CRYSTAL FORMS OF AN AGENT RELATED APPLICATION This application claims the benefit of U.S. Provisional Application No. 63/649,576 filed May 20, 2024. The entire contents of the above-referenced application are incorporated by reference herein. FIELD OF THE INVENTION The present invention relates to crystalline polymorphic forms of Compound I tosylate, process for their preparation, pharmaceutical compositions comprising the polymorphic forms, methods of using the same to prepare pharmaceutical compositions, and methods of using the polymorphic forms to treat or prevent diseases and conditions associated with activity of one or more of Fms, and/or Trk, such as TrkA, TrkB and TrkC. SUMMARY OF THE INVENTION The present invention provides polymorphic forms of the tosylate salt of Compound I [chemical name: 6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-(2,2,2- trifluoroethylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone] (also referred to herein as Compound I tosylate or Compound I-TsOH), which has the structure below.
Compound I tosylate. In certain embodiments, the invention provides Compound I tosylate in a polymorphic form as disclosed herein. In certain embodiments, the invention provides methods of producing the polymorphs of Compound I tosylate disclosed herein. In certain embodiments, the invention provides compositions comprising a polymorph of Compound I tosylate disclosed herein. In certain embodiments, the composition is a pharmaceutical composition comprising at least one polymorph of Compound I tosylate and a
pharmaceutically acceptable carrier or excipient. In certain embodiments, the composition is substantially free of other polymorphs of Compound I tosylate. In certain embodiments, the invention provides a method of treating or preventing a diseases and conditions associated with regulation of the activity of one or more of Fms, Kit, Flt3, TrkA, TrkB and TrkC, including any mutations thereof, in a subject in need thereof. The method comprises the step of administering to the subject (a) a therapeutically effective amount of a polymorph of Compound I tosylate, (b) a therapeutically effective amount of two or more polymorph forms of Compound I tosylate, or (c) a therapeutically effective amount of one or more polymorphs of Compound I tosylate and an amorphous form of Compound I tosylate. Thus, the use of compounds for therapeutic methods involving modulation of protein kinases are provided. In certain embodiments, the compounds are used for therapeutic methods involving the treatment of a variety of indications, including, but not limited to, rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis, systemic sclerosis, demyelinating disorders, multiple sclerosis, Charcot Marie Tooth syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Langerhans cell histiocytosis (LCH), graft-versus-host disease, global ischemia, ulcerative colitis, Crohn's disease, immune thrombocytopenic purpura, atherosclerosis, systemic lupus erythematosus, myelopreparation for autologous transplantation, transplant rejection, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, renal hypertrophy, type I diabetes, acute pain, inflammatory pain, neuropathic pain, acute myeloid leukemia, melanoma, multiple myeloma, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, gliomas, glioblastoma, neurofibromatosis, osteolytic bone metastases, brain metastases, gastrointestinal stromal tumors, and giant cell tumors. BRIEF DESCRIPTION OF THE DRAWINGS The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention. Fig. 1 is the x-ray powder diffraction pattern (XRPD) of Form A of Compound I tosylate.
Fig. 2 is the differential scanning calorimetry (DSC) thermogram of Form A of Compound I tosylate. Fig. 3 is the XRPD of Form B of Compound I tosylate. Fig. 4 is the DSC thermogram of Form B of Compound I tosylate. Fig.5 is the Fourier-transform infrared (FT-IR) spectrum of Form B of Compound I tosylate. Fig. 6 is the XRPD of Form C of Compound I tosylate. Fig. 7 is the DSC thermogram of Form C of Compound I tosylate. Fig. 8 is the XRPD of Form D of Compound I tosylate. Fig. 9 is the XRPD of Form E of Compound I tosylate. Fig. 10 is the XRPD of Form F of Compound I tosylate. Fig.11 is the XRPD of Form G of Compound I tosylate. Fig.12 is the XRPD of Form H of Compound I tosylate. Fig. 13 is the XRPD of Form J of Compound I tosylate. DETAILED DESCRIPTION OF THE INVENTION The present invention provides polymorphic forms of the tosylate salt of Compound I [chemical name: 6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-(2,2,2- trifluoroethylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone] (also referred to herein as Compound I tosylate), which has the structure below.
Compound I tosylate. Compound I is a potent colony-stimulating factor-1 receptor (CSF1R or Fms) and TRK tyrosine kinase inhibitor and is described in patent application WO 2011/133637, the contents of which are incorporated herein by reference in their entirety. The method for preparing Compound I disclosed in WO 2011/133637 yields the amorphous form of Compound I disclosed herein. Solid-state techniques such as Differential Scanning
Calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), and Powder X-Ray Diffractometry (XRD) revealed the differences among those forms. In one embodiment, reference to a form of Compound I tosylate means that at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of Compound I tosylate present in a composition is in the designated form. For instance, in one embodiment, reference to Compound I tosylate Form B means that at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of Compound I tosylate present in a composition is in Form B. As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. The term "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense, that is, as "including, but not limited to." Further, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art. Reference to "about" a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In some embodiments, the term "about" includes the indicated amount ± 10%. In some embodiments, the term "about" includes the indicated amount ± 5%. In some other embodiments, the term "about" includes the indicated amount ± 1%. Also, the term "about X" includes description of "X". The term "crystalline form" refers to polymorphs as well as solvates, hydrates, etc. The term "polymorph" refers to a particular crystal structure having particular physical properties such as X-ray diffraction, melting point, and the like. As used herein, the term “Fms related disease or condition” and the like refers to a disease or condition in which the biological function of a Fms protein kinase, including any mutations thereof, affects the development, course, and/or symptoms of the disease or condition, and/or in which modulation of the Fms protein kinase alters the development, course, and/or symptoms of the disease or condition. The Fms related disease or condition includes a disease or condition for which Fms inhibition provides a therapeutic benefit, e.g., wherein treatment with a Fms inhibitor, preferably a Fms selective inhibitor including one or
more compound(s) described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition. As used herein, the terms “treat,” “treating”, “therapy”, “therapies”, and like terms refer to the administration of material, e.g., any one or more compound(s) as described herein in an amount effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or condition, i.e., indication, and/or to prolong the survival of the subject being treated. As used herein, the term “composition” refers to a pharmaceutical preparation suitable for administration to an intended animal subject for therapeutic purposes that contains at least one pharmaceutically active compound, including any solid form thereof. The composition may include at least one pharmaceutically acceptable component to provide an improved formulation of the compound, such as a suitable carrier or excipient. The term “pharmaceutically acceptable” indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectables. In the present context, the term “therapeutically effective” or “effective amount” indicates that the materials or amount of material is effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition, and/or to prolong the survival of the subject being treated. The term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra- arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. As used herein, the term "protein kinase mediated disease or condition," refers to a disease or condition in which the biological function of a protein kinase, including any mutations thereof, affects the development, course, and/or symptoms of the disease or condition, and/or in which modulation of the protein kinase alters the development, course, and/or symptoms of the disease or condition. The protein kinase mediated disease or
condition includes a disease or condition for which inhibition provides a therapeutic benefit, e.g., wherein treatment with protein kinase inhibitor(s), including one or more solid forms of Compound I tosylate as described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition. As used herein, the term "subject" or "patient" refers to a living organism that is treated with compounds as described herein, including, but not limited to, any mammal, such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats. X-Ray Powder Diffraction (XRPD) The various crystalline forms of Compound I tosylate were analyzed using x-ray powder diffraction (XRPD). XRPD diffractograms can be obtained using, for example, a Panalytical X’Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror was used to focus Cu Kα x-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640e) was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position. A specimen of the sample was sandwiched between 3-μm-thick films and analyzed in transmission geometry. A beam-stop, short antiscatter extension, and antiscatter knife edge were used to minimize the background generated by air. Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v.2.2b. The data acquisition parameters for each pattern are displayed above the image in the Data section of this report including the divergence slit (DS) before the mirror. The data presented herein contain x-ray diffraction patterns with labeled peaks and tables with peak lists. Under most circumstances, peaks within the range of up to about 30º 2 were selected. Rounding algorithms were used to round each peak to the nearest 0.1º or 0.01º 2 , depending upon the instrument used to collect the data and/or the inherent peak resolution. The location of the peaks along the x-axis (º 2 ) in both the figures and the tables were determined using proprietary software and rounded to one or two significant figures after the decimal point based upon the above criteria. Peak position variabilities are given to within ±0.2º 2 based upon recommendations outlined in the United States Pharmacopeia
(USP) discussion of variability in x-ray powder diffraction. For d-space listings, the wavelength used to calculate d-spacings was 1.5405929Å, the Cu-Kα1 wavelength. Variability associated with d-spacing estimates was calculated from the USP recommendation, at each d-spacing, and provided in the respective data tables. Per USP guidelines, variable hydrates and solvates may display peak variances greater than 0.2º 2 and therefore peak variances of 0.2º 2 are not applicable to these materials. For samples with only one XRPD pattern and no other means to evaluate whether the sample provides a good approximation of the powder average, peak tables contain data identified only as "Prominent Peaks". These peaks are a subset of the entire observed peak list. Prominent peaks are selected from observed peaks by identifying preferably non- overlapping, low-angle peaks, with strong intensity. If multiple diffraction patterns are available, then assessments of particle statistics (PS) and/or preferred orientation (PO) are possible. Reproducibility among XRPD patterns from multiple samples analyzed on a single diffractometer indicates that the particle statistics are adequate. Consistency of relative intensity among XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, the observed XRPD pattern may be compared with a calculated XRPD pattern based upon a single crystal structure, if available. Two-dimensional scattering patterns using area detectors can also be used to evaluate PS/PO. If the effects of both PS and PO are determined to be negligible, then the XRPD pattern is representative of the powder average intensity for the sample and prominent peaks may be identified as “Representative Peaks.” In general, the more data collected to determine Representative Peaks, the more confident one can be of the classification of those peaks. “Characteristic peaks,” to the extent they exist, are a subset of Representative Peaks and are used to differentiate one crystalline polymorph from another crystalline polymorph (polymorphs being crystalline forms having the same chemical composition). Characteristic peaks are determined by evaluating which representative peaks, if any, are present in one crystalline polymorph of a compound against all other known crystalline polymorphs of that compound to within ±0.2 º2Θ. Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak. XRPD diffractograms of the various Compound I tosylate materials obtained by the methods described herein are shown in the Examples and Figures. The Compound I tosylate
forms of the invention are not limited to those made in accordance with the methods described herein. Differential Scanning Calorimetry (DSC) DSC analysis was performed using a TA Instruments differential scanning calorimeter Q2000 or 2920. The sample was placed into an aluminum DSC pan, its weight accurately recorded. The lid was either crimped or hermetically sealed and perforated with a laser pinhole. The sample cell was equilibrated at -30 C and heated under a nitrogen purge at a rate of 10 °C/min, up to final temperature of 250 °C or 260 °C. Indium metal was used as the calibration standard. Those skilled in the art will recognize other appropriate means of measuring DSC. Infrared Spectroscopy (IR) The IR spectrum was acquired on the Nicolet Fourier transform infrared (FT-IR) spectrophotometer equipped with an Ever-Glo mid/far IR source, and a deuterated triglycine sulfate (DTGS) detector. Wavelength verification was performed using NIST SRM 1921b (polystyrene). An attenuated total reflectance (ATR) accessory (Thunderdome™, Thermo Spectra-Tech), with a germanium (Ge) crystal was used for data acquisition. The spectrum represents 256 co-added scans collected at a spectral resolution of 4 cm–1. A background data set was acquired with a clean Ge crystal. A Log 1/R (R = reflectance) spectrum was obtained by taking a ratio of these two data sets against each other. Those skilled in the art will recognize other appropriate means of measuring IR. In one embodiment, the present invention provides nine polymorph forms (Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, and Form J), which are further characterized by X-ray powder diffraction (XRPD). The characteristic powder diffraction peaks are expressed in degrees 2θ. The positions of the peaks (2θ) for all the forms are different to each other. The relative intensity, as well as the position of intense peaks in Fig. 1, Fig.3, Fig. 6, Fig. 8, Fig. 9, Fig. 10, Fig. 11, Fig. 12, and Fig. 13 may change or shift under certain conditions, although the crystalline form is the same. One of ordinary skill in the art is able to readily determine whether a given polymorph Form is the same polymorph Form as described in one of Fig. 1, Fig. 3, Fig. 6, Fig. 8, Fig. 9, Fig. 10, Fig. 11, Fig. 12, or Fig. 13, by comparing their peak positions and intensities in the XRPD data.
In one embodiment, three of the polymorphic forms (Forms A, B, C), were characterized by differential scanning calorimetry (DSC). The DSC thermal characteristics of the polymorph forms are described in Fig. 2, Fig. 4, and Fig. 7. In one embodiment, Forms B was further characterized by Fourier-transform infrared spectroscopy (FT-IR) (see Fig. 5). The characteristic peaks are expressed in wave numbers (cm-1). The positions of the characteristic peaks for each form are unique to that form. The relative intensity, as well as the position of intense peaks in Fig. 5, may change or shift under certain condition, although the crystalline form is the same. One of ordinary skill in the art should be able to readily determine whether a given polymorph Form is the same polymorph Form as described in Fig. 5 by comparing their peak positions and intensities in the IR data. The characteristic peaks (2θ) in the X-ray powder diffraction pattern of crystalline Form A are shown in Fig. 1. The characteristic peaks are at values of two theta (2θ) of 6.13, 7.95, 8.60, 9.80, 10.12, 11.32, 12.12, 12.31, 12.94, 13.60, 14.22, 15.44, 15.95, 17.27, 17.88, 18.65, 19.18, 19.69, 19.94, 20.38, 20.93, 21.64, 21.99, 22.63, 23.30, 23.80, 24.13, 24.40, 24.80, 25.32, 25.56, 25.83, 26.85, 27.42, 28.10, 28.71, 29.65, and 30.04. The characteristic peaks can alternatively be represented as (2θ) 6.1 , 8.0, 8.6, 9.8, 10.1, 11.3, 12.1, 12.3, 12.9, 13.6, 14.2, 15.4, 16.0, 17.3, 17.9, 18.7, 19.2, 19.7, 19.9, 20.4, 20.9, 21.6, 22.0, 22.6, 23.3, 23.8, 24.1, 24.4, 24.8, 25.3, 25.6, 25.8, 26.9, 27.4, 28.1, 28.7, 29.7, and 30.0. The prominent peaks of Form A are at values of two theta (2θ) of 6.13, 9.80, 10.12, 12.12, 12.94, 17.27, 17.88, 18.65, 19.69, 19.94, 21.99, 23.30, and 24.40. The prominent peaks can alternatively be represented as (2θ) 6.1, 9.8, 10.1, 12.1, 12.9, 17.3, 17.9, 18.7, 19.7, 19.9, 22.0, 23.3, and 24.4. The DSC thermogram of the crystalline Form A is shown in Fig. 2. The DSC thermogram of the crystalline Form A has a characteristic endotherm at 239.6°C with an onset temperature at 212.7°C. The characteristic peaks (2θ) in the X-ray powder diffraction pattern of crystalline Form B are shown in Fig. 3. The characteristic peaks are at values of two theta (2θ) of 6.36, 9.95, 10.92, 12.56, 12.75, 13.35, 14.86, 15.62, 16.75, 18.07, 18.28, 19.04, 19.91, 20.67, 21.19, 21.43, 21.58, 21.98, 22.13, 23.07, 23.28, 24.33, 24.83, 25.09, 25.47, 26.01, 26.38, 26.63, 26.89, 27.79, 28.15, 28.72, and 30.03. The characteristic peaks can alternatively be represented as (2θ) 6.4, 10.0, 10.9, 12.6, 12.8, 13.4, 14.9, 15.6, 16.8, 18.1, 18.3, 19.0, 19.9, 20.7, 21.2, 21.4, 21.6, 22.0, 22.1, 23.1, 23.3, 24.3, 24.8, 25.1, 25.5, 26.0, 26.4, 26.6, 26.9, 27.8, 28.2, 28.7, and 30.0.
The prominent peaks of Form B are at values of two theta (2θ) of 6.36, 9.95, 10.92, 12.56, 14.86, 18.07, 18.28, 19.04, 19.91, 21.43, 21.58, and 25.47. The prominent peaks can alternatively be represented as (2θ) 6.4, 10.0, 10.9, 12.6, 14.9, 18.1, 18.3, 19.0, 19.9, 21.4, 21.6, and 25.5. The DSC thermogram of the crystalline Form B is shown in Fig. 4. The DSC thermogram of the crystalline Form B has a characteristic endotherm at 245.3°C with an onset temperature at 225°C. The characteristic peaks of the Fourier-transform infrared (FT-IR) spectrum of the crystalline Form B are shown in Fig. 5. The characteristic peaks in wave numbers (cm-1) are at 680.8, 710.4, 733.7, 746.3, 774.1, 786.5, 816.7, 839.9, 890.5, 947.9, 970.5, 1008.7, 1032.5, 1086.2, 1109.1, 1120.8, 1142.4, 1168.5, 1187.4, 1223.6, 1240.6, 1263.3, 1279.6, 1299.9, 1320.9, 1360.7, 1373.7, 1406.9, 1428.6, 1493.2, 1517.8, 1539.5, 1591.1, 1616.2, 1675.4, 2874.3, 2946.7, 3047.0, 3156.9, and 3303.4. The characteristic peaks (2θ) in the X-ray powder diffraction pattern of crystalline Form C are shown in Fig. 6. The characteristic peaks are at values of two theta (2θ) of 6.00, 8.40, 10.26, 10.80, 12.04, 12.25, 13.09, 14.18, 14.80, 15.51, 16.43, 16.87, 17.24, 17.87, 18.37, 18.96, 19.33, 20.04, 20.64, 21.09, 21.42, 21.71, 22.63, 23.01, 23.47, 24.28, 24.66, 26.08, 26.63, 27.02, 27.38, 28.61, 29.02, and 30.10. The characteristic peaks can alternatively be represented as (2θ) 6.0, 8.4, 10.3, 10.8, 12.0, 12.3, 13.1, 14.2, 14.8, 15.5, 16.4, 16.9, 17.2, 17.9, 18.4, 19.0, 19.3, 20.0, 20.6, 21.1, 21.4, 21.7, 22.6, 23.0, 23.5, 24.3, 24.7, 26.1, 26.6, 27.0, 27.4, 28.6, 29.0, and 30.1. The prominent peaks of Form C are at values of two theta (2θ) of 6.00, 10.26, 10.80, 12.04, 12.25, 13.09, 16.87, 17.87, 18.37, 23.01, and 24.66. The prominent peaks can alternatively be represented as (2θ) 6.0, 10.3, 10.8, 12.0, 12.3, 13.1, 16.9, 17.9, 18.4, 23.0, and 24.7. The DSC thermogram of the crystalline Form C is shown in Fig. 7. The DSC thermogram of the crystalline Form C has a characteristic endotherm at 239.5°C with an onset temperature at 212°C. The characteristic peaks (2θ) in the X-ray powder diffraction pattern of crystalline Form D are shown in Fig. 8. The characteristic peaks are at values of two theta (2θ) of 6.09, 7.02, 8.65, 9.83, 10.34, 11.31, 12.20, 12.85, 13.88, 14.41, 15.54, 16.05, 17.36, 17.53, 17.91, 18.37, 18.70, 19.76, 20.30, 20.90, 21.14, 21.53, 22.00, 22.27, 22.76, 23.53, 23.83, 24.18, 24.55, 24.72, 25.24, 25.63, 25.95, 26.16, 26.61, 27.32, 27.80, 27.95, 29.08, 29.58, 30.01, and 30.21. The characteristic peaks can alternatively be represented as (2θ) 6.1, 7.0, 8.7, 9.8,
10.3, 11.3, 12.2, 12.9, 13.9, 14.4, 15.5, 16.1, 17.4, 17.5, 17.9, 18.4, 18.7, 19.8, 20.3, 20.9, 21.1, 21.5, 22.0, 22.3, 22.8, 23.5, 23.8, 24.2, 24.6, 24.7, 25.2, 25.6, 26.0, 26.2, 26.6, 27.3, 27.8, 28.0, 29.1, 29.6, 30.0, and 30.2. The prominent peaks of Form D are at values of two theta (2θ) of 6.09, 12.20, 12.85, 17.36, 17.53, 17.91, 18.70, 19.76, 20.30, 22.27, and 23.83. The prominent peaks can alternatively be represented as (2θ) 6.1, 12.2, 12.9, 17.4, 17.5, 17.9, 18.7, 19.8, 20.3, 22.3, and 23.8. The characteristic peaks (2θ) in the X-ray powder diffraction pattern of crystalline Form E are shown in Fig. 9. The characteristic peaks are at values of two theta (2θ) of 6.10, 9.83, 9.98, 11.30, 12.11, 13.06, 13.35, 15.38, 15.91, 16.88, 17.20, 17.78, 17.93, 18.60, 19.69, 20.41, 20.78, 21.03, 21.63, 22.37, 22.86, 23.30, 23.76, 24.38, 24.77, 25.10, 25.30, 25.70, 25.91, 26.42, 26.88, 27.09, 28.13, and 29.63. The characteristic peaks can alternatively be represented as (2θ) 6.1, 9.8, 10.0, 11.3, 12.1, 13.1, 13.4, 15.4, 15.9, 16.9, 17.2, 17.8, 17.9, 18.6, 19.7, 20.4, 20.8, 21.0, 21.6, 22.4, 22.9, 23.3, 23.8, 24.4, 24.8, 25.1, 25.3, 25.7, 25.9, 26.4, 26.9, 27.1, 28.1, and 29.6. The prominent peaks of Form E are at values of two theta (2θ) of 6.10, 12.11, 13.06, 17.20, 17.93, 18.60, 19.69, 21.63, and 22.86. The prominent peaks can alternatively be represented as (2θ) 6.1, 12.1, 13.1, 17.2, 17.9, 18.6, 19.7, 21.6, and 22.9. The characteristic peaks (2θ) in the X-ray powder diffraction pattern of crystalline Form F are shown in Fig. 10. The characteristic peaks are at values of two theta (2θ) of 6.02, 9.73, 10.17, 11.23, 12.00, 12.69, 13.62, 13.84, 13.96, 15.53, 16.02, 16.19, 17.32, 17.54, 17.72, 18.16, 18.58, 18.98, 19.54, 20.23, 20.82, 21.17, 21.99, 22.59, 23.18, 23.40, 23.95, 24.15, 24.69, 25.19, 25.69, 25.97, 26.23, 26.80, 27.50, 27.89, 28.16, 28.64, 29.14, 29.47, 29.76, and 30.71. The characteristic peaks can alternatively be represented as (2θ) 6.0, 9.7, 10.2, 11.2, 12.0, 12.7, 13.6, 13.8, 14.0, 15.5, 16.0, 16.2, 17.3, 17.5, 17.7, 18.2, 18.6, 19.0, 19.5, 20.2, 20.8, 21.2, 22.0, 22.6, 23.2, 23.4, 24.0, 24.2, 24.7, 25.2, 25.7, 26.0, 26.2, 26.8, 27.5, 27.9, 28.2, 28.6, 29.1, 29.5, 29.8, and 30.7. The prominent peaks of Form F are at values of two theta (2θ) of 6.02, 12.69, 17.32, 17.72, 18.58, 19.54, 20.23, 21.99, 23.40, and 24.15. The prominent peaks can alternatively be represented as (2θ) 6.0, 12.7, 17.3, 17.7, 18.6, 19.5, 20.2, 22.0, 23.4, and 24.2. The characteristic peaks (2θ) in the X-ray powder diffraction pattern of crystalline Form G are shown in Fig. 11. The characteristic peaks are at values of two theta (2θ) of 6.05, 8.68, 9.78, 10.19, 11.03, 12.22, 12.81, 13.63, 14.44, 15.47, 15.98, 17.00, 17.43, 17.62, 17.89, 18.24, 18.52, 18.88, 19.69, 20.43, 21.10, 21.68, 21.92, 22.73, 23.44, 24.03, 24.59, 24.81,
25.31, 25.63, 25.93, 26.24, 26.96, 27.22, 27.49, 27.79, 28.06, 28.46, and 29.83. The characteristic peaks can alternatively be represented as (2θ) 6.1, 8.7, 9.8, 10.2, 11.0, 12.2, 12.8, 13.6, 14.4, 15.5, 16.0, 17.0, 17.4, 17.6, 17.9, 18.2, 18.5, 18.9, 19.7, 20.4, 21.1, 21.7, 21.9, 22.7, 23.4, 24.0, 24.6, 24.8, 25.3, 25.6, 25.9, 26.2, 27.0, 27.2, 27.5, 27.8, 28.1, 28.5, and 29.8. The prominent peaks of Form G are at values of two theta (2θ) of 6.05, 12.81, 17.43, 17.89, 18.24, 18.88, 19.69, 21.68, and 23.44. The prominent peaks can alternatively be represented as (2θ) 6.1, 12.8, 17.4, 17.9, 18.2, 18.9, 19.7, 21.7, and 23.4. The characteristic peaks (2θ) in the X-ray powder diffraction pattern of crystalline Form H are shown in Fig. 12. The characteristic peaks are at values of two theta (2θ) of 5.00, 6.11, 8.61, 9.78, 10.08, 11.23, 12.11, 12.91, 13.53, 13.93, 14.21, 15.42, 15.88, 17.08, 17.29, 17.85, 18.53, 18.65, 19.66, 19.82, 20.34, 20.91, 21.08, 21.84, 22.11, 22.60, 23.20, 24.03, 24.38, 24.81, 25.27, 25.83, 26.79, 27.28, 28.09, and 28.66. The characteristic peaks can alternatively be represented as (2θ) 5.0, 6.1, 8.6, 9.8, 10.1, 11.2, 12.1, 12.9, 13.5, 13.9, 14.2, 15.4, 15.9, 17.1, 17.3, 17.9, 18.5, 18.7, 19.7, 19.8, 20.3, 20.9, 21.1, 21.8, 22.1, 22.6, 23.2, 24.0, 24.4, 24.8, 25.3, 25.8, 26.8, 27.3, 28.1, and 28.7. The prominent peaks of Form H are at values of two theta (2θ) of 5.00, 6.11, 9.78, 10.08, 12.11, 12.91, 17.29, 17.85, 18.53, 18.65, 19.66, 19.82, 23.20, and 24.38. The prominent peaks can alternatively be represented as (2θ) 5.0, 6.1, 9.8, 10.1, 12.1, 12.9, 17.3, 17.9, 18.5, 18.7, 19.7, 19.8, 23.2, and 24.4. The characteristic peaks (2θ) in the X-ray powder diffraction pattern of crystalline Form J are shown in Fig. 13. The characteristic peaks are at values of two theta (2θ) of 5.38, 5.93, 7.68, 8.35, 10.79, 11.90, 12.76, 15.39, 16.79, 17.77, 18.76, 20.14, 20.55, 20.87, 21.58, 22.00, 23.01, 23.19, 23.86, 24.60, 26.55, 27.33, 28.42, 28.99, and 30.22. The characteristic peaks can alternatively be represented as (2θ) 5.4, 5.9, 7.7, 8.4, 10.8, 11.9, 12.8, 15.4, 16.8, 17.8, 18.8, 20.1, 20.6, 20.9, 21.6, 22.0, 23.0, 23.2, 23.9, 24.6, 26.6, 27.3, 28.4, 29.0, and 30.2. The prominent peaks of Form J are at values of two theta (2θ) of 5.38, 5.93, 10.79, 16.79, 17.77, 20.14, 20.55, 20.87, 21.58, 24.60, 28.42, and 30.22. The prominent peaks can alternatively be represented as (2θ) 5.4, 5.9, 10.8, 16.8, 17.8, 20.1, 20.6, 20.9, 21.6, 24.6, 28.4, and 30.2. In another aspect, the present invention features a crystalline form of Compound I tosylate which has characteristic peaks in the X-ray powder diffraction (XRPD) pattern as shown in Fig. 1, Fig. 3, Fig. 6, Fig. 8, Fig. 9, Fig. 10, Fig. 11, Fig. 12, or Fig. 13.
As is known in the art, the relative intensity of each peak in Fig. 1 - Fig. 13 may change or shift under certain conditions, although the polymorph forms are the same. One of ordinary skill in the art is able to readily determine whether a given polymorphic form is the same polymorph form as described herein by comparing its XRPD pattern with Fig. 3, Fig. 6, Fig. 8, Fig. 9, Fig. 10, Fig. 11, Fig. 12, or Fig. 13; comparing its DSC thermogram with Fig. 2, Fig.4, and Fig. 7 for DSC; and comparing its FTIR spectrum with Fig. 5. In embodiments, the crystalline form of Compound I tosylate is substantially pure. As used herein, the term “substantially pure,” when used in reference to a given crystalline form, refers to the crystalline form which is at least about 75% pure. This means that the crystalline form does not contain more than about 25% of any other form of Compound I tosylate. Preferably, the term “substantially pure” refers to a crystalline form of Compound I tosylate which is at least about 90% pure. This means that the crystalline form does not contain more than about 10% of any other form of Compound I tosylate. Preferably, the term “substantially pure” refers to a crystalline form of Compound I tosylate which is at least about 95% pure. This means that the crystalline form of Compound I tosylate does not contain more than about 5% of any other form of Compound I tosylate. More preferably, the term “substantially pure” refers to a crystalline form of Compound I tosylate which is at least about 97% pure. This means that the crystalline form of Compound I tosylate does not contain more than about 3% of any other form of Compound I tosylate. More preferably, the term “substantially pure” refers to a crystalline form of Compound I tosylate which is at least about 99% pure. This means that the crystalline form of Compound I tosylate does not contain more than about 1% of any other form of Compound I tosylate. Pharmaceutical Compositions and Modes of Administration Compound I tosylate, and the forms thereof as described herein, may be administered in a pharmaceutical composition. Thus, provided herein are pharmaceutical compositions comprising Compound I tosylate, or one or more of the forms of Compound I tosylate described herein, and one or more pharmaceutically acceptable vehicles such as carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); Handbook of Pharmaceutical Excipients – 9th Edition (2020), Handbook of
Pharmaceutical Additives – 3rd Edition, and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.). As known to the person of skill in the art, excipients can be multi-functional and can serve more than one purpose in the pharmaceutical composition. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Some embodiments are directed to pharmaceutical compositions comprising Compound I tosylate. Some embodiments are directed to pharmaceutical compositions comprising a crystalline form of Compound I tosylate as described herein. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 95% of Compound I tosylate is in a crystalline form as described herein. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 95% of Compound I tosylate is in Form A. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 95% of Compound I tosylate is in Form B. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 95% of Compound I tosylate is in Form C. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 95% of Compound I tosylate is in Form D. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 95% of Compound I tosylate is Compound I tosylate Form E. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 95% of Compound I tosylate is Compound I tosylate Form F. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 95% of Compound I tosylate is Compound I tosylate Form G. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 95% of Compound I tosylate is Compound I tosylate Form H. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 95% of Compound I tosylate is Compound I tosylate Form J. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 97% of Compound I tosylate is in a crystalline form as described herein. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 97% of Compound I tosylate is in Form A. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 97% of Compound I tosylate is in Form B. In one embodiment, a pharmaceutical composition comprises Compound I
tosylate, wherein at least 97% of Compound I tosylate is in Form C. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 97% of Compound I tosylate is in Form D. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 97% of Compound I tosylate is Compound I tosylate Form E. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 97% of Compound I tosylate is Compound I tosylate Form F. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 97% of Compound I tosylate is Compound I tosylate Form G. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 97% of Compound I tosylate is Compound I tosylate Form H. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 97% of Compound I tosylate is Compound I tosylate Form J. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 99% of Compound I tosylate is in a crystalline form as described herein. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 99% of Compound I tosylate is in Form A. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 99% of Compound I tosylate is in Form B. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 99% of Compound I tosylate is in Form C. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 99% of Compound I tosylate is in Form D. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 99% of Compound I tosylate is Compound I tosylate Form E. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 99% of Compound I tosylate is Compound I tosylate Form F. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 99% of Compound I tosylate is Compound I tosylate Form G. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 99% of Compound I tosylate is Compound I tosylate Form H. In one embodiment, a pharmaceutical composition comprises Compound I tosylate, wherein at least 99% of Compound I tosylate is Compound I tosylate Form J. Some embodiments are directed to pharmaceutical compositions comprising a therapeutically effective amount of a compound selected from: Compound I tosylate, Compound I tosylate Form A, Compound I tosylate Form B, Compound I tosylate Form C, Compound I tosylate Form D, Compound I tosylate Form E, Compound I tosylate Form F,
Compound I tosylate Form G, Compound I tosylate Form H, and Compound I tosylate Form J as described herein; and one or more pharmaceutically acceptable carriers. In some embodiments, compositions will comprise pharmaceutically acceptable carriers or excipients, such as fillers, binders, disintegrants, glidants, lubricants, complexing agents, solubilizers, and surfactants, which may be chosen to facilitate administration of the compound by a particular route. Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, types of starch, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, and the like. Carriers also include physiologically compatible liquids as solvents or for suspensions, including, for example, sterile solutions of water for injection (WFI), saline solution, dextrose solution, Hank's solution, Ringer's solution, vegetable oils, mineral oils, animal oils, polyethylene glycols, liquid paraffin, and the like. Excipients may also include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, macrocrystalline cellulose, carboxymethyl cellulose, cross-linked sodium carboxymethylcellulose, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, syloid, stearowet C, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated cotton seed oil, castor seed oil mineral oil, polyethylene glycol (e.g. PEG 4000-8000), polyoxyethylene glycol, poloxamers, povidone, crospovidone, croscarmellose sodium, alginic acid, casein, methacrylic acid divinylbenzene copolymer, sodium docusate, cyclodextrins (e.g. 2-hydroxypropyl- -cyclodextrin), polysorbates (e.g. polysorbate 80), cetrimide, TPGS (d- alpha-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ethers, di-fatty acid ester of polyethylene glycols, or a polyoxyalkylene sorbitan fatty acid ester (e.g., polyoxyethylene sorbitan ester Tween®), polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid ester, e.g. a sorbitan fatty acid ester from a fatty acid such as oleic, stearic or palmitic acid, mannitol, xylitol, sorbitol, maltose, lactose, lactose monohydrate or lactose spray dried, sucrose, fructose, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, dextrates, dextran, dextrin, dextrose, cellulose acetate, maltodextrin, simethicone, polydextrosem, chitosan, gelatin, HPMC (hydroxypropyl methyl celluloses), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose, and the like.
Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the present disclosure (as a free-acid, solvate (including hydrate) or salt, in any form), depending on the condition being treated, the route of administration, and the age, weight and condition of the subject. Preferred unit dosage formulations are those containing a daily dose, weekly dose, monthly dose, a sub-dose or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art. Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including capsules, tablets, liquid-filled capsules, disintegrating tablets, immediate, delayed and controlled release tablets, oral strips, solutions, syrups, buccal and sublingual), rectal, nasal, inhalation, topical (including transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s), excipient(s) or diluent. In some embodiments, oral administration may be used. Pharmaceutical preparations for oral use can be formulated into conventional oral dosage forms such as discreet units capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops. Compounds described herein may be combined with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (e.g., aqueous, alcoholic, or oily solutions) and the like. Suitable excipients are, in particular, fillers such as sugars, including lactose, glucose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone); oily excipients, including vegetable and animal oils, such as sunflower oil, olive oil, or cod-liver oil. The oral dosage formulations may also contain disintegrating agents, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate; a lubricant, such as talc or magnesium stearate; a plasticizer, such as glycerol or sorbitol; a sweetening such as sucrose, fructose, lactose, or aspartame; a natural or artificial flavoring agent, such as peppermint, oil of wintergreen, or
cherry flavoring; or dye-stuffs or pigments, which may be used for identification or characterization of different doses or combinations, such as unit dosages. Also provided are dragee cores with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain, for example, gum arabic, talc, poly-vinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin ("gelcaps"), as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, injection (parenteral administration) may be used, e.g., intramuscular, intravenous, intraperitoneal, and/or subcutaneous. Compounds described herein for injection may be formulated in sterile liquid solutions, preferably in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution. Dispersions may also be prepared in non-aqueous solutions, such as glycerol, propylene glycol, ethanol, liquid polyethylene glycols, triacetin, and vegetable oils. Solutions may also contain a preservative, such as methylparaben, propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In addition, the compounds may be formulated in solid form, including, for example, lyophilized forms, and redissolved or suspended prior to use. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. In some embodiments, transmucosal, topical or transdermal administration may be used. In such formulations of compounds described herein, penetrants appropriate to the barrier to be permeated are used. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration, for example, may be through nasal sprays or suppositories (rectal or vaginal). Compositions of
compounds described herein for topical administration may be formulated as oils, creams, lotions, ointments, and the like by choice of appropriate carriers known in the art. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C12). In some embodiments, carriers are selected such that the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Creams for topical application are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of solvent (e.g., an oil), is admixed. Additionally, administration by transdermal means may comprise a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents known in the art. To be administered in the form of a transdermal delivery system, the dosage administration will be continuous rather than intermittent throughout the dosage regimen. In some embodiments, the compounds as disclosed herein (e.g., one or more solid forms of Compound I tosylate) are administered as inhalants. Compounds described herein may be formulated as dry powder or a suitable solution, suspension, or aerosol. Powders and solutions may be formulated with suitable additives known in the art. For example, powders may include a suitable powder base such as lactose or starch, and solutions may comprise propylene glycol, sterile water, ethanol, sodium chloride and other additives, such as acid, alkali and buffer salts. Such solutions or suspensions may be administered by inhaling via spray, pump, atomizer, or nebulizer, and the like. The compounds described herein may also be used in combination with other inhaled therapies, for example corticosteroids such as fluticasone propionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide, and mometasone furoate; beta agonists such as albuterol, salmeterol, and formoterol; anticholinergic agents such as ipratropium bromide or tiotropium; vasodilators such as Treprostinil and iloprost; enzymes such as DNase; therapeutic proteins; immunoglobulin antibodies; an oligonucleotide, such as single or double stranded DNA or RNA, siRNA; antibiotics such as tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine antagonists; protease inhibitors; cromolyn sodium; nedocril sodium; and sodium cromoglycate. The amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound activity (in vitro, e.g., the compound IC50 vs. target, or in vivo activity in animal efficacy models), pharmacokinetic results in animal models (e.g., biological half-life or bioavailability), the age, size, and weight
of the subject, and the disorder associated with the subject. The importance of these and other factors are well known to those of ordinary skill in the art. Generally, a dose will be in the range of about 0.01 to 50 mg/kg, also about 0.1 to 20 mg/kg of the subject being treated. Multiple doses may be used. The compounds described herein (e.g., one or more solid forms of Compound I tosylate) may also be used in combination with other therapies, drugs, medical procedures, etc. for treating the same disease. In some embodiments, such combination use includes administration of one or more other therapies, drugs, or medical procedures at different times (e.g. within a short time, such as within hours (e.g. 1, 2, 3, 4-24 hours), or within a longer time (e.g. 1-2 days, 2-4 days, 4-7 days, 1-4 weeks)) than a compound described herein, or at the same time as a compound described herein. In some embodiments, use in combination includes use with at least one other therapy, drug or medical procedure that is administered once or infrequently, such as surgery, along with a compound described herein administered within a short time or longer time before or after the other therapy, drug or procedure. In some embodiments, use in combination includes delivery of a compound described herein and one or more other drug therapeutics by the same route or different routes of administration. In some embodiments, a compound described herein and one or more other drug therapeutics may be delivered together in any formulation by the same route of administration, including formulations where the compounds and other drug therapeutic(s) are chemically linked in such a way that they maintain their therapeutic activity when administered. In some embodiments, the other drug therapeutic(s) may be co-administered with a compound described herein. In some embodiments, co-administration includes administration of co-formulations or formulations of chemically joined compounds, or administration of two or more compounds in separate formulations within a short time of each other (e.g., within an hour, 2 hours, 3 hours, up to 24 hours), administered by the same or different routes. Co-administration of separate formulations includes co-administration by delivery via one device, for example the same inhalant device, the same syringe, etc., or administration from separate devices within a short time of each other. Co-formulations of a compound described herein and one or more additional drug therapeutics delivered by the same route includes preparation of the materials together such that they can be administered by one device, including the separate compounds combined in one formulation, or compounds that are modified such that they are chemically joined, yet still maintain their biological activity. Such chemically joined compounds may have a linkage that is substantially maintained in vivo, or the linkage may break down in vivo, separating the two
active components. In some embodiments, the compounds as disclosed herein may be used in adjuvant or neoadjuvant therapy in combination with other therapies or therapeutic agents as described herein. In some embodiments involving combination use, dosage may be modified for one or more of the compounds of the present disclosure or other therapeutics used in combination, e.g., reduction in the amount dosed relative to a compound or therapy used alone, by methods well known to those of ordinary skill in the art. Exemplary combination therapies are discussed below. Preferably, the compounds described herein (e.g., or one or more solid forms of Compound I tosylate) is an inhibitor of Fms kinase and has an IC50 of less than 500 nM, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted Fms kinase activity assay. Preferably, the compounds described herein (e.g., or one or more solid forms of Compound I tosylate) is a dual Fms/Trk inhibitor, i.e. will be approximately equipotent with respect to inhibition of Fms kinase and Trk kinase. In some embodiments the compound will have an IC50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted Fms kinase activity assay and will have an IC50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a comparable generally accepted Trk kinase activity assay (including any one or more of TrkA, TrkB, and TrkC), wherein the ratio of IC50 for Trk kinase (at least one of TrkA, TrkB, and TrkC) divided by the IC50 for Fms kinase is in the range of 20 to 0.05, also 10 to 0.1, also 5 to 0.2. In some embodiments, the compound is selective relative to other protein kinases, such that the ratio of IC50 for another kinase assessed comparably, divided by the IC50 for Fms kinase (and/or Trk kinase) is >20, also >30, also >40, also >50, also >60, also >70, also >80, also >90, also >100, wherein the other protein kinase includes, but is not limited to CSK, Insulin receptor kinase, AMPK, PDGFR or VEGFR. In some embodiments, the dual Fms/Trk inhibitor is selective with respect to Kit. In some embodiments, the dual Fms/Trk inhibitor also inhibits Kit. Preferably, the compounds described herein (e.g., or one or more solid forms of Compound I tosylate) will also inhibit the effects of a mutation of the kinase, including, but not limited to, a mutation that is related to a disease state, such as a cancer. While it is understood that a dual Fms/Trk inhibitor may be used to treat any Fms related mediated disease or condition, the dual inhibition of Fms and Trk provides beneficial
effects in treating certain diseases or conditions, including, but not limited to, pancreatic cancer, prostate cancer, and multiple myeloma. The invention also provides kits that include any one or more compounds described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof. In some embodiments, the compound or composition is packaged, e.g., in a vial, bottle, flask, which may be further packaged, e.g., within a box, envelope, or bag; the compound or composition is approved by the U.S. Food and Drug Administration or similar regulatory agency for administration to a mammal, e.g., a human; the compound or composition is approved for administration to a mammal, e.g., a human, for a protein kinase mediated disease or condition; the invention kit includes written instructions for use and/or other indication that the compound or composition is suitable or approved for administration to a mammal, e.g., a human, for a protein kinase-mediated disease or condition; and the compound or composition is packaged in unit dose or single dose form, e.g., single dose pills, capsules, or the like. Target kinase Fms (i.e., feline McDonough sarcoma) is a member of the family of genes originally isolated from the Susan McDonough strain of feline sarcoma viruses. Fms is a transmembrane tyrosine kinase of 108.0 kDa coded by chromosome 5q33.2-q33.3 (symbol: CSF1R). The structure of the transmembrane receptor Fms comprises two Ig-like domains, an IgC2-like domain, two additional Ig-like domains, a TM domain, and the TK domain. Fms is the receptor for the macrophage colony-stimulating factor (M-CSF) and is crucial for the growth and differentiation of the monocyte-macrophage lineage. Upon binding of M-CSF to the extracellular domain of Fms, the receptor dimerizes and trans-autophosphorylates cytoplasmic tyrosine residues. Fms inhibitors may be useful in treating inflammatory and autoimmune indications, including, but not limited to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, psoriasis, dermatitis, ankylosing spondylitis, polymyositis, dermatomyositis, systemic sclerosis, juvenile idiopathic arthritis, polymyalgia rheumatica, Sjogren's disease, Langerhans cell histiocytosis (LCH), Still's disease, graft-versus-host disease, inflammatory bowel syndrome, ulcerative colitis, Crohn's disease, systemic lupus erythematosus (SLE), transplant rejection, chronic obstructive pulmonary disease (COPD), emphysema, Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, and atherosclerosis; metabolic disorders, including, but not limited to, Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesity, and lipolysis; disorders of bone structure, mineralization and bone formation and resorption, including, but
not limited to, osteoporosis, osteodystrophy, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e.g. osteomyelitis), and peri-prosthetic or wear-debris-mediated osteolysis; kidney and genitourinary diseases, including, but not limited to, endometriosis, nephritis (e.g. glomerulonephritis, interstitial nephritis, Lupus nephritis), tubular necrosis, diabetes-associated renal complications (e.g. diabetic nephropathy), and renal hypertrophy; disorders of the central nervous system, including, but not limited to, multiple sclerosis, amyotrophic lateral sclerosis (ALS), myasthenia gravis, chronic demyelinating polyneuropathy, other demyelinating disorders, stroke, Alzheimer's disease and Parkinson's disease; inflammatory and chronic pain, including, but not limited to, bone pain; malignancies, including, but not limited to, multiple myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lung cancer, pancreatic cancer, prostate cancer, breast cancer, ovarian cancer, neuroblastoma, sarcoma, osteosarcoma, giant cell tumor of bone, giant cell tumor of tendon sheath (TGCT), pigmented villonodular synovitis (PVNS), tumor angiogenesis, melanoma, glioblastoma multiforme, glioma, other tumors of the central nervous system, metastasis of tumors to other tissues, and other chronic myeloproliferative diseases such as myelofibrosis; vasculitis, including but not limited to collagen vascular disease, polyarteritis nodosa, Behcet's disease, sarcoidosis, familiar Mediterranean fever, Churg-Strauss vasculitis, temporal arteritis, giant cell arteritis, Takayasu's arteritis; ophthalmic indications, including but not limited to uveitis, scleritis, retinitis, age related macular degeneration, choroidal neovascularization, diabetic retinopathy; inherited disorders, including but not limited to cherubism, neurofibromatosis; infectious disease indications, including but not limited to infections associated with human immunodeficiency virus, hepatitis B virus, hepatitis C virus, human granulocytic anaplasmosis; lysosomal storage disorders, including but not limited to Gaucher's disease, Fabry's disease, Niemann-Pick disease; gastrointestinal indications, including but not limited to liver cirrhosis; pulmonary indications, including but not limited to pulmonary fibrosis, acute lung injury (e.g. ventilator-induced, smoke- or toxin-induced); and surgical indications, including but not limited to (cardiopulmonary) bypass surgery, vascular surgery, and vascular grafts. Target kinase TrkA (i.e., neurotrophic tyrosine kinase, receptor, type 1) is a 140 kDa tyrosine kinase encoded by chromosome 1q21-q22 (symbol: NTRK1). TrkA is a plasma member receptor composed of an extracellular domain (responsible for high affinity binding to nerve growth factor, NGF), a transmembrane segment and an intracellular protein tyrosine kinase domain (responsible to transmit the NGF signal to initiate and coordinate neuronal
responses). NGF binding induces TrkA clustering on the membrane and activates the kinase. The kinase initiates a cascade of protein phosphorylation events through multiple pathways including SHC/Ras/MAPK, PI3K and PLCg1. A TrkA kinase inhibitor would not be expected to prevent NGF/TrkA binding but could prevent down-stream signal transduction. TrkA inhibitors may be useful in treating pain (e.g., chronic pain, neuropathic pain), cancer (e.g., prostate cancer, lung cancer, myeloid leukemia, pancreatic cancer), allergic disorders (e.g., asthma), arthritis, diabetic retinopathy, macular degeneration and psoriasis. Target kinase TrkB (i.e., neurotrophic tyrosine kinase, receptor, type 2) is a 145 kDa tyrosine kinase encoded by chromosome 9q22.1 (symbol: NTRK2). TrkB inhibitors may be useful in treating various cancers and their metastases (e.g., prostate cancer, lung cancer, Wilms tumors, neuroblastoma, and pancreatic cancer), and various neuropathies (e.g., stroke, multiple sclerosis, transverse myelitis, and encephalitis). Target kinase TrkC (i.e., neurotrophic tyrosine kinase, receptor, type 3) is a 145 kDa tyrosine kinase encoded by chromosome 15q25 (symbol: NTRK3). TrkC inhibitors may be useful in treating pain (e.g., chronic pain, neuropathic pain), cancer (e.g., lung cancer, breast cancer, pancreatic cancer, mesoblastic nephroma, infantile fibrosarcoma, neuroblastoma, gastric cancer), and panic disorder. Provided herein are methods for treating a disease or condition related to any one or more of Fms protein kinase and Trk protein kinase in an animal subject in need thereof, wherein the method involves administering to the subject an effective amount of any one or more the compounds described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof. In certain embodiments, the method involves administering to the subject an effective amount of a compound described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof in combination with one or more other therapies for the disease or condition. Provided herein are methods for treating a disease or condition related to Fms protein kinase in an animal subject in need thereof, wherein the method involves administering to the subject an effective amount of any one or more compounds described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof. In certain embodiments, the method involves administering to the subject an effective amount of a compound described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof in combination with one or more other therapies for the disease or condition. Provided herein are methods for treating a disease or condition related to Trk protein kinase in an animal subject in need thereof, wherein the method involves administering to the
subject an effective amount of any one or more compounds described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof. In certain embodiments, the method involves administering to the subject an effective amount of a compound described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof in combination with one or more other therapies for the disease or condition. Provided herein are methods for treating a disease or condition related to Fms protein kinase and Trk protein kinase in an animal subject in need thereof, wherein the method involves administering to the subject an effective amount of any one or more dual Fms/Trk inhibitor compounds described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof. In certain embodiments, the method involves administering to the subject an effective amount of a dual Fms/Trk inhibitor compound described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof in combination with one or more other therapies for the disease or condition. Provided herein are methods for treating a cancer in a subject in need thereof by administering to the subject an effective amount of any one or more compounds described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof. In certain embodiments, the method involves administering to the subject an effective amount of a compound described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof in combination with one or more other therapies or medical procedures effective in treating the cancer. Other therapies or medical procedures include suitable anticancer therapy (e.g., drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedure (e.g., surgery, radiation treatment, hyperthermia heating, bone marrow or stem cell transplant). In one embodiment, the one or more suitable anticancer therapies or medical procedures is selected from treatment with a chemotherapeutic agent (e.g. chemotherapeutic drug), radiation treatment (e.g. x-ray, γ-ray, or electron, proton, neutron, or a particle beam), hyperthermia heating (e.g. microwave, ultrasound, radiofrequency ablation), Vaccine therapy (e.g. AFP gene hepatocellular carcinoma vaccine, AFP adenoviral vector vaccine, AG-858, allogeneic GM-CSF-secretion breast cancer vaccine, dendritic cell peptide vaccines), gene therapy (e.g. Ad5CMV-p53 vector, adenovector encoding MDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy (e.g. aminolaevulinic acid, motexafin lutetium), surgery, or bone marrow and stem cell transplantation. Provided herein are methods for treating a cancer in a subject in need thereof by administering to the subject an effective amount of any one or more compounds described
herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof, in combination with one or more suitable chemotherapeutic agents. In one embodiment, the one or more suitable chemotherapeutic agents is selected from an alkylating agent, including, but not limited to, adozelesin, altretamine, bendamustine, bizelesin, busulfan, carboplatin, carboquone, carmofur, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, etoglucid, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mannosulfan, mechlorethamine, melphalan, mitobronitol, nedaplatin, nimustine, oxaliplatin, piposulfan, prednimustine, procarbazine, ranimustine, satraplatin, semustine, streptozocin, temozolomide, thiotepa, treosulfan, triaziquone, triethylenemelamine, triplatin tetranitrate, trofosphamide, and uramustine; an antibiotic, including, but not limited to, aclarubicin, amrubicin, bleomycin, dactinomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, idarubicin, menogaril, mitomycin, neocarzinostatin, pentostatin, pirarubicin, plicamycin, valrubicin, and zorubicin; an antimetabolite, including, but not limited to, aminopterin, azacitidine, azathioprine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, 2′-F-ara-deoxyuridine, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, raltitrexed, tegafur-uracil, thioguanine, trimethoprim, trimetrexate, and vidarabine; an immunotherapy, including, but not limited to, alemtuzumab, bevacizumab, cetuximab, denileukin diftitox, galiximab, gemtuzumab, ofatumumab, panitumumab, pertuzumab, rituximab, tositumomab, trastuzumab, and 90 Y ibritumomab tiuxetan, ipilimumab, and tremelimumab; a hormone or hormone antagonist, including, but not limited to, anastrozole, androgens, bicalutamide, buserelin, Degarelix, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, megestrol, nilutamide, raloxifene, tamoxifen, 4-hydroxytamoxifen, toremifene, and triptorelin; a taxane, including, but not limited to, DJ-927, docetaxel, TPI 287, larotaxel, ortataxel, paclitaxel, DHA- paclitaxel, and tesetaxel; a retinoid, including, but not limited to, alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; an alkaloid, including, but not limited to, demecolcine, homoharringtonine, vinblastine, vincristine, vindesine, vinflunine, and vinorelbine; an antiangiogenic agent, including, but not limited to, AE-941 (GW786034, Neovastat), ABT- 510, 2-methoxyestradiol, lenalidomide, and thalidomide; a topoisomerase inhibitor, including, but not limited to, amsacrine, belotecan, edotecarin, etoposide, etoposide phosphate, exatecan, irinotecan (also active metabolite SN-38 (7-ethyl-10-hydroxy- camptothecin)), lucanthone, mitoxantrone, pixantrone, rubitecan, teniposide, topotecan, and 9-aminocamptothecin; a kinase inhibitor, including, but not limited to, axitinib (AG 013736),
dasatinib (BMS 354825), erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, motesanib diphosphate (AMG 706), nilotinib (AMN107), pazopanib, seliciclib, sorafenib, sunitinib malate, AEE-788, BMS-599626, UCN-01 (7-hydroxystaurosporine), PLX4032, vatalanib, mTOR inhibitors (e.g. temsirolimus, everolimus, deforolimus, rapamycin), PI3K inhibitors (e.g. BEZ235, GDC-0941, XL147, XL765, CAL-101, PX-866, BGT226, GSK1059615), Cdk4 inhibitors (e.g. PD-332991, AG-024322), Akt inhibitors (e.g. GSK2110183, SR13668), MEK inhibitors (e.g. PD0325901, AZD8330, GSK1120212, RO4987655, RDEA119, XL518); a targeted signal transduction inhibitor including, but not limited to bortezomib, and geldanamycin; a biological response modifier, including, but not limited to, imiquimod, interferon-α, and interleukin-2; and other chemotherapeutics, including, but not limited to 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, COX-2 inhibitors (e.g. celecoxib, rofecoxib, valdecoxib, lumiracoxib, etoricoxib), Hsp90 inhibitors (e.g. tanespimycin) and farnesyltransferase inhibitors (e.g. tipifarnib). In aspects and embodiments involving treatment or prophylaxis of a disease or condition with any one or more compound described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof, the invention provides methods for treating a disease or condition related to Fms in an animal subject in need thereof (e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), e.g., a disease or condition characterized by abnormal Fms activity (e.g. kinase activity). In some embodiments, invention methods may involve administering to the subject suffering from or at risk of a disease or condition related to Fms an effective amount of any one or more compounds described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof. In one embodiment, the disease related to Fms is selected from the group consisting of inflammatory and autoimmune indications, including, but not limited to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, psoriasis, dermatitis, ankylosing spondylitis, polymyositis, dermatomyositis, systemic sclerosis, juvenile idiopathic arthritis, polymyalgia rheumatica, Sjogren's disease, Langerhans cell histiocytosis (LCH), Still's disease, graft- versus-host disease, inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosus (SLE), immune thrombocytopenic purpura (ITP), myelopreparation for
autologous transplantation, transplant rejection, chronic obstructive pulmonary disease (COPD), emphysema, Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, and atherosclerosis; metabolic disorders, including, but not limited to, Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesity, and lipolysis; disorders of bone structure, mineralization and bone formation and resorption, including, but not limited to, osteoporosis, osteodystrophy, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e.g. osteomyelitis), and peri-prosthetic or wear-debris-mediated osteolysis; kidney and genitourinary diseases, including, but not limited to, endometriosis, nephritis (e.g. glomerulonephritis, interstitial nephritis, Lupus nephritis), tubular necrosis, diabetes- associated renal complications (e.g. diabetic nephropathy), and renal hypertrophy; disorders of the nervous system, including, but not limited to, demyelinating disorders (e.g. multiple sclerosis, Charcot Marie Tooth syndrome), amyotrophic lateral sclerosis (ALS), myasthenia gravis, chronic demyelinating polyneuropathy, other demyelinating disorders, stroke, Alzheimer's disease and Parkinson's disease; pain, including, but not limited to, chronic pain, acute pain, inflammatory pain, neuropathic pain, bone pain; malignancies, including, but not limited to, multiple myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia (CIVIL), lung cancer, pancreatic cancer, prostate cancer, breast cancer, ovarian cancer, neuroblastoma, sarcoma, osteosarcoma, giant cell tumors, (e.g. giant cell tumor of bone, giant cell tumor of tendon sheath (TGCT)), pigmented villonodular synovitis (PVNS), tumor angiogenesis, melanoma, glioblastoma multiforme, glioma, other tumors of the central nervous system, brain metastases, osteolytic bone metastases, metastasis of tumors to other tissues, and other chronic myeloproliferative diseases such as myelofibrosis; vasculitis, including but not limited to collagen vascular disease, polyarteritis nodosa, Behcet's disease, sarcoidosis, familiar Mediterranean fever, Churg-Strauss vasculitis, temporal arteritis, giant cell arteritis, Takayasu's arteritis; ophthalmic indications, including but not limited to uveitis, scleritis, retinitis, age related macular degeneration, choroidal neovascularization, diabetic retinopathy; inherited disorders, including but not limited to cherubism, neurofibromatosis; infectious disease indications, including but not limited to infections associated with human immunodeficiency virus, hepatitis B virus, hepatitis C virus, human granulocytic anaplasmosis; lysosomal storage disorders, including but not limited to Gaucher's disease, Fabry's disease, Niemann-Pick disease; gastrointestinal indications, including but not limited to liver cirrhosis; pulmonary indications, including but not limited to pulmonary fibrosis, acute lung injury (e.g. ventilator-induced, smoke- or toxin-induced); global ischemia, and
surgical indications, including but not limited to (cardiopulmonary) bypass surgery, vascular surgery, and vascular grafts. In aspects and embodiments involving treatment or prophylaxis of a disease or condition with the any one or more compounds described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof, the invention provides methods for treating a disease or condition related to Trk in an animal subject in need thereof (e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), e.g., a disease or condition characterized by abnormal Trk activity (e.g. kinase activity). In some embodiments, invention methods may involve administering to the subject suffering from or at risk of a disease or condition related to Trk an effective amount of any one or more compounds described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof. In one embodiment, the disease related to Trk is selected from the group consisting of malignancies, including, but not limited to, prostate cancer, small cell lung cancer, non-small cell lung cancer, Wilms tumors, mesoblastic nephroma, infantile fibrosarcoma, neuroblastoma, brain cancer, squamous cell cancer, bladder cancer, gastric cancer, pancreatic cancer, breast cancer, head and neck cancer, esophageal cancer, colorectal cancer, renal cancer, hepatocellular cancer, ovarian cancer, gynecological cancer, thyroid cancer, cervical cancer, ewings tumor, tumors of the central and peripheral nervous system, melanoma, multiple myeloma, acute myelogenous leukemia, and myeloid leukemia; neuropathies, including, but not limited to, stroke, multiple sclerosis, Parkinson's disease, Alzheimer's disease, transverse myelitis, and encephalitis; pain, including, but not limited to, chronic pain, acute pain, inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, or bone fracture; bone-related diseases, including, but not limited to, metastatic bone disease, treatment-induced bone loss, osteoporosis, rheumatoid arthritis, ankylosing spondylitis, Paget's disease, and periodontal disease; other diseases, including, but not limited to, asthma, arthritis, diabetic retinopathy, macular degeneration, psoriasis, acute and chronic inflammation, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, fibrosarcoma, osteosarcoma, panic disorder, and infectious disease (e.g. Typanosoma cruzi infection (Chagas disease)). In aspects and embodiments involving treatment or prophylaxis of a disease or condition, methods may involve administering an effective amount of any one or more compound(s) described herein (e.g., one or more solid forms of Compound I tosylate) or a
composition thereof to a subject in need thereof suffering from or at risk of a disease or condition selected from the group consisting of rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis, systemic sclerosis, demyelinating disorders, multiple sclerosis, Charcot Marie Tooth syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, global ischemia, graft-versus-host disease, ulcerative colitis, Crohn's disease, immune thrombocytopenic purpura, atherosclerosis, systemic lupus erythematosus, myelopreparation for autologous transplantation, transplant rejection, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, renal hypertrophy, type I diabetes, acute pain, inflammatory pain, neuropathic pain, acute myeloid leukemia, melanoma, multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, gliomas, glioblastomas, neurofibromatosis, osteolytic bone metastases, brain metastases, gastrointestinal stromal tumors, and giant cell tumors. In aspects and embodiments involving treatment or prophylaxis of a disease or condition, methods may involve administering an effective amount of any one or more compound(s) described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof to a subject in need thereof suffering from or at risk of a disease or condition selected from the group consisting of rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, global ischemia, renal hypertrophy, acute myeloid leukemia, melanoma, multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, glioblastoma, neurofibromatosis, brain metastases, and gastrointestinal stromal tumors. In aspects and embodiments involving treatment or prophylaxis of a disease or condition, methods may involve administering an effective amount of any one or more Fms selective inhibitor compounds described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof to a subject in need thereof suffering from or at risk of a disease or condition selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease, global ischemia, rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis, glomerulonephritis, interstitial nephritis, Lupus nephritis, diabetic nephropathy, and renal hypertrophy. In aspects and embodiments involving treatment or prophylaxis of a disease or condition, methods may involve administering an effective amount of any one or more dual Fms/Trk inhibitor compounds described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof to a subject in need thereof suffering from or at risk of a
disease or condition selected from the group consisting of pancreatic cancer, prostate cancer, and multiple myeloma. Any one or more compounds described herein (e.g., one or more solid forms of Compound I tosylate) can be used in the preparation of a medicament for the treatment of a disease or condition related to Fms selected from the group consisting of inflammatory and autoimmune indications, including, but not limited to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, psoriasis, dermatitis, ankylosing spondylitis, polymyositis, dermatomyositis, systemic sclerosis, juvenile idiopathic arthritis, polymyalgia rheumatica, Sjogren's disease, Langerhans cell histiocytosis (LCH), Still's disease, graft-versus-host disease, inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosus (SLE), immune thrombocytopenic purpura (ITP), myelopreparation for autologous transplantation, transplant rejection, chronic obstructive pulmonary disease (COPD), emphysema, Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, and atherosclerosis; metabolic disorders, including, but not limited to, Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesity, and lipolysis; disorders of bone structure, mineralization and bone formation and resorption, including, but not limited to, osteoporosis, osteodystrophy, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e.g. osteomyelitis), and peri-prosthetic or wear-debris-mediated osteolysis; kidney and genitourinary diseases, including, but not limited to, endometriosis, nephritis (e.g. glomerulonephritis, interstitial nephritis, Lupus nephritis), tubular necrosis, diabetes- associated renal complications (e.g. diabetic nephropathy), and renal hypertrophy; disorders of the nervous system, including, but not limited to, demyelinating disorders (e.g. multiple sclerosis, Charcot Marie Tooth syndrome), amyotrophic lateral sclerosis (ALS), myasthenia gravis, chronic demyelinating polyneuropathy, other demyelinating disorders, stroke, Alzheimer's disease and Parkinson's disease; pain, including, but not limited to, chronic pain, acute pain, inflammatory pain, neuropathic pain, bone pain; malignancies, including, but not limited to, multiple myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia (CIVIL), lung cancer, pancreatic cancer, prostate cancer, breast cancer, ovarian cancer, neuroblastoma, sarcoma, osteosarcoma, giant cell tumors, (e.g. giant cell tumor of bone, giant cell tumor of tendon sheath (TGCT)), pigmented villonodular synovitis (PVNS), tumor angiogenesis, melanoma, glioblastoma multiforme, glioma, other tumors of the central nervous system, brain metastases, osteolytic bone metastases, metastasis of tumors to other tissues, and other chronic myeloproliferative diseases such as myelofibrosis; vasculitis,
including but not limited to collagen vascular disease, polyarteritis nodosa, Behcet's disease, sarcoidosis, familiar Mediterranean fever, Churg-Strauss vasculitis, temporal arteritis, giant cell arteritis, Takayasu's arteritis; ophthalmic indications, including but not limited to uveitis, scleritis, retinitis, age related macular degeneration, choroidal neovascularization, diabetic retinopathy; inherited disorders, including but not limited to cherubism, neurofibromatosis; infectious disease indications, including but not limited to infections associated with human immunodeficiency virus, hepatitis B virus, hepatitis C virus, human granulocytic anaplasmosis; lysosomal storage disorders, including but not limited to Gaucher's disease, Fabry's disease, Niemann-Pick disease; gastrointestinal indications, including but not limited to liver cirrhosis; pulmonary indications, including but not limited to pulmonary fibrosis, acute lung injury (e.g. ventilator-induced, smoke- or toxin-induced); global ischemia, and surgical indications, including but not limited to (cardiopulmonary) bypass surgery, vascular surgery, and vascular grafts. Any one or more compounds described herein (e.g., one or more solid forms of Compound I tosylate) can be used in the preparation of a medicament for the treatment of a disease or condition related to Trk selected from the group consisting of malignancies, including, but not limited to, prostate cancer, small cell lung cancer, non-small cell lung cancer, Wilms tumors, mesoblastic nephroma, infantile fibrosarcoma, neuroblastoma, brain cancer, squamous cell cancer, bladder cancer, gastric cancer, pancreatic cancer, breast cancer, head and neck cancer, esophageal cancer, colorectal cancer, renal cancer, hepatocellular cancer, ovarian cancer, gynecological cancer, thyroid cancer, cervical cancer, ewings tumor, tumors of the central and peripheral nervous system, melanoma, multiple myeloma, acute myelogenous leukemia, and myeloid leukemia; neuropathies, including, but not limited to, stroke, multiple sclerosis, Parkinson's disease, Alzheimer's disease, transverse myelitis, and encephalitis; pain, including, but not limited to, chronic pain, acute pain, inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, or bone fracture; bone-related diseases, including, but not limited to, metastatic bone disease, treatment-induced bone loss, osteoporosis, rheumatoid arthritis, ankylosing spondylitis, Paget's disease, and periodontal disease; other diseases, including, but not limited to, asthma, arthritis, diabetic retinopathy, macular degeneration, psoriasis, acute and chronic inflammation, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, fibrosarcoma, osteosarcoma, panic disorder, and infectious disease (e.g. Typanosoma cruzi infection (Chagas disease)).
Any one or more compounds described herein (e.g., one or more solid forms of Compound I tosylate) can be used in the preparation of a medicament for the treatment of a disease or condition selected from the group consisting of rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis, systemic sclerosis, demyelinating disorders, multiple sclerosis, Charcot Marie Tooth syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, global ischemia, ulcerative colitis, Crohn's disease, immune thrombocytopenic purpura, atherosclerosis, systemic lupus erythematosus, myelopreparation for autologous transplantation, transplant rejection, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, renal hypertrophy, type I diabetes, acute pain, inflammatory pain, neuropathic pain, acute myeloid leukemia, melanoma, multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, gliomas, glioblastomas, neurofibromatosis, osteolytic bone metastases, brain metastases, gastrointestinal stromal tumors, and giant cell tumors. Any one or more compounds described herein (e.g., one or more solid forms of Compound I tosylate) can be used in the preparation of a medicament for the treatment of a disease or condition selected from the group consisting of rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, global ischemia, renal hypertrophy, acute myeloid leukemia, melanoma, multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, glioblastoma, neurofibromatosis, brain metastases, and gastrointestinal stromal tumors. One or more compounds as described herein that are dual Fms/Trk inhibitors can be used in the preparation of a medicament for the treatment of pancreatic cancer, prostate cancer, and multiple myeloma. Provided are compounds described herein (e.g., one or more solid forms of Compound I tosylate) for the treatment of a disease or condition related to Fms selected from the group consisting of inflammatory and autoimmune indications, including, but not limited to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, psoriasis, dermatitis, ankylosing spondylitis, polymyositis, dermatomyositis, systemic sclerosis, juvenile idiopathic arthritis, polymyalgia rheumatica, Sjogren's disease, Langerhans cell histiocytosis (LCH), Still's disease, graft-versus-host disease, inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosus (SLE), immune thrombocytopenic purpura (ITP), myelopreparation for autologous transplantation, transplant rejection, chronic obstructive pulmonary disease (COPD), emphysema, Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, and atherosclerosis;
metabolic disorders, including, but not limited to, Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesity, and lipolysis; disorders of bone structure, mineralization and bone formation and resorption, including, but not limited to, osteoporosis, osteodystrophy, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e.g. osteomyelitis), and peri-prosthetic or wear-debris-mediated osteolysis; kidney and genitourinary diseases, including, but not limited to, endometriosis, nephritis (e.g. glomerulonephritis, interstitial nephritis, Lupus nephritis), tubular necrosis, diabetes- associated renal complications (e.g. diabetic nephropathy), and renal hypertrophy; disorders of the nervous system, including, but not limited to, demyelinating disorders (e.g. multiple sclerosis, Charcot Marie Tooth syndrome), amyotrophic lateral sclerosis (ALS), myasthenia gravis, chronic demyelinating polyneuropathy, other demyelinating disorders, stroke, Alzheimer's disease and Parkinson's disease; pain, including, but not limited to, chronic pain, acute pain, inflammatory pain, neuropathic pain, bone pain; malignancies, including, but not limited to, multiple myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lung cancer, pancreatic cancer, prostate cancer, breast cancer, ovarian cancer, neuroblastoma, sarcoma, osteosarcoma, giant cell tumors, (e.g. giant cell tumor of bone, giant cell tumor of tendon sheath (TGCT)), pigmented villonodular synovitis (PVNS), tumor angiogenesis, melanoma, glioblastoma multiforme, glioma, other tumors of the central nervous system, brain metastases, osteolytic bone metastases, metastasis of tumors to other tissues, and other chronic myeloproliferative diseases such as myelofibrosis; vasculitis, including but not limited to collagen vascular disease, polyarteritis nodosa, Behcet's disease, sarcoidosis, familiar Mediterranean fever, Churg-Strauss vasculitis, temporal arteritis, giant cell arteritis, Takayasu's arteritis; ophthalmic indications, including but not limited to uveitis, scleritis, retinitis, age related macular degeneration, choroidal neovascularization, diabetic retinopathy; inherited disorders, including but not limited to cherubism, neurofibromatosis; infectious disease indications, including but not limited to infections associated with human immunodeficiency virus, hepatitis B virus, hepatitis C virus, human granulocytic anaplasmosis; lysosomal storage disorders, including but not limited to Gaucher's disease, Fabry's disease, Niemann-Pick disease; gastrointestinal indications, including but not limited to liver cirrhosis; pulmonary indications, including but not limited to pulmonary fibrosis, acute lung injury (e.g. ventilator-induced, smoke- or toxin-induced); global ischemia, and surgical indications, including but not limited to (cardiopulmonary) bypass surgery, vascular surgery, and vascular grafts.
Provided are compounds described herein (e.g., one or more solid forms of Compound I tosylate) for the treatment of a disease or condition related to Trk selected from the group consisting of malignancies, including, but not limited to, prostate cancer, small cell lung cancer, non-small cell lung cancer, Wilms tumors, mesoblastic nephroma, infantile fibrosarcoma, neuroblastoma, brain cancer, squamous cell cancer, bladder cancer, gastric cancer, pancreatic cancer, breast cancer, head and neck cancer, esophageal cancer, colorectal cancer, renal cancer, hepatocellular cancer, ovarian cancer, gynecological cancer, thyroid cancer, cervical cancer, ewings tumor, tumors of the central and peripheral nervous system, melanoma, multiple myeloma, acute myelogenous leukemia, and myeloid leukemia; neuropathies, including, but not limited to, stroke, multiple sclerosis, Parkinson's disease, Alzheimer's disease, transverse myelitis, and encephalitis; pain, including, but not limited to, chronic pain, acute pain, inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, or bone fracture; bone-related diseases, including, but not limited to, metastatic bone disease, treatment-induced bone loss, osteoporosis, rheumatoid arthritis, ankylosing spondylitis, Paget's disease, and periodontal disease; other diseases, including, but not limited to, asthma, arthritis, diabetic retinopathy, macular degeneration, psoriasis, acute and chronic inflammation, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, fibrosarcoma, osteosarcoma, panic disorder, and infectious disease (e.g. Typanosoma cruzi infection (Chagas disease)). Provided are compounds described herein (e.g., one or more solid forms of Compound I tosylate) for the treatment of a disease or condition selected from the group consisting of rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis, systemic sclerosis, demyelinating disorders, multiple sclerosis, Charcot Marie Tooth syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, global ischemia, ulcerative colitis, Crohn's disease, immune thrombocytopenic purpura, atherosclerosis, systemic lupus erythematosus, myelopreparation for autologous transplantation, transplant rejection, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, renal hypertrophy, type I diabetes, acute pain, inflammatory pain, neuropathic pain, acute myeloid leukemia, melanoma, multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, gliomas, glioblastomas, neurofibromatosis, osteolytic bone metastases, brain metastases, gastrointestinal stromal tumors, and giant cell tumors. Provided are compounds described herein (e.g., one or more solid forms of Compound I tosylate) for the treatment of a disease or condition selected from the group
consisting of rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, global ischemia, renal hypertrophy, acute myeloid leukemia, melanoma, multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, glioblastoma, neurofibromatosis, brain metastases, and gastrointestinal stromal tumors. Provided are compounds as described herein (e.g., one or more solid forms of Compound I tosylate) that are dual Fms/Trk inhibitors for the treatment of a disease or condition selected from the group consisting of pancreatic cancer, prostate cancer, and multiple myeloma. In some embodiments, the present disclosure provides a method for treating a subject suffering from or at risk of a Fms and/or TRK mediated disease or condition by administering to the subject an effective amount of any one or more solid forms of Compound I tosylate as described herein (e.g., Compound I tosylate Form A, Compound I tosylate Form B, Compound I tosylate Form C, Compound I tosylate Form D, Compound I tosylate Form E, Compound I tosylate Form F, Compound I tosylate Form G, Compound I tosylate Form H, or Compound I tosylate Form J), or a composition thereof. In any of the methods, treatments, and/or uses described herein, administration of one or more compounds described herein (e.g., one or more solid forms of Compound I tosylate) or a composition thereof, preferably refers to the administration of one or more of the polymorphs of the invention, e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, and Form J. In any of the methods, treatments, and/or uses described herein, the subject is a human. In some embodiments of the methods, treatments, and/or uses described herein, the subject is a non-human animal. In any of the methods, treatments, and/or uses described herein, the disease, disorder, and/or condition is Langerhans cell histiocytosis (LCH), graft-versus-host disease, or colorectal cancer. In any of the methods, treatments, and/or uses described herein, the disease, disorder, and/or condition is Langerhans cell histiocytosis (LCH). In any of the methods, treatments, and/or uses described herein, the disease, disorder, and/or condition is graft- versus-host disease. In any of the methods, treatments, and/or uses described herein, the disease, disorder, and/or condition is colorectal cancer.
Examples The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration only and not limiting of the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims. Methods of Preparation Form A A 12 L, 3-neck round bottom flask was equipped with a mechanical stirrer, condenser, thermocouple, heating mantel and nitrogen inlet/outlet. To the flask was charged 944 g Compound 1, 380 g of PTSA, and 4.74 L of premixed DMSO (940 ml) and 2-butanol (3.8 L) mixture. Agitation started and reaction was heated to 80 oC for 5 h. Reaction was slowly cooled to ambient temperature and filtered. Cake was consequently washed with 2 L of 2- butanol and 1 L of MTBE. Dried in vacuum at 45 oC over 48 h to yield 743 g of Compound 1-TsOH. Yield: 58%. Form B In one method for preparing Form B, 8 mL methanol was added to 98 mg Form A with sonication. The clear solution was syringe filtered into a 40 mL scintillation vial. 30 mL methyltertbutyl ether was added to the filtered solution and the sample remained clear. The sample was capped and stirred at RT. After ~15 minutes, precipitation was observed. The sample was stirred at RT for ~1 day and solids were isolated by vacuum filtration using a 0.2 μm Nylon filter. In another method for preparing Form B, 82.6 mg Form A was dissolved in 7 mL methanol with sonication. The sample was syringe filtered using a 0.2 μM Nylon filter. 15 mL H2O was added to the filtered clear solution and white precipitate was observed. A stir bar was added and the sample was stirred at RT for ~ 4 hours and solids were collected by vacuum filtration. In yet another method for preparing Form B, 95 mg Form A was dissolved in 9 mL methanol. The clear solution was filtered into a clean scintillation vial. The sample vial was placed open in a glass jar containing 30 mL isopropyl ether and the glass jar was closed and
the sample left for vapor diffusion at RT. After ~3 days, the sample vial was removed from the glass jar and solids were isolated by vacuum filtration using a 0.2 μm Nylon filter. Form C In one method for preparing Form C, 0.5 mL acetonitrile was added to 51.8 mg Form A and solids remained. A stir bar was added to the vial and the sample was capped, parafilmed and stirred at RT. After ~3 days, the sample (slightly thick slurry) was vacuum filtered and the solids collected for analysis. In another method for preparing Form C, 990.1 mg Form A was weighed into a pre- weighed vial and the sample vial was left open in a preheated ~154°C heating block placed on a hot plate for ~40 minutes, with stirring. The sample was scraped with a spatula intermittently. The post-heated vial was weighed and the solvent loss was calculated. The resulting solid was submitted for analysis. Form D 1 mL nitromethane was added to 74.8 mg Form A at RT and solids remained. A stir bar was added and the sample placed on a pre-warmed (~92 °C) oil bath (solids left).5 mL nitromethane was added incrementally and the resulting solution was hot filtered using a 0.2 μm Nylon filter into a pre-warmed (~92 °C) scintillation vial. A stir bar was added and the sample was capped and stirred at ~92 °C for ~ 5 minutes. The heating source was turned off and the sample allowed to slowly cool to RT in the oil bath. After 1 day, the sample was removed and solids were collected by vacuum filtration using a 0.2 μm Nylon filter. Form E 0.5 mL THF was added to 55.6 mg Form A and solids remained. A stir bar was added to the vial and the sample was capped, parafilmed and stirred at RT. After ~3 days, the sample (slightly thick slurry) was vacuum filtered and the solids collected for analysis. Form F 1 mL ethyl acetate was added to a combination of Form C and minor Form A and solids remained. A stir bar was added and the sample capped then parafilmed. The sample was stirred at RT for ~2 days. The sample was vacuum filtered using a 0.2 μm Nylon filter and solids collected were submitted for analysis.
Form G 5 mL acetonitrile was added to 515.7 mg Form A and solids remained. The sample was capped and stirred at RT for ~2 days. Solids were isolated by vacuum filtration. Form H 153.2 mg Compound I free base (3.24 x10-4 mole) was dissolved in 6 mL MEK at 70 °C to produce a clear light solution. 62.9 mg p-toluenesulfonic acid monohydrate (3.31 x10-4 mole) was added to the sample resulting in a hazy solution. The sample was stirred at 70 °C for ~15 minutes (precipitation observed) then fast cooled to RT. The sample was stirred at RT for ~ 1 hour and the solids present were collected by vacuum filtration. Form J 4 mL ACN: H2O (9:1 v/v) was added to 202.2 mg Compound I free base (4.28 x10-4 mole) and solids remained. 81.8 mg p-toluenesulfonic acid monohydrate (4.30 x10-4 mole) was added at RT. The sample was capped and stirred at ~70 °C. The sample went clear but immediately after few solids precipitated. The heating source was turned off and the sample slow cooled. At ~55 °C, clear solution was observed. Seeds of Form B were added and precipitation was observed. The sample was slow cooled to RT (solids present). 1.75 mL water was added at RT (solids present) to reach ACN: H2O (2:1 v/v). Sample was stirred at ~2-8 °C in cold room for ~2 hours. Solids were collected by vacuum filtration. While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.