum acacia; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or enteric-coated, or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. The tablets may also be coated by the techniques described in U.S. Pat. Nos. 4,256,108, 4,166,452, and 4,265,874 to form osmotically controlled-release therapeutic tablets.

[0112] Oral formulations may be provided as hard gelatin capsules in which Compound 1 in salt form is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which Compound 1 in salt form is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil. Emulsions may also be prepared using water-immiscible ingredients such as oils and stabilized with surfactants such as mono- or diglycerides and PEG esters.

[0113] Aqueous suspensions for oral use contain Compound 1 in salt form mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum, and the dispersing or wetting agent may be a natural phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long-chain aliphatic alcohol such as heptadecaethyleneoxycetanol, or a condensation product of ethylene oxide with a fatty acid and a partial ester derived from a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of ethylene oxide with a fatty acid and a partial ester derived from a hexitol anhydride such as polyethylene sorbitan monooleate, as well as other poloxamers (e.g., poloxamer F-68). The said aqueous suspensions may also contain one or more preservatives such as ethyl benzoate, n-propyl benzoate, or p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0114] Accordingly, provided herein is an aqueous suspension comprising Compound 1 in salt form and at least one excipient, which in one embodiment is at least one suspending agent and / or at least one wetting agent, as described above.

[0115] Oral oil suspensions can be prepared by suspending Compound 1 in a salt form in vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, or in mineral oils such as liquid paraffin. The oil suspensions can contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners, such as the above-mentioned sweeteners and flavoring agents, can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[0116] The pharmaceutical compositions may be in the form of aqueous or oily sterile injectable or infusion solutions or suspensions. These solutions or suspensions can be formulated according to known techniques using the above-mentioned suitable dispersing or wetting agents and suspending agents. The sterile injectable preparations may also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among these, acceptable vehicles and solvents that can be used include water, Ringer's solution, isotonic sodium chloride solution, isotonic aqueous buffer, and mixtures of saline, disintegrating agents such as PEG (e.g., PEG 200, PEG 400, PEG 800, etc.), and nonionic surfactants such as Tween 80. Sterile, fixed oils are conventionally used as solvents or suspending media. Any brand of fixed oil, including synthetic monoglycerides or diglycerides, can be used for this purpose. Fatty acids, such as oleic acid, are also used in the preparation of injectable and infusion solutions. Compositions suitable for injection and infusion administration optionally include a local anesthetic, such as lignocaine, to ease pain at the injection site. The components may be supplied premixed or supplied separately and mixed immediately prior to use. In some embodiments, mixing immediately prior to use is desirable to take advantage of the initially high solubility of the salt forms of Compound 1 described herein in certain liquid formulation mixtures.

[0117] Injectable or infusion compositions include, but are not limited to, compositions for intravenous administration, intramuscular administration, and subcutaneous or intrasternal injection. Accordingly, in one embodiment, provided herein is an intravenous pharmaceutical composition comprising Compound 1 and at least one wetting agent or solvent, wherein the intravenous pharmaceutical composition is prepared using a salt form of Compound 1 described herein. In one embodiment, the injectable or infusion solution is prepared for intravenous administration. In one embodiment, the injectable or infusion solution is prepared for intramuscular administration. In one embodiment, the injectable or infusion solution is prepared for subcutaneous injection. In one embodiment, the injectable or infusion solution is prepared for intrasternal injection. In one embodiment, the at least one wetting agent or solvent in the injectable or infusion pharmaceutical composition comprises saline, a disintegrant, and a non-ionic surfactant.

[0118] Injectable or infusion compositions may be prepared at any time convenient for the medical practitioner or user, including immediately before use or well before use. In some embodiments, the compositions are prepared immediately before use. Immediately before use includes 0-24 hours, 0-10 hours, 0-5 hours, or 0-1 hour before use. In some embodiments, the injectable or infusion compositions are prepared 0-5 hours before use. Well before use typically refers to one or more days before use. Accordingly, methods for preparing injectable or infusion solutions are also provided herein. The methods include dissolving Compound 1 in a salt form with at least one wetting agent or solvent to prepare an injectable or infusion solution, and administering the injectable or infusion solution to a subject in need thereof.

[0119] Dispersible powders and granules suitable for preparation of aqueous oral formulations or suspensions by the addition of water present Compound 1 in salt form in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweetening, flavoring, and coloring agents, may also be present.

[0120] The pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be natural gums such as acacia gum or tragacanth gum, natural phospholipids such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, or condensation products of such partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

[0121] Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain demulcents, preservatives, and flavoring and coloring agents. Oral liquid preparations can be prepared in combination with cyclodextrin, PEG, surfactants, and the like.

[0122] The compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing Compound 1 in salt form with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol. The compounds can also be administered via intraocular delivery in solutions or ointments. Furthermore, transdermal delivery of the subject compounds can be achieved by iontophoretic patches, etc. For topical use, creams, ointments, jellies, solutions, or suspensions containing the compounds of the present invention are used. As used herein, topical application also refers to the use of mouthwashes and gargles.

[0123] The compounds of the present invention can also be linked to polymeric carriers suitable as targetable drug transporters. Examples of such polymers include polyvinylpyrrolidone, pyran copolymers, poly(hydroxypropylmethacrylamide)phenol, poly(hydroxyethylaspartamide)phenol, and palmitoyl-substituted polyethylene oxide polylysine. Furthermore, the compounds of the present invention can be linked to certain biodegradable polymeric carriers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly(ε-caprolactone), polyhydroxybutyric acid, poly(orthoesters), polyacetals, poly(dihydropyrans), polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels. Polymers and semipermeable polymer matrices can be formed into shaped articles such as valves, stents, tubes, and prostheses. In one embodiment of the present invention, the compounds of the present invention are linked to polymeric or semipermeable polymeric matrices formed as stents or stent-graft devices.

[0124] C. Treatment method Also provided herein are methods of treating individuals suffering from conditions that are responsive to C5a receptor modulation.

[0125] In one aspect, provided herein is a method for treating an individual suffering from or susceptible to a disease or disorder associated with activation of the C5a receptor by a condition, the method comprising administering to the individual an effective amount of Compound 1 in salt form or an effective amount of a pharmaceutical formulation comprising Compound 1 as described herein.

[0126] In one embodiment, the salt forms of Compound 1 described herein are used to treat a patient suffering from a condition that is responsive to C5a receptor modulation.

[0127] Conditions that may be treated by C5a modulation autoimmune disease For example, rheumatoid arthritis, systemic lupus erythematosus, Guillain-Barré syndrome, pancreatitis, C3 glomerulopathy (C3G), hidradenitis suppurativa (HS), lupus nephritis, lupus glomerulonephritis, immunoglobulin A (IgA) nephropathy, psoriasis, Crohn's disease, vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic thrombocytopenia, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), immune-mediated vasculitis, tissue graft rejection, hyperacute rejection of transplanted organs, etc.

[0128] Inflammatory Disorders and Related Conditions For example, neutropenia, sepsis, septic shock, Alzheimer's disease, multiple sclerosis, stroke, inflammatory bowel disease (IBD), age-related macular degeneration (AMD, both wet and dry), severe burn-related inflammation, lung injury, and ischemia-reperfusion injury, osteoarthritis, as well as acute (adult) respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), systemic inflammatory response syndrome (SIRS), atopic dermatitis, psoriasis, chronic urticaria, and multiple organ dysfunction syndrome (MODS). Also included are sequelae associated with insulin-dependent diabetes mellitus (including diabetic retinopathy), lupus nephropathy, Heymann nephritis, membranous nephritis and other forms of glomerulonephritis, contact hypersensitivity reactions, and inflammation resulting from blood contact with artificial surfaces that can cause complement activation when contact occurs, such as during extracorporeal circulation of blood (e.g., during hemodialysis or by heart-lung machine in connection with vascular surgery such as coronary artery bypass grafting or heart valve replacement), or inflammation associated with contact with other artificial vascular or container surfaces (e.g., ventricular assist devices, artificial heart devices, infusion tubing, blood storage bags, plasma exchange, platelet exchange, etc.). Also included are diseases associated with ischemia-reperfusion injury, such as ischemia-reperfusion injury following transplantation, including solid organ transplantation, and syndromes such as ischemia-reperfusion injury, ischemic colitis, and cardiac ischemia. The salt forms of Compound 1 described herein may also be useful in the treatment of age-related macular degeneration (Hageman et al., PNAS 102:7227-7232, 2005).

[0129] Cardiovascular and cerebrovascular disorders For example, myocardial infarction, coronary artery thrombosis, vascular occlusion, postoperative vascular reocclusion, atherosclerosis, traumatic central nervous system injury, and ischemic heart disease. In one embodiment, an effective amount of Compound 1 in the salt form described herein may be administered to a patient at risk of myocardial infarction or thrombosis (i.e., a patient with one or more recognized risk factors for myocardial infarction or thrombosis, including, but not limited to, obesity, smoking, hypertension, hypercholesterolemia, a past history or genetic history of myocardial infarction or thrombosis) to reduce the risk of myocardial infarction or thrombosis.

[0130] vasculitis disease Vasculitic diseases are characterized by vascular inflammation. Infiltration of leukocytes leads to destruction of the vascular wall, and the complement pathway is thought to play a major role in initiating leukocyte migration and the resulting damage that occurs at the site of inflammation (Vasculitis, 2nd ed., Ball and Bridges, eds., Oxford University Press, pp. 47-53, 2008). The salt forms of Compound 1 described herein can be used to treat vasculitides, including antineutrophil cytoplasmic antibody-associated vasculitis (or ANCA-associated vasculitis, including microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and granulomatosis with polyangiitis, also known as Wegener's disease), Churg-Strauss syndrome, Henoch-Schönlein purpura, polyarteritis nodosa, rapidly progressive glomerulonephritis (RPGN), cryoglobulinemia, giant cell arteritis (GCA), Behçet's disease, and Takayasu's arteritis (TAK).

[0131] HIV infection and AIDS The salt forms of Compound 1 described herein can be used to inhibit HIV infection, slow the progression of AIDS, or reduce the severity of the symptoms of HIV infection and AIDS.

[0132] Neurodegenerative and related disorders In other embodiments, the salt forms of Compound 1 described herein may be used to treat cognitive decline associated with Alzheimer's disease, multiple sclerosis, and cardiac bypass surgery and related procedures.

[0133] cancer The salt forms of Compound 1 described herein are also useful for treating cancer and precancerous conditions in a subject. Specific cancers that can be treated include, but are not limited to, sarcoma, carcinoma, and mixed tumors. Exemplary conditions that can be treated according to the present invention include fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, angiosarcoma, lymphangiosarcoma, synovium, mesothelioma, meningioma, leukemia, lymphoma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, melanoma, renal cell carcinoma, hepatocellular carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, pleomorphic adenoma, hepatocellular papilloma, tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, and fibroma.

[0134] In one embodiment, the salt forms of Compound 1 described herein can be used to treat a disease selected from the group consisting of sepsis (and related disorders), COPD, rheumatoid arthritis, lupus nephritis, and multiple sclerosis.

[0135] In one embodiment, the salt forms of Compound 1 described herein can be used to treat a disease selected from the group consisting of antineutrophil cytoplasmic antibody-associated (ANCA) vasculitis, C3 glomerulopathy, hidradenitis suppurativa, and lupus nephritis.

[0136] The therapeutic methods provided herein generally involve administering to a patient an effective amount of Compound 1 in salt form. Suitable patients include those suffering from or susceptible to the disorders or diseases identified herein (i.e., prophylactic treatment). Typical patients for treatment as described herein include mammals, particularly primates, and especially humans. Other suitable patients include companion animals such as dogs, cats, and horses, or livestock such as cows, pigs, and sheep.

[0137] Generally, the therapeutic methods provided herein comprise administering to a patient an effective amount of the salt form of Compound 1 described herein. The appropriate formulation, route of administration, and dosage of the pharmaceutical compositions of the present invention can be selected by the individual physician in light of the patient's condition (see, e.g., Fingl et al., 1975, The Pharmacological Basis of Therapeutics, especially Chapter 1, page 1, which is incorporated herein by reference in its entirety). In some embodiments, the salt form of Compound 1 described herein is administered orally to a patient (e.g., a human). In some embodiments, the salt form of Compound 1 described herein is administered to a patient (e.g., a human) intravenously, intramuscularly, or by subcutaneous or intrasternal injection. The effective amount can be an amount sufficient to modulate C5a receptor activity and / or to reduce or ameliorate symptoms exhibited by the patient. The dose is preferably one that produces a plasma concentration of the compound (or an active metabolite thereof, if the compound is a prodrug) high enough to detectably inhibit chemotaxis of white blood cells (e.g., neutrophils) in vitro.

[0138] For treatment of most disorders via oral administration, one of skill in the art can determine the appropriate dosing frequency. In some embodiments, a dosing frequency of four times per day or less is preferred. In some embodiments, a twice-daily dosing regimen is used. In some embodiments, a once-daily dosing regimen is used. The patient may be administered the salt form of Compound 1 in a fed or fasted state. In some embodiments, the patient takes the salt form of Compound 1 with a meal. In some embodiments, the patient takes the salt form of Compound 1 without a meal.

[0139] For treatment of most disorders via intravenous administration, intramuscular administration, or subcutaneous or intrasternal injection, one of skill in the art can determine the appropriate dosing frequency. In some embodiments, the dosing frequency is about once every two weeks. In some embodiments, the dosing frequency is about once per week. In some embodiments, the dosing frequency is about three times per week. In some embodiments, the dosing frequency is about two to five times per week. In some embodiments, the dosing frequency is about once every two days. In some embodiments, the dosing frequency is about once per day.

[0140] It should be understood, however, that the specific dosage level and treatment regimen for any particular patient will depend on a variety of factors, including the age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combinations (i.e., other drugs being administered to the patient), and the severity of the particular disease being treated, as well as the judgment of the prescribing medical practitioner. In general, it is preferable to use the minimum dose sufficient to achieve effective treatment. Patients may generally be monitored for therapeutic effectiveness using medical or veterinary standards appropriate for the condition being treated or prevented.

[0141] Dosage levels on the order of about 0.1 mg to about 140 mg per kilogram of body weight per day are useful for treating or preventing conditions associated with C5a activity in diseases (about 0.5 mg to about 7 g per human patient per day). The amount of the salt form of Compound 1 that may be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. Dosage unit forms typically contain between about 1 mg and about 500 mg of the salt form of Compound 1. When administered orally, transdermally, intravenously, or subcutaneously, it is preferred to administer an amount of the salt form of Compound 1 sufficient to achieve a serum concentration of 5 ng (nanogram) / mL to 10 μg (microgram) / mL of serum, more preferably 20 ng to 1 μg / mL of serum, and most preferably 50 ng / mL to 200 ng / mL of serum. For direct injection into the synovium (for the treatment of arthritis), a sufficient amount of the salt form of Compound 1 is administered to achieve a local concentration of about 1 micromolar.

[0142] D. Combination Therapy The methods of the present disclosure may include combination therapy with one or more additional therapeutic agents used in the treatment, prevention, suppression, or amelioration of the disease or condition associated with C5a receptor activation by the condition. Such one or more additional therapeutic agents may be administered simultaneously or sequentially with the salt forms of Compound 1 described herein, by a route and in an amount commonly used. When the salt forms of Compound 1 described herein are used simultaneously with such additional therapeutic agents, pharmaceutical compositions containing such other agents in addition to the salt forms of Compound 1 are preferred. Thus, the pharmaceutical compositions of the present disclosure also include pharmaceutical compositions containing one or more other active ingredients or therapeutic agents in addition to the salt forms of Compound 1 described herein.

[0143] Examples of the one or more additional therapeutic agents include corticosteroids, steroids, immunosuppressants, immunoglobulin G agonists, dipeptidyl peptidase IV inhibitors, lymphocyte function-associated antigen-3 receptor antagonists, interleukin-2 ligands, interleukin-1 beta ligand inhibitors, IL-2 receptor alpha subunit inhibitors, HGF gene stimulators, IL-6 antagonists, IL-5 antagonists, alpha 1-antitrypsin stimulators, cannabinoid receptor antagonists, histone deacetylase inhibitors, AKT protein kinase inhibitors, CD20 inhibitors, and the like. anti-inflammatory agents, Abl tyrosine kinase inhibitors, JAK tyrosine kinase inhibitors, TNFα ligand inhibitors, hemoglobin regulators, TNF antagonists, proteasome inhibitors, CD3 regulators, Hsp70 family inhibitors, immunoglobulin agonists, CD30 antagonists, tubulin antagonists, sphingosine-1-phosphate receptor-1 agonists, connective tissue growth factor ligand inhibitors, caspase inhibitors, adrenocorticotropic hormone ligands, Btk tyrosine kinase inhibitors, complement C1 accessory component inhibitors, erythropoietin receptor agonists, B-lymphocyte Cell-stimulating factor ligand inhibitors, cyclin-dependent kinase-2 inhibitors, P-selectin glycoprotein ligand-1 stimulators, mTOR inhibitors, elongation factor 2 inhibitors, cell adhesion molecule inhibitors, factor XIII agonists, calcineurin inhibitors, immunoglobulin G1 agonists, inosine monophosphate dehydrogenase inhibitors, complement C1 accessory component inhibitors, thymidine kinase modulators, cytotoxic T-lymphocyte protein-4 modulators, angiotensin II receptor antagonists, angiotensin II receptor modulators, TNF superfamily receptor 12A antagonists, CD5 2 antagonists, adenosine deaminase inhibitors, T-cell differentiation antigen CD6 inhibitors, FGF-7 ligands, dihydroorotate dehydrogenase inhibitors, Syk tyrosine kinase inhibitors, type I interferon receptor antagonists, interferon α ligand inhibitors, macrophage migration inhibitory factor inhibitors, integrin α-V / β-6 antagonists, cysteine ​​protease stimulators, p38 MAP kinase inhibitors, TP53 gene inhibitors, Shiga-like toxin I inhibitors, fucosyltransferase 6 stimulators, interleukin 22 ligands, IRS1 gene inhibitors,Protein kinase C stimulators, protein kinase C α inhibitors, CD74 antagonists, immunoglobulin gamma Fc receptor IIB antagonists, T cell antigen CD7 inhibitors, CD95 antagonists, N-acetylmannosamine kinase stimulators, cardiotrophin-1 ligands, leukocyte elastase inhibitors, CD40 ligand receptor antagonists, CD40 ligand modulators, IL-17 antagonists, TLR-2 antagonists, mannan-binding lectin-associated serine protease-2 (MASP-2) inhibitors, factor B inhibitors, factor D inhibitors, C3 aR modulators, C5aR2 modulators, T cell receptor antagonists, PD-1 inhibitors, PD-L1 inhibitors, TIGIT inhibitors, TIM-3 inhibitors, LAG-3 inhibitors, VISTA inhibitors, STING agonists, IDO inhibitors, adenosine receptor modulators, CD39 inhibitors, CD73 inhibitors, antagonists of chemokine receptors, particularly CXCR1, CXCR2, CXCR3, CXCR4, CXCR7, CCR1, CCR2, CCR3, CCR4, CCR5, CCR7, CCR7, CCR9, CX3CR1, and CXCR6, and combinations thereof.

[0144] In one embodiment, the additional therapeutic agent used in the methods of treatment herein is obinutuzumab, rituximab, ocrelizumab, tositumomab, obinutuzumab, ibritumomab, cyclophosphamide, prednisone, hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, halcinonide, betamethasone, benzamidine, benzodiazepine, benzocaine, benzophenone, benzocaine ... Tamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17 valerate, halometasone, alclometasone dipropionate, beclomethasone, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17 butyrate, clobetasol-17 propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate, hydrocortisone-17 butyrate, hydrocortisone-17 aceponate Terephthalate, hydrocortisone-17 butyrate propionate, ciclesonide and prednicarbate, GB-0998, Imguro, begelomab, alefacept, aldesleukin, gevokizumab, daclizumab, basiliximab, inolimomab, beperminogen perplasmid, sirukumab, tocilizumab, clazakizumab, mepolizumab, fingolimod, panobinostat, triciribine, nilotinib, imatinib, tofacitinib, momelotinib, peficitinib, itacitinib, infliximab, PEG-bHb-CO, etanercept, iki Sazomib, bortezomib, muromonab, otelixizumab, gusperimus, brentuximab vedotin, ponesimod, KRP-203, FG-3019, emricasan, corticotropin, ibrutinib, cinryze, conestat, methoxypolyethylene glycol-epoetin beta, belimumab, blissibimod, atacicept, seliciclib, neiflizumab, everolimus, sirolimus, denileukin diftitox, LMB-2, natalizumab, catridecacog, cyclosporine, tacrolimus, voclosporin,Canakinumab, mycophenolate, mizoribine, CE-1145, TK-DLI, abatacept, belatacept, olmesartan medoxomil, sparsentan, TXA-127, BIIB-023, alemtuzumab, pentostatin, itolizumab, palifermin, leflunomide, PRO-140, cenicriviroc, fostamatinib, anifrolumab, sifalimumab, BAX-069, BG-00011, rosmapimod, QPI-1002, ShigamAb, TZ-101, F-652, reparixin, ladarixin darixin), PTX-9908, aganirsen, APH-703, sotrastaurin, milatuzumab, SM-101, T-guard, APG-101, DEX-M74, cardiotrophin-1, tiprelestat, ASKP-1240, BMS-986004, HPH-116, KD-025, OPN-305, TOL-101, difibrotide, pomalidomide, thymoglobulin, laquinimod, remestemcel-L, equine anti-thymocyte immunoglobulin, stempeucel ( Stempeucel, LIV-γ, Octagam 10%, t2c-001, 99mTc-sestamibi, Claryg, Prasova, pomalidomide, laquinimod, teplizumab, FCRx, solnatide, foralumab, ATIR-101, BPX-501, ACP-01, ALLO-ASC-DFU, irbesartan + propagermanium, ApoCell, cannabidiol, RGI-2001, Saratin, anti-CD3 bivalent antibody-diphtheria toxin conjugate, NOX-100, LT-1951, OMS721, ALN-CC5 , ACH-4471, AMY-101, ActaGel, and CD4+CD25+ regulatory T cells, MEDI7814, P32, P59, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, CCX354, CCX721, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX587, CCX624, CCX282, CCX025, CCX507, CCX430, CCX765, CCX758, CCX771, CCX662, CCX650, and combinations thereof.

[0145] E. Preparation method Crude Compound 1 can be prepared as previously described, see, e.g., WO 2010 / 075257 and WO 2016 / 053890, the contents of each of which are incorporated by reference in their entirety for all purposes.

[0146] The various salt forms described herein can be prepared as described in the Examples, and it is understood that there may be more than one crystallization method that produces the tosylate, besylate, napsylate, napadisylate, camsylate, and edisylate salt forms described. [Example]

[0147] The following examples are presented to help illustrate the described invention, and are not intended to limit the scope of what the inventors regard as their invention.

[0148] Example 1: Besylate salt of Compound 1 (Form I) [ka] A 3 L round-bottom flask equipped with a magnetic stirrer was charged with (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide (Compound 1, 250 g, 430 mmol) and MeCN (1.84 L, 8 volumes). The resulting mixture was stirred for 30 minutes, heated to 75 °C (internal temperature) to form a clear solution, filtered through a polyethylene frit filter, and washed with MeCN (230 mL). To this 60 °C solution was slowly added a pre-filtered solution of benzenesulfonic acid hydrate (77.9 g, 442 mmol (monohydrate basis), 1.03 equiv.) in MeCN (276 mL, 3 volumes) over 10 minutes, followed by a MeCN (92 mL) wash (internal temperature decreased to 55 °C). The resulting solution was cooled to 50°C, sprinkled with compound 1 besylate crystals (approximately 100 mg), and slowly cooled to 45°C over 1 hour. The resulting mixture was slowly cooled to room temperature and stirred for 42 hours. The solid was collected by filtration, washed with MeCN (2 x 230 mL), air-dried, and then dried under vacuum at 50°C overnight (48 hours) to give N-cyclopentyl-4-((2R,3S)-1-(2-fluoro-6-methylbenzoyl)-3-((4-methyl-3-(trifluoromethyl)phenyl)-carbamoyl)piperidin-2-yl)benzeneaminium benzenesulfonate in a yield of 266.5 g (84%) as off-white crystals. 1H NMR (400 MHz, DMSO-d6) (room temperature) δ 10.44 (s, 1H), 7.90-7.83 (m, 1H), 7.65-6.95 (m, 14H), 6.42-6.34 (m, 1H), 6.05-5.00 (br, 1H), 3.85-3.70 (m, 1H), 3.22-3.00 (m, 3H), 2.38-2.28 (m, 4H), 2.20-1.40 (m, 15H), (65℃) δ 10.22 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.68-6.70 (m, 15H), 6.44-6.35 (m, 1H), 3.72-3.65 (m, 1H), 3.25-2.98 (m, 3H), 2.40-2.28 (m, 4H), 2.22-1.40 (m, 15H). MS: (ES) C at m / z 33 H 36 F4N3O2[M+H] + Calculated for: 582.3, Found: 582.2. The XRPD plot is shown in Figure 1 and the significant peaks observed in the XRPD plot are summarized in Table 1 below. HPLC (both non-chiral analytical chromatography and chiral chromatography): >99%. Elemental analysis was C 39 H 41 Fits the formula F4N3O5S. KF: 0.66%. [Table 1]

[0149] Differential scanning calorimetry (DSC) was performed on the collected crystals using a Waters LLC TA Instruments DSC25. Samples were weighed into standard aluminum pans and sealed with standard aluminum lids with pinholes. Measurements were completed using a scan rate of 10°C / min under a nitrogen purge. The melting point (onset) was determined by DSC analysis to be approximately 200.6°C. The DSC plot also shows an endothermic peak at approximately 207.2°C. A plot of this DSC thermogram is shown in Figure 2.

[0150] TGA data were collected on a TA Instruments Q500 TGA. Each sample was placed on a pre-weighed platinum crucible and purged with nitrogen prior to analysis, with the balance and furnace set at 40±5 mL / min and 60±5 mL / min, respectively. The heating process was programmed to begin at ambient temperature and heat at a ramp rate of 10°C / min. Compound 1 besylate Form I exhibited a weight loss of approximately 0.14% upon heating to approximately 202.9°C, as determined by this TGA analysis. A plot of this TGA thermogram is shown in Figure 2 (top trace).

[0151] To evaluate the hygroscopicity and physical stability of the collected crystals under various humidities, dynamic vapor sorption (DVS) data were collected at 25°C after pre-equilibrating the samples at 0% relative humidity (RH) to remove unbound water. DVS was measured using a VTI SGA-100 water vapor sorption analyzer. Adsorption and desorption data were collected over a range from 5% RH to 95% RH in 10% RH increments under a nitrogen purge. The equilibrium criteria used for analysis was a weight change within 5 minutes of less than 0.0100% with a maximum equilibration time of 3 hours. The parameters of the DVS test are listed in Table 2. [Table 2]

[0152] A plot of this DVS measurement is shown in Figure 3. A weight change of 0.73% was measured from 5% to 95% relative humidity (RH). A weight change of approximately 0.5% was also measured from approximately 0% relative humidity (RH) to approximately 75% relative humidity. No change in XRPD was observed before or after the DVS measurement (data not shown).

[0153] The collected crystals were magnified and observed using an FEI Quanta 200 scanning electron microscope equipped with an Everhart-Thornley (ET) detector. Images were collected and analyzed using xTm software (version 2.01) and XT Docu software (version 3.2), respectively. Magnification was verified using National Institute of Standards and Technology (NIST) certified reference materials. These samples were prepared by placing a small amount on a carbon adhesive tab supported on an aluminum mount. The samples were then sputter-coated with Au / Pd in ​​two passes (at different orientations) using a Cressington 108 automated sputter coater at approximately 20 mA and 0.13 mbar (argon) for 75 seconds. Representative images of these crystals are shown in Figure 4. Under magnification, the crystals were prismatic or other shaped and ranged in size from approximately 1 μm to approximately 73 μm.

[0154] The collected crystals were observed under magnification using polarized light microscopy (Leica DM LP microscope equipped with a Spot Insight color camera). Various objectives were used to view the samples, along with cross-polarized light and a primary red compensator. The samples were placed on glass slides, a No. 1.5 cover slip was placed on the sample, and a drop of mineral oil was added. Images were acquired at ambient temperature using Spot Advanced software (version 4.5.9). A micrometer bar was inserted on the image as a size reference. Representative images of the crystals are shown in Figure 5. Under magnification, the crystals were needle-like, flat, and other shapes, ranging in size from approximately 2.5 μm to approximately 83 μm.

[0155] The stability of the collected crystals was tested by storing them at 40°C and 75% relative humidity for 45 days. These conditions did not result in any appreciable deterioration, as indicated by HPLC, LCMS, and NMR analysis (data not shown). Heating in a vacuum oven at 55°C for 24 hours or at 75°C (open to air) for 1 week did not result in any appreciable deterioration, as indicated by HPLC, LCMS, and NMR analysis (data not shown). The physical form of both samples remained the same based on XRPD taken before and after these tests (data not shown).

[0156] Example 2: Besylate salt of Compound 1 (Form II) A 250 mL round-bottom flask equipped with a magnetic stirrer was charged with (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide (Compound 1, 5.18 g, 8.9 mmol) and MeCN (70 mL, 14 volumes). The resulting mixture was stirred for 20 minutes, heated to 70 °C (hotplate temperature) to form a clear solution, and then cooled to 65 °C (hotplate temperature). To this solution was slowly added a solution of benzenesulfonic acid hydrate (1.73 g, 9.81 mmol (monohydrate basis), 1.1 equiv.) in deionized HO (1.5 mL) and MeCN (15 mL) over 3 minutes and washed in with MeCN (10 mL). The resulting solution was stirred at the same temperature for 15 minutes, then filtered through a polyethylene frit filter and washed with MeCN (10 mL). The resulting solution was stirred at 65°C (hotplate temperature) for 30 minutes, slowly cooled to room temperature, and stirred overnight (18 hours). The resulting solution was sprinkled with compound 1 besylate crystals (approximately 50 mg) and stirred at the same temperature for 2 hours. The solid was collected by filtration, washed with MeCN (15 mL x 2), air-dried (1 hour), and then dried under high vacuum overnight (18 hours) to give N-cyclopentyl-4-((2R,3S)-1-(2-fluoro-6-methylbenzoyl)-3-((4-methyl-3-(trifluoromethyl)phenyl)-carbamoyl)piperidin-2-yl)benzeneaminium benzenesulfonate in a yield of 2 g (30%) as off-white crystals. 1H NMR (400 MHz, DMSO-d6) (room temperature) δ 10.44 (s, 1H), 7.90-7.83 (m, 1H), 7.65-7.25 (m, 10H), 7.18-7.07 (m, 3H), 6.42-6.34 (m, 1H), 4.85-4.00 (br, 2H), 3.85-3.70 (m, 1H), 3.22-3.00 (m, 3H), 2.38-2.28 (m, 4H), 2.20-1.40 (m, 15H), (65℃) δ 10.22 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.68-7.56 (m, 3H), 7.44-7.20 (m, 6H), 7.18-6.70 (m, 4H), 6.44-6.35 (m, 1H), 6.20-5.20 (br, 2H), 3.72-3.65 (m, 1H), 3.25-2.98 (m, 3H), 2.40-2.28 (m, 4H), 2.22-1.40 (m, 15H). MS:(ES)C at m / z 33 H 36 F4N3O2[M+H] + Calculated for: 582.3, Found: 582.2. The XRPD plot is shown in Figure 6 and the significant peaks observed in the XRPD plot are summarized in Table 3 below. HPLC: >99%. Elemental analysis was C 39 H 41 Fits the formula F4N3O5S. KF: 0.42%. [Table 3]

[0157] Differential scanning calorimetry (DSC) was performed as described in Example 1. The melting point (onset) was determined by DSC analysis to be about 180.5° C. The DSC plot also shows an endothermic peak at about 187.2° C. A plot of this DSC thermogram is shown in FIG. 7 (bottom trace).

[0158] TGA was performed as described in Example 1. It was determined from this TGA analysis that besylate Form II of Compound 1 exhibits a weight loss of about 0.095% when heated to about 189.5° C. A plot of this TGA thermogram is shown in Figure 7 (top trace).

[0159] Example 3: Tosylate salt of Compound 1 (Form I) [ka] A 5 L three-neck flask equipped with an overhead stirrer was charged with (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide (Compound 1, 261.2 g, 449.1 mmol) and MeCN (2 L, 8 volumes). The resulting mixture was stirred for 20 minutes and heated to 75° C. (internal temperature) to form a clear solution. The solution was cooled to 65°C (internal temperature), and a solution of paratoluenesulfonic acid hydrate (1.25 hydrate, corrected by KF analysis, 89.1 g, 458 mmol, 1.02 equiv.) in deionized HO (45 mL, 0.5 vol.) was slowly added over 20 min and washed with MeCN (2 x 45 mL) (internal temperature was maintained between 60 and 65°C). The resulting solution was stirred at the same temperature for 15 min, then filtered through a polyethylene frit filter and washed with MeCN (200 mL). The filtrate was cooled to 45°C, sprinkled with crystalline tosylate of compound 1 (approximately 100 mg), and stirred at the same temperature for 1 h. The resulting mixture was slowly cooled to room temperature and stirred overnight (18 h). The solid was collected by filtration, washed with MeCN (2 x 250 mL), air-dried (1 h), and then dried under vacuum at 50°C overnight (24 h) to give N-cyclopentyl-4-((2R,3S)-1-(2-fluoro-6-methylbenzoyl)-3-((4-methyl-3-(trifluoromethyl)phenyl)-carbamoyl)piperidin-2-yl)benzeneaminium 4-methylbenzenesulfonate in a yield of 297.3 g (87%) as off-white crystals. 1H NMR (400 MHz, DMSO-d6) (room temperature) δ 10.45 (s, 1H), 7.89-7.85 (m, 1H), 7.65-7.53 (m, 1H), 7.53-7.41 (m, 4H), 7.38-7.27 (m, 2H), 7.20-7.00 (m, 5H), 6.42-6.36 (m, 1H), 5.10-4.35 (br, 2H), 3.85-3.70 (m, 1H), 3.20-3.01 (m, 3H), 2.40-2.30 (m, 4H), 2.27 (s, 3H), 2.20-1.40 (m, 15H), (65℃) δ 10.23 (d, J = 8.4 Hz, 1H), 7.85 (dd, J = 8.8, 2.0 Hz, 1H), 7.68-7.56 (m, 1H), 7.49 (J = 8.0 Hz, 2H), 7.44-6.89 (m, 11H), 6.43-6.37 (m, 1H), 3.81-3.73 (m, 1H), 3.26-2.99 (m, 3H), 2.40-2.30 (m, 5H), 2.28 (s, 3H), 1.98-1.40 (m, 14H). MS:(ES)C at m / z 33 H 36 F4N3O2[M+H] + Calculated for: 582.3, Found: 582.2. The XRPD plot is shown in Figure 8 and the significant peaks observed in the XRPD plot are summarized in Table 4 below. HPLC (both non-chiral analytical chromatography and chiral chromatography): >99%. Elemental analysis was C 40 H 43 Fits the formula F4N3O5S. KF: 0.85%. [Table 4]

[0160] Differential scanning calorimetry (DSC) was performed as described in Example 1. The melting point (onset) was determined by DSC analysis to be about 206.2°C. The DSC plot also shows an endothermic peak at about 209.8°C. A plot of this DSC thermogram is shown in Figure 9 (bottom trace).

[0161] TGA was performed as described in Example 1. It was determined from this TGA analysis that Compound 1 in tosylate Form I exhibits a weight loss of about 0.19% when heated to about 204.2° C. A plot of this TGA thermogram is shown in Figure 9 (top trace).

[0162] The hygroscopicity and physical stability of the collected crystals were measured using dynamic vapor sorption (DVS) as described in Example 1. A plot of the DVS measurement is shown in Figure 10. A weight change of 0.83% was measured from 5% to 95% relative humidity (RH). A weight change of about 0.58% was also measured from about 0% relative humidity (RH) to about 75% relative humidity. No change in XRPD was observed before and after the DVS measurement (data not shown).

[0163] The collected crystals were observed using a scanning electron microscope (SEM) as described in Example 1. Representative images of these crystals are shown in Figure 11. Under magnification, the crystals were flat, rod-like, or equidimensional, and ranged in size from about 1 μm to about 500 μm.

[0164] The collected crystals were observed using polarized light microscopy (PLM) as described in Example 1. Representative images of the crystals are shown in Figure 12. Under magnification, the crystals were needle-shaped, flattened, and other shapes, and ranged in size from about 2.5 μm to about 440 μm.

[0165] The stability of the collected crystals was tested by storing them at 40°C and 75% relative humidity for 45 days. These conditions did not result in any appreciable deterioration, as indicated by HPLC, LCMS, and NMR analysis (data not shown). Heating in a vacuum oven at 55°C for 24 hours or at 75°C (open to air) for 1 week did not result in any appreciable deterioration, as indicated by HPLC, LCMS, and NMR analysis (data not shown). The physical form of both samples remained the same based on XRPD taken before and after these tests (data not shown).

[0166] Example 4: Napadisylate salt of Compound 1 (Form I) [ka] A 5 L three-neck flask equipped with an overhead stirrer was charged with (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide (Compound 1, 261.2 g, 450 mmol) and MeCN (2 L, approximately 8 volumes). The resulting mixture was stirred for 20 minutes and heated to 75° C. (internal temperature) to give a clear solution. The resulting solution was cooled to 70 °C (internal temperature), filtered through a polyethylene fritted filter, and washed with MeCN (200 mL). To this solution was added slowly a pre-filtered solution of naphthalene-1,5-disulfonic acid hydrate (89.2 g, 247.5 mmol (based on tetrahydrate, (KF)), 0.6 equiv.) in deionized HO (90 mL, 1 vol.) and MeCN (270 mL) over 25 min (the reaction mixture became cloudy after 2 / 3 of the acid had been added). The resulting mixture was stirred at 70°C for 40 minutes, and any large chunks of solid material were manually broken up with a speculum. The resulting mixture was allowed to cool slowly to room temperature and stirred for 3 hours. The solid material was collected by filtration and washed with 3% HO in MeCN (250 mL x 100 mL). The residue was washed with MeCN (250 mL x 2), air-dried (1 h), and then dried under vacuum at 50° C. overnight (30 h) to give N-cyclopentyl-4-((2R,3S)-1-(2-fluoro-6-methylbenzoyl)-3-((4-methyl-3-(trifluoromethyl)phenyl)-carbamoyl)piperidin-2-yl)benzeneaminium naphthalene-1,5-disulfonic acid in a yield of 299.4 g (91%) as off-white crystals. 1H NMR (400 MHz, DMSO-d6) (room temperature) δ 10.44 (s, 1H), 8.83 (d, J = 8.8 Hz 1H), 7.95-7.80 (m, 2H), 7.65-7.28 (m, 6H), 7.19-7.00 (m, 3H), 6.43-6.34 (m, 1H), 4.55-3.95 (br, 2H), 3.85-3.68 (m, 1H), 3.25-2.99 (m, 3H), 2.38-2.00 (m, 5H), 1.90-1.40 (m, 14H), (65℃) δ 10.21 (d, J = 8.8 Hz, 1H), 8.90 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 6.8 Hz, 1H), 7.89-7.82 (m, 1H), 7.68-7.58 (m, 1H), 7.46-7.20 (m, 5H), 7.16-6.70 (m, 4H), 6.44-6.35 (m, 1H), 5.80-5.20 (br, 1H), 3.80-3.64 (m, 1H), 3.22-2.98 (m, 3H), 2.40-2.00 (m, 6H), 1.96-1.40 (m, 13H). MS:(ES)C at m / z 33 H 36 F4N3O2[M+H] + Calculated for: 582.3, Found: 582.2. The XRPD plot is shown in Figure 13 and the significant peaks observed in the XRPD plot are summarized in Table 5 below. HPLC: >99%. Elemental analysis was C 38 H 39 Fits the formula F4N3O5S. KF: 1.63%. [Table 5]

[0167] Differential scanning calorimetry (DSC) was performed as described in Example 1. The melting points at the onset and peak of the endothermic peak were determined by DSC analysis to be 222.7° C. and 232.8° C., respectively. A plot of this DSC thermogram is shown in FIG. 14 (bottom trace).

[0168] TGA was performed as described in Example 1. It was determined from this TGA analysis that napadisylate Form I of Compound 1 exhibits a weight loss of about 2.0% when heated to about 233.1° C. A plot of this TGA thermogram is shown in Figure 14 (top trace).

[0169] The hygroscopicity and physical stability of the collected crystals were measured using dynamic vapor sorption (DVS) as described in Example 1. A plot of the DVS measurement is shown in Figure 15. A weight change of 1.42% was measured from 5% to 95% relative humidity (RH). A weight change of about 0.6% was also measured from about 0% relative humidity (RH) to about 55% relative humidity. No change in XRPD was observed before and after the DVS measurement (data not shown).

[0170] The collected crystals were observed using a scanning electron microscope (SEM) as described in Example 1. Representative images of these crystals are shown in Figure 16. Under magnification, the crystals were flat, rod-like, and equidimensional, with sizes ranging from about 1 μm to about 150 μm.

[0171] The collected crystals were observed using polarized light microscopy (PLM) as described in Example 1. Representative images of the crystals are shown in Figure 17. Under magnification, the crystals were needle-like, flat, or other shapes, and ranged in size from about 1.3 μm to about 75 μm.

[0172] The stability of the collected crystals was tested by storing them at 40°C and 75% relative humidity for 45 days. These conditions did not result in any appreciable deterioration, as indicated by HPLC, LCMS, and NMR analysis (data not shown). Heating in a vacuum oven at 55°C for 24 hours or at 75°C (open to air) for 1 week did not result in any appreciable deterioration, as indicated by HPLC, LCMS, and NMR analysis (data not shown). The physical form of both samples remained the same based on XRPD taken before and after these tests (data not shown).

[0173] Example 5: Napsylate salt of Compound 1 (Form I) [ka] A 5 L three-neck flask equipped with an overhead stirrer was charged with (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide (Compound 1, 263.3 g, 452.7 mmol) and MeCN (2 L, 8 volumes). The resulting mixture was stirred for 15 minutes, heated to 75° C. (internal temperature) to form a clear solution, filtered through a polyethylene fritted filter, and washed with MeCN (200 mL). To this solution at 70°C (internal temperature) was slowly added a pre-filtered solution of 2-naphthalenesulfonic acid hydrate (108 g, 466.2 mmol (1.3 hydrate basis, KF), 1.03 equiv) in deionized HO (54 mL, 0.5 vol) and MeCN (300 mL) over 25 min and washed with MeCN (100 mL) (internal temperature decreased to 64°C). The resulting solution was stirred at 65°C for 40 min. The resulting mixture was slowly cooled to room temperature and stirred over 3 h. The solid was collected by filtration, washed with MeCN (2 x 250 mL), air-dried (1 h), and then dried under vacuum at 50°C overnight (24 h) to give N-cyclopentyl-4-((2R,3S)-1-(2-fluoro-6-methylbenzoyl)-3-((4-methyl-3-(trifluoromethyl)phenyl)-carbamoyl)piperidin-2-yl)benzeneaminium naphthalene-2-sulfonate in a yield of 330.3 g (92%) as off-white crystals. 1H NMR (400 MHz, DMSO-d6) (room temperature) δ 10.44 (s, 1H), 8.12 (s, 1H), 8.00-7.80 (m, 4H), 7.70-7.28 (m, 8H), 7.19-7.00 (m, 3H), 6.43-6.34 (m, 1H), 4.80-4.10 (br, 2H), 3.70-3.68 (m, 1H), 3.40-2.99 (m, 3H), 2.38-2.00 (m, 5H), 1.90-1.40 (m, 14H), (65℃) δ 10.21 (d, J = 8.8 Hz, 1H), 8.13 (s, 1H), 7.99-7.78 (m, 4H), 7.75-7.20 (m, 8H), 7.18-6.64 (m, 4H), 6.42-6.36 (m, 1H), 5.80-5.20 (br, 1H), 3.25-2.98 (m, 3H), 2.40-2.00 (m, 6H), 1.96-1.40 (m, 13H). MS:(ES)C at m / z 33 H 36 F4N3O2[M+H] + Calculated for: 582.3, Found: 582.2. The XRPD plot is shown in Figure 18 and the significant peaks observed in the XRPD plot are summarized in Table 6 below. HPLC (both non-chiral analytical chromatography and chiral chromatography): >99%. Elemental analysis was C 43 H 43 Fits the formula F4N3O5S. KF: 0.79%. [Table 6]

[0174] Differential scanning calorimetry (DSC) was performed as described in Example 1. The melting point (onset) was determined by DSC analysis to be about 211.7°C. The DSC plot also shows an endothermic peak at about 218.3°C. A plot of this DSC thermogram is shown in Figure 19 (bottom trace).

[0175] TGA was performed as described in Example 1. It was determined from this TGA analysis that napsylate salt Form I of Compound 1 exhibits a weight loss of about 0.49% when heated to about 217.0° C. A plot of this TGA thermogram is shown in Figure 19 (top trace).

[0176] The hygroscopicity and physical stability of the collected crystals were measured using dynamic vapor sorption (DVS) as described in Example 1. A plot of this DVS measurement is shown in Figure 20. A weight change of 0.65% was measured from 5% to 95% relative humidity (RH). A weight change of about 0.2% was also measured from about 0% relative humidity (RH) to about 55% relative humidity. No change in XRPD was observed before and after the DVS measurement (data not shown).

[0177] The collected crystals were observed using a scanning electron microscope (SEM) as described in Example 1. Representative images of these crystals are shown in Figure 21. Under magnification, the crystals were flat, rod-like, and equidimensional, with sizes ranging from about 1 μm to about 150 μm.

[0178] The collected crystals were observed using polarized light microscopy (PLM) as described in Example 1. Representative images of the crystals are shown in Figure 22. Under magnification, the crystals were flattened and ranged in size from about 5 μm to about 470 μm.

[0179] The stability of the collected crystals was tested by storing them at 40°C and 75% relative humidity for 45 days. These conditions did not result in any appreciable deterioration, as indicated by HPLC, LCMS, and NMR analysis (data not shown). Heating in a vacuum oven at 55°C for 24 hours or at 75°C (open to air) for 1 week did not result in any appreciable deterioration, as indicated by HPLC, LCMS, and NMR analysis (data not shown). The physical form of both samples remained the same based on XRPD taken before and after these tests (data not shown).

[0180] Example 6: Camsylate salt of Compound 1 (Form I) [ka] A 1 L round-bottom flask equipped with a magnetic stirrer was charged with (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide (Compound 1, 54.5 g, 94 mmol) and MeCN (400 mL, 8 volumes). The resulting mixture was stirred for 30 minutes, heated to 75° C. (internal temperature) to form a clear solution, cooled to 65° C. (internal temperature), filtered through a polyethylene fritted filter, and washed with MeCN (50 mL). To this solution, a pre-filtered solution of (1S)-(+)-10-camphorsulfonic acid (22.9 g, 98.06 mmol, 1.05 equiv.) in deionized HO (11.5 mL, 0.5 vol.) and MeCN (46 mL) was slowly added over 5 min and washed with MeCN (23 mL) (internal temperature decreased to 60 °C). The resulting solution was cooled to 55 °C, seeded with crystalline camsylate of compound 1 (approximately 50 mg), and stirred at the same temperature for 1 h. The resulting mixture was slowly cooled to room temperature and stirred for 3 h. The solid was collected by filtration, washed with 2% HO in MeCN (2×50 mL), MeCN (2×50 mL), air-dried (1 h), and then dried under vacuum at 50° C. overnight (24 h) to give N-cyclopentyl-4-((2R,3S)-1-(2-fluoro-6-methylbenzoyl)-3-((4-methyl-3-(trifluoromethyl)phenyl)-carbamoyl)piperidin-2-yl)benzeneaminium (1S)-(+)-10-camphorsulfonic acid in 69 g (90%) yield as off-white crystals. 1H NMR (400 MHz, DMSO-d6) (room temperature) δ 10.45 (s, 1H), 7.90 - 7.82 (m, 1H), 7.65 - 7.48 (m, 3H), 7.38 - 7.07 (m, 6H), 6.42-6.34 (m, 1H), 5.90-5.20 (br, 1H), 3.85-3.70 (m, 1H), 3.22-3.00 (m, 3H), 2.85 (d, J = 14.7 Hz, 1H), 2.71 - 2.58 (m, 1H), 2.40 - 1.98 (m, 8H), 1.94 - 1.40 (m, 17H), 1.31 - 1.18 (m, 2H), 1.02 (s, 3H), 0.71 (s, 3H), (65℃) δ 10.22 (d, J = 8.4 Hz, 1H), 7.89-7.81 (m, 1H), 7.68-7.56 (m, 1H), 7.46-7.25 (m, 4H), 7.18-6.80 (m, 5H), 6.42-6.34 (m, 1H), 3.81 - 3.72 (m, 1H), 3.26 - 2.99 (m, 3H), 2.90 (d, J = 14.7 Hz, 1H), 2.75 - 2.62 (m, 1H), 2.48 - 2.00 (m, 8H), 1.94 - 1.40 (m, 17H), 1.35 - 1.20 (m, 2H), 1.06 (s, 3H), 0.75 (s, 3H). MS: (ES) C at m / z 33 H 36 F4N3O2[M+H] + Calculated for: 582.3, Found: 582.2. XRPD: The XRPD plot is shown in Figure 23 and the significant peaks observed in the XRPD plot are summarized in Table 7 below. HPLC: >99%. Elemental analysis was C 43 H 51 Fits the formula F4N3O6S. KF: 1.09%. [Table 7]

[0181] Differential scanning calorimetry (DSC) was performed as described in Example 1. The melting point (onset) was determined by DSC analysis to be about 202.8°C. The DSC plot also shows an endothermic peak at about 209.8°C. A plot of this DSC thermogram is shown in Figure 24 (bottom trace).

[0182] TGA was performed as described in Example 1. It was determined from this TGA analysis that camsylate Form I of Compound 1 exhibits a weight loss of about 0.23% when heated to about 205.0° C. A plot of this TGA thermogram is shown in Figure 24 (top trace).

[0183] The hygroscopicity and physical stability of the collected crystals were measured using dynamic vapor sorption (DVS) as described in Example 1. A plot of this DVS measurement is shown in Figure 25. A weight change of 0.96% was measured from 5% to 95% relative humidity (RH). A weight change of about 0.35% was also measured from about 0% relative humidity (RH) to about 65% relative humidity. No change in XRPD was observed before and after the DVS measurement (data not shown).

[0184] The collected crystals were observed using a scanning electron microscope (SEM) as described in Example 1. Representative images of these crystals are shown in Figure 26. Under magnification, the crystals were thick, flat, and rod-shaped, ranging in size from just under 1 μm to about 77 μm.

[0185] The collected crystals were observed using polarized light microscopy (PLM) as described in Example 1. Representative images of the crystals are shown in Figure 27. Under magnification, the crystals were loose, needle-like, flattened, and other shapes, ranging in size from about 2.5 μm to about 84 μm.

[0186] The stability of the collected crystals was tested by storing them at 40°C and 75% relative humidity for 45 days. These conditions did not result in any appreciable deterioration, as indicated by HPLC, LCMS, and NMR analysis (data not shown). Heating in a vacuum oven at 55°C for 24 hours or at 75°C (open to air) for 1 week did not result in any appreciable deterioration, as indicated by HPLC, LCMS, and NMR analysis (data not shown). The physical form of both samples remained the same based on XRPD taken before and after these tests (data not shown).

[0187] Example 7: Edisylate salt of Compound 1 (Form I) [ka] A 200 mL round-bottom flask equipped with a magnetic stirrer was charged with (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide (CCX168, Lot No. D-15-012, 10 g, 17.2 mmol) and MeCN (120 mL, 12 volumes). The resulting mixture was stirred for 30 minutes and heated to 65° C. (internal temperature) to form a clear solution. To this solution, 1,2-ethanedisulfonic acid dihydrate (1.97 g, 8.6 mmol, 0.5 equiv.) was slowly added in portions. The resulting solution was stirred at the same temperature for 30 minutes and then cooled to room temperature. The mixture was concentrated to dryness in vacuo and then placed under high vacuum overnight.

[0188] To the dried solid was added EtOH (100 mL, 10 volumes). The mixture was heated at 80° C. (internal temperature) for 1 hour. The solution was allowed to slowly cool to room temperature and stirred overnight. The solid was collected by filtration, washed with EtOH (20 mL x 2), and then dried under high vacuum overnight to give N-cyclopentyl-4-((2R,3S)-1-(2-fluoro-6-methylbenzoyl)-3-((4-methyl-3-(trifluoromethyl)phenyl)carbamoyl)piperidin-2-yl)benzeneaminium ethane-1,2-disulfonic acid in a yield of 8.94 g (77%) as off-white crystals. 1 H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.85 (dd, J = 10.8, 2.2 Hz, 1H), 7.68-7.47 (m, 3H), 7.39-7.22 (m, 4H), 7.20-7.00 (m, 2H), 6.41 (dd, J = 11.3, 6.2 Hz, 1H), 3.81 (m, J = 6.6 Hz, 1H), 3.23-3.02 (m, 3H), 2.69 (s, 2H), 2.33 (m, 5H), 2.22-2.00 (m, 1H), 1.87 (s, 3H), 1.85-1.72 (m, 3H), 1.72-1.63 (m, 2H), 1.62-1.45 (m, 5H). MS: (ES) C at m / z 33 H 36 F4N3O2[M+H] + Calculated for: 582.3, Found: 582.2. The XRPD plot is shown in Figure 28 and the significant peaks observed in the XRPD plot are summarized in Table 8 below. HPLC: >99%. Elemental analysis was C 68 H 76 F8N6O 10 Conforms to the S2 formula. KF: 1.13%. [Table 8]

[0189] Differential scanning calorimetry (DSC) was performed as described in Example 1. The melting point (onset) was determined by DSC analysis to be about 205.2°C. The DSC plot also shows an endothermic peak at about 213.3°C. A plot of this DSC thermogram is shown in Figure 29.

[0190] Example 8: Aqueous Suspension Formulation Using Compound 1 in Salt Form An in vivo rat PK study was conducted to compare the PK profiles and bioavailability of the free base crystalline form of Compound 1 to various salt forms of Compound 1 in an aqueous liquid suspension formulation containing 0.5% (w / v) hydroxypropylcellulose (Klucel GF grade) and 0.5% (w / v) poloxamer F-68 (BASF Kolliphor P188). Each animal was orally administered 10 mg / kg body weight of Compound 1 (2 mg / mL dose concentration) in a dose volume of 5 mL / kg. Table 9 summarizes the measured PK parameters. The PK profiles of these formulations are shown in Figure 30. [Table 9]

[0191] Example 9: Aqueous Suspension Formulation Using Compound 1 in Salt Form An in vivo rat PK study was conducted to compare the PK profile and bioavailability of the free base crystalline form of Compound 1 to various salt forms of Compound 1 in an aqueous liquid suspension formulation containing 1% HPMC. Each animal was orally administered 10 mg / kg body weight of Compound 1 (2 mg / mL dose concentration) in a dose volume of 5 mL / kg. Table 10 summarizes the measured PK parameters. The PK profiles of these formulations are shown in Figure 31. [Table 10]

[0192] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will recognize that certain changes and modifications can be practiced within the scope of the appended claims. Furthermore, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. In the event of a conflict between the present invention and a reference provided herein, the present invention shall control.

Claims

1. Besylate salt of Compound 1 【Chemistry 1】

2. 10. The besylate salt of claim 1 in a single crystalline form substantially free of other crystalline or amorphous forms.

3. 3. The besylate salt of claim 2, wherein the single crystalline form is besylate Form I.

4. 4. The besylate Form I of claim 3, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.9 degrees, 13.3 degrees, 16.2 degrees, 17.6 degrees, and 21.8 degrees 2θ (±0.2 degrees 2θ).

5. 5. The besylate Form I of claim 4, further characterized by XRPD peaks at 6.6 degrees, 7.6 degrees, 14.5 degrees, 16.2 degrees, and 28.2 degrees 2θ (±0.2 degrees 2θ).

6. 5. Besylate Form I of claim 4, characterized by an X-ray powder diffraction pattern substantially in accordance with FIG.

7. 7. The besylate Form I of any one of claims 4 to 6, further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 207.2°C.

8. 7. Besylate Form I of any one of claims 4 to 6, further characterized by an onset melting temperature of about 200.6°C as determined by differential scanning calorimetry (DSC) thermogram.

9. 7. Besylate Form I according to any one of claims 4 to 6, wherein the DSC thermogram is substantially in accordance with Figure 2.

10. 10. The besylate Form I of any one of claims 4 to 9, further characterized by a weight loss of about 0.14% upon heating to about 202.9°C as measured by thermogravimetric analysis (TGA).

11. 10. Besylate Form I of any one of claims 4 to 9, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 2.

12. 12. The besylate Form I of any one of claims 4 to 11, further characterized by a weight gain of about 0.5% after undergoing dynamic water vapor sorption cycling from about 0% relative humidity (RH) to about 75% RH at 25°C.

13. 12. The besylate Form I of any one of claims 4 to 11, further characterized by a weight gain of about 0.73% after undergoing dynamic water vapor sorption cycling from about 5% relative humidity (RH) to about 95% RH at 25°C.

14. 12. Besylate Form I of any one of claims 4 to 11, having a dynamic water vapor sorption profile substantially as shown in Figure 3.

15. 15. Besylate Form I of any one of claims 4 to 14, further characterized by a scanning electron microscopy (SEM) image with predominantly prismatic or irregularly shaped particles.

16. 16. The besylate Form I of claim 15, having a particle size of about 1 μm to about 73 μm as measured by scanning electron microscopy (SEM).

17. 15. Besylate Form I of any one of claims 4 to 14, further characterized by a scanning electron microscopy (SEM) image substantially in accordance with Figure 4.

18. 18. Besylate Form I according to any one of claims 4 to 17, further characterized by particles with a size ranging from about 2.5 μm to about 83 μm as measured by polarized light microscopy (PLM).

19. 18. Besylate Form I according to any one of claims 4 to 17, further characterized by a polarized light microscope (PLM) profile substantially as shown in Figure 5.

20. 3. The besylate salt of claim 2, wherein the single crystalline form is besylate Form II.

21. 21. Besylate Form II of claim 20, characterized by a powder X-ray diffraction pattern comprising peaks at 3.6, 7.1, 12.3, 12.8, and 16.7 degrees 2θ (±0.2 degrees 2θ).

22. 22. Besylate Form II of claim 21, characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 6.

23. 23. Besylate Form II of any one of claims 21-22, further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 187.2°C.

24. 23. Besylate Form II of any one of claims 21-22, further characterized by an onset melting temperature of about 180.5°C as determined by differential scanning calorimetry (DSC) thermogram.

25. 23. Besylate Form II according to any one of claims 21 to 22, wherein the DSC thermogram is substantially in accordance with Figure 7.

26. 26. Besylate Form II of any one of claims 21 to 25, further characterized by a weight loss of about 0.095% upon heating to about 189.5°C as measured by thermogravimetric analysis (TGA).

27. 26. Besylate Form II of any one of claims 21 to 25, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 7.

28. Tosylate salt of Compound 1 【Chemistry 2】

29. 29. The tosylate salt of claim 28 in a single crystalline form substantially free of other crystalline or amorphous forms.

30. 30. The tosylate salt of claim 29, wherein the single crystalline form is tosylate salt form I.

31. 31. Tosylate Form I of claim 30, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.6 degrees, 10.8 degrees, 13.1 degrees, 16.5 degrees, 19.7 degrees, and 21.6 degrees 2θ (±0.2 degrees 2θ).

32. 32. The tosylate salt Form I of claim 31 , further characterized by XRPD peaks at 6.6 degrees, 15.3 degrees, 16.0 degrees, and 27.8 degrees 2θ (±0.2 degrees 2θ).

33. 31. Tosylate Form I of claim 30, characterized by an X-ray powder diffraction pattern substantially in accordance with FIG.

8.

34. 34. The tosylate salt Form I of any one of claims 30-33, further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 209.8°C.

35. 34. Tosylate Form I of any one of claims 30 to 33, further characterized by an onset melting temperature of about 206.2°C as determined by differential scanning calorimetry (DSC) thermogram.

36. 34. Tosylate Form I of any one of claims 30 to 33, wherein the DSC thermogram is substantially in accordance with Figure 9.

37. 37. The tosylate salt Form I of any one of claims 30-36, further characterized by a weight loss of about 0.19% upon heating to about 204.2°C as measured by thermogravimetric analysis (TGA).

38. 37. Tosylate Form I of any one of claims 30-36, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 9.

39. 39. The tosylate salt Form I of any one of claims 30-38, further characterized by a weight gain of about 0.58% after dynamic water vapor sorption cycling from about 0% relative humidity (RH) to about 75% RH at 25°C.

40. 39. The tosylate salt Form I of any one of claims 30-38, further characterized by a weight gain of about 0.83% after dynamic water vapor sorption cycling from about 5% relative humidity (RH) to about 95% RH at 25°C.

41. 39. The tosylate salt Form I of any one of claims 30 to 38, having a dynamic water vapor sorption profile substantially as shown in Figure 10.

42. 42. The tosylate salt Form I of any one of claims 30 to 41, further characterized by a scanning electron microscopy (SEM) image with predominantly flat, rod-shaped, or equidimensional particles.

43. 43. The tosylate Form I of claim 42, having a particle size of about 1 μm to about 500 μm as measured by scanning electron microscopy (SEM).

44. 42. The tosylate salt Form I of any one of claims 30-41, further characterized by a scanning electron microscopy (SEM) image substantially in accordance with Figure 11.

45. 42. The tosylate salt Form I of any one of claims 30 to 41, further characterized by particles with a size ranging from about 2.5 μm to about 440 μm as measured by polarized light microscopy (PLM).

46. 42. Tosylate Form I according to any one of claims 30 to 41, further characterized by a polarized light microscope (PLM) profile substantially as shown in Figure 12.

47. Napadisylate salt of compound 1 【Transformation 3】

48. 48. The napadisylate salt of claim 47 in a single crystalline form substantially free of other crystalline or amorphous forms.

49. 49. The napadisylate salt of claim 48, wherein the single crystalline form is napadisylate Form I.

50. 50. Napadisylate Form I of claim 49, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.5 degrees, 7.0 degrees, 12.4 degrees, 14.7 degrees, 15.2 degrees, and 18.0 degrees 2θ (±0.2 degrees 2θ).

51. 51. Napadisylate Form I of claim 50, further characterized by XRPD peaks at 9.6 degrees, 11.2 degrees, 18.6 degrees, and 20.4 degrees 2θ (±0.2 degrees 2θ).

52. 50. Napadisylate Form I of claim 49, characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 13.

53. 53. The napadisylate Form I of any one of claims 50-52, further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 232.8°C.

54. 53. Napadisylate Form I of any one of claims 50-52, further characterized by an onset melting temperature of about 222.7°C as determined by differential scanning calorimetry (DSC) thermogram.

55. 53. Napadisylate Form I of any one of claims 50-52, wherein the DSC thermogram is substantially in accordance with Figure 14.

56. 56. The napadisylate Form I of any one of claims 50-55, further characterized by a weight loss of about 2.0% upon heating to about 233.1°C as measured by thermogravimetric analysis (TGA).

57. 56. Napadisylate Form I of any one of claims 50-55, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 14.

58. 58. The napadisylate Form I of any one of claims 50-57, further characterized by a weight gain of about 0.6% after dynamic water vapor sorption cycling from about 0% relative humidity (RH) to about 55% RH at 25°C.

59. 58. The napadisylate Form I of any one of claims 50-57, further characterized by a weight gain of about 1.42% after dynamic water vapor sorption cycling from about 5% relative humidity (RH) to about 95% RH at 25°C.

60. 58. The napadisylate Form I of any one of claims 50-57, having a dynamic water vapor sorption profile substantially as shown in Figure 15.

61. 61. Napadisylate Form I of any one of claims 50 to 60, further characterized by a scanning electron microscopy (SEM) image with predominantly flat, rod-shaped, or equidimensional particles.

62. 61. The napadisylate Form I of any one of claims 50 to 60, having a particle size of about 1 μm to about 150 μm as measured by scanning electron microscopy (SEM).

63. 61. Napadisylate Form I of any one of claims 50-60, further characterized by a scanning electron microscopy (SEM) image substantially in accordance with Figure 16.

64. 64. The napadisylate Form I of any one of claims 50-63, further characterized by particles with a size ranging from about 1.3 μm to about 75 μm as measured by polarized light microscopy (PLM).

65. 64. Napadisylate Form I according to any one of claims 50 to 63, further characterized by a polarized light microscope (PLM) profile substantially as shown in Figure 17.

66. Napsylate salt of compound 1 【Chemistry 4】

67. 67. The napsylate salt of claim 66 in a single crystalline form substantially free of other crystalline or amorphous forms.

68. 68. The napsylate salt of claim 67, wherein the single crystalline form is napsylate Form I.

69. 69. Napsylate Form I of claim 68, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.5, 7.7, 10.4, 12.9, and 16.1 degrees 2θ (±0.2 degrees 2θ).

70. 70. The napsylate salt Form I of claim 69, further characterized by XRPD peaks at 15.4 degrees, 15.5 degrees, 17.8 degrees, and 20.8 degrees 2θ (±0.2 degrees 2θ).

71. 69. Napsylate Form I of claim 68, characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 18.

72. 72. The napsylate salt Form I of any one of claims 69-71, further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 218.3°C.

73. 72. Napsylate Form I of any one of claims 69-71, further characterized by an onset melting temperature of about 211.7°C as determined by differential scanning calorimetry (DSC) thermogram.

74. 72. The napsylate salt Form I of any one of claims 69-71, wherein the DSC thermogram is substantially in accordance with Figure 19.

75. 75. The napsylate salt Form I of any one of claims 69-74, further characterized by a weight loss of about 0.49% upon heating to about 217.0°C as measured by thermogravimetric analysis (TGA).

76. 75. The napsylate salt Form I of any one of claims 69-74, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 19.

77. 77. The napsylate salt Form I of any one of claims 69-76, further characterized by a weight gain of about 0.2% after dynamic water vapor sorption cycling from about 0% relative humidity (RH) to about 55% RH at 25°C.

78. 77. The napsylate salt Form I of any one of claims 69-76, further characterized by a weight gain of about 0.65% after dynamic water vapor sorption cycling from about 5% relative humidity (RH) to about 95% RH at 25°C.

79. 77. The napsylate salt Form I of any one of claims 69 to 76, having a dynamic water vapor sorption profile substantially as shown in Figure 20.

80. 80. Napsylate Form I of any one of claims 69 to 79, further characterized by a scanning electron microscopy (SEM) image with predominantly flat, rod-shaped, and equidimensional particles.

81. 80. Napsylate Form I of any one of claims 69 to 79, having a particle size of about 1 μm to about 150 μm as measured by scanning electron microscopy (SEM).

82. 80. The napsylate salt Form I of any one of claims 69-79, further characterized by a scanning electron microscopy (SEM) image substantially in accordance with Figure 21.

83. 83. Napsylate Form I of any one of claims 69 to 82, characterized by particles with a size ranging from about 5 μm to about 470 μm as measured by polarized light microscopy (PLM).

84. 83. The napsylate salt Form I of any one of claims 69 to 82, further characterized by a polarized light microscope (PLM) profile substantially as shown in Figure 22.

85. Compound 1 camsylate salt 【Transformation 5】

86. 86. The camsylate salt of claim 85 in a single crystalline form substantially free of other crystalline or amorphous forms.

87. 87. The camsylate salt of claim 86, wherein the single crystalline form is camsylate Form I.

88. 88. The camsylate salt Form I of claim 87, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.3 degrees, 7.9 degrees, 10.8 degrees, 12.2 degrees, and 16.1 degrees 2θ (±0.2 degrees 2θ).

89. 89. The camsylate salt Form I of claim 88, further characterized by XRPD peaks at 7.4 degrees, 8.5 degrees, 13.6 degrees, 17.0 degrees, and 18.5 degrees 2θ (±0.2 degrees 2θ).

90. 88. Camsylate Form I of claim 87, characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 23.

91. 91. The camsylate salt Form I of any one of claims 88-90, further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 209.8°C.

92. 91. The camsylate salt Form I of any one of claims 88-90, further characterized by an onset melting temperature of about 202.8°C as determined by differential scanning calorimetry (DSC) thermogram.

93. 91. The camsylate salt Form I of any one of claims 88-90, wherein the DSC thermogram is substantially in accordance with Figure 24.

94. 94. The camsylate salt Form I of any one of claims 88-93, further characterized by a weight loss of about 0.23% upon heating to about 205.0°C as measured by thermogravimetric analysis (TGA).

95. 94. The camsylate salt Form I of any one of claims 88-93, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 24.

96. 96. The camsylate salt Form I of any one of claims 88-95, further characterized by a weight gain of about 0.35% after undergoing dynamic water vapor sorption cycling from about 0% relative humidity (RH) to about 65% RH at 25°C.

97. 96. The camsylate salt Form I of any one of claims 88-95, further characterized by a weight gain of about 0.96% after undergoing dynamic water vapor sorption cycling from about 5% relative humidity (RH) to about 95% RH at 25°C.

98. 96. The camsylate salt Form I of any one of claims 88-95, having a dynamic water vapor sorption profile substantially as shown in Figure 25.

99. 99. The camsylate salt Form I of any one of claims 88 to 98, further characterized by a scanning electron microscopy (SEM) image with predominantly thick flat particles and rod-shaped particles.

100. 99. The camsylate salt Form I of any one of claims 88-98, having a particle size of from just under 1 μm to about 77 μm as measured by scanning electron microscopy (SEM).

101. 99. The camsylate salt Form I of any one of claims 88-98, further characterized by a scanning electron microscopy (SEM) image substantially in accordance with Figure 26.

102. 102. The camsylate salt Form I of any one of claims 88-101, further characterized by particles with a size ranging from about 2.5 μm to about 84 μm as measured by polarized light microscopy (PLM).

103. 102. The camsylate salt Form I of any one of claims 88-101, further characterized by a polarized light microscope (PLM) profile substantially as shown in Figure 27.

104. Edisylate salt of compound 1 【Transformation 6】

105. 105. The edisylate salt of claim 104 in a single crystalline form substantially free of other crystalline or amorphous forms.

106. 106. The edisylate salt of claim 105, wherein the single crystalline form is edisylate form I.

107. 107. The edisylate salt Form I of claim 106, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 3.4 degrees, 5.6 degrees, 12.9 degrees, 15.3 degrees, 18.1 degrees, and 20.8 degrees 2θ (±0.2 degrees 2θ).

108. 108. The edisylate salt Form I of claim 107, further characterized by XRPD peaks at 7.3 degrees, 10.7 degrees, 14.5 degrees, 15.6 degrees, 19.1 degrees, and 19.7 degrees 2θ (±0.2 degrees 2θ).

109. 107. Edisylate Form I of claim 106, characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 28.

110. 110. The edisylate salt Form I of any one of claims 106-109, further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 213.3°C.

111. 110. The edisylate salt Form I of any one of claims 106-109, further characterized by an onset melting temperature of about 205.2°C as determined by differential scanning calorimetry (DSC) thermogram.

112. 110. The edisylate salt Form I of any one of claims 106-109, wherein the DSC thermogram is substantially in accordance with Figure 29.

113. 113. A pharmaceutical composition comprising Compound 1 in a salt form according to any one of claims 1 to 112 and at least one pharmaceutically acceptable excipient.

114. 113. An aqueous suspension comprising Compound 1 in a salt form according to any one of claims 1 to 112 and at least one excipient.

115. 115. An aqueous suspension according to claim 114, wherein the at least one excipient is at least one suspending agent and / or at least one wetting agent.

116. 116. An aqueous suspension according to claim 114 or 115, wherein the aqueous suspension further comprises a sweetener.

117. 113. An injection or infusion solution comprising Compound 1 and at least one wetting agent or solvent, wherein the injection or infusion solution is prepared using a salt form of Compound 1 according to any one of claims 1 to 112.

118. 118. The injection or infusion solution of claim 117, which is formulated for intravenous administration.

119. 118. The injectable or infusion solution of claim 117, which is formulated for intramuscular administration.

120. 118. The injectable or infusion solution of claim 117, which is prepared for subcutaneous injection.

121. 114. A method for treating an individual suffering from or susceptible to a disease or disorder associated with C5a receptor activation by a condition, said method comprising administering to said individual an effective amount of Compound 1 in the form of a salt according to any one of claims 1 to 112.

122. 122. The method of claim 121, wherein the disease or disorder is an inflammatory disease or disorder.

123. 123. The method of claim 122, wherein the disease or disorder is selected from the group consisting of neutropenia, sepsis, septic shock, Alzheimer's disease, multiple sclerosis, stroke, inflammatory bowel disease, age-related macular degeneration, chronic obstructive pulmonary disease, burn-related inflammation, lung injury, osteoarthritis, atopic dermatitis, chronic urticaria, ischemia-reperfusion injury, acute respiratory distress syndrome, systemic inflammatory response syndrome, multiple organ dysfunction syndrome, tissue graft rejection, cancer, and hyperacute rejection of a transplanted organ.

124. 122. The method of claim 121, wherein the disease or disorder is a cardiovascular disorder or a cerebrovascular disorder.

125. 125. The method of claim 124, wherein the disease or disorder is selected from the group consisting of myocardial infarction, coronary thrombosis, vascular occlusion, postoperative vascular reocclusion, atherosclerosis, traumatic central nervous system injury, and ischemic heart disease.

126. 122. The method of claim 121, wherein the disease or disorder is an autoimmune disease.

127. 127. The method of claim 126, wherein the disease or disorder is selected from the group consisting of rheumatoid arthritis, C3 glomerulopathy (C3G), hidradenitis suppurativa (HS), systemic lupus erythematosus, Guillain-Barré syndrome, pancreatitis, lupus nephritis, lupus glomerulonephritis, psoriasis, immunoglobulin A (IgA) nephropathy, Crohn's disease, vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic thrombocytopenia, Goodpasture's syndrome, immune vasculitis, tissue graft rejection, and hyperacute rejection of transplanted organs.

128. The method of claim 121, wherein the disease or disorder is a sequela associated with the group consisting of insulin-dependent diabetes mellitus, diabetes, lupus nephropathy, Heymann nephritis, membranous nephritis, glomerulonephritis, contact hypersensitivity response, and inflammation resulting from blood contact with artificial surfaces.

129. 122. The method of claim 121, wherein the disease or disorder is selected from the group consisting of antineutrophil cytoplasmic antibody-associated (ANCA) vasculitis, C3 glomerulopathy, hidradenitis suppurativa, and lupus nephritis.

130. 122. The method of claim 121, wherein the disease or disorder is antineutrophil cytoplasmic antibody-associated (ANCA) vasculitis.

131. 122. The method of claim 121, wherein the disease or disorder is granulomatosis with polyangiitis.

132. 122. The method of claim 121, wherein the disease or disorder is microscopic polyangiitis.

133. 122. The method of claim 121, wherein the disease or disorder is C3 glomerulopathy.

134. 122. The method of claim 121, wherein the disease or disorder is hidradenitis suppurativa.

135. 122. The method of claim 121, wherein the disease or disorder is lupus nephritis.

136. 136. The method of any one of claims 121-135, further comprising administering to the individual an effective amount of one or more additional therapeutic agents.

137. 137. The method of claim 136, wherein the one or more additional therapeutic agents is rituximab.

138. 137. The method of claim 136, wherein the one or more additional therapeutic agents is cyclophosphamide.

Images