Formulation of furin inhibitors for inhalation

Abstract

Provided herein is a pharmaceutical composition comprising Compound (I), where Compound (I) is represented by the formula or a pharma- ceutically acceptable salt, polymorph, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof. Also disclosed are polymorphs of Compound (I), and methods of using the pharmaceutical compositions and polymorphs of Compound (I) as described herein to treat diseases (e.g., fibrosis, such as cystic fibrosis and pulmonary fibrosis), comprising administering to a subject in need thereof a therapeutically effective amount of a polymorph of Compound (I) or a pharmaceutical composition comprising Compound (I) as described herein. In some aspects, the composition is formulated for inhalation (e.g., oral or nasal inhalation).

Description

[Technical field]

[0001] Related Applications This application claims priority under 35 USC § 119(e) to U.S. Provisional Application No. 63 / 145,363, filed February 3, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] background Inactive precursor proteins of many enzymes, receptors, and secreted proteins require processing and maturation to exert their biological functions (Thomas G. Nat. Rev. Mol. Cell. Biol. 2002, 3(10), 753-766). Proteolytic cleavage of the propeptide sequence depends on the proprotein convertase (PC) family of calcium-dependent endoproteases. The PC family consists of the following serine proteases: proprotein convertase subtilisin kexin 1 (PCSK1), PCSK2, furin / PCSK3, PCSK4, PCSK5, PCSK6 / paired basic amino acid cleaving enzyme 4 (PACE4), PCSK7, PCSK8 / subtilisin kexin isoenzyme 1 (SK-1) / membrane-bound transcription factor peptidase site 1 (MBTPS1), and PCSK9 (Thomas G. Nat. Rev. Mol. Cell. Biol. 2002,3(10),753-766; Nakayama K. Biochem. J. 1997,327(3),625-635; Klein-Szanto AJ, Bassi DE. Biochem.Pharmacol. 2017,140,8-15; Turpeinen H, Ortutay Z, Pesu M. Curr. Genomics 2013,14(7),453-467). Of these PCSKs, furin (PCSK3) is the best characterized and most extensively studied member of the family with diverse biological functions.

[0003] Furin is a 794 amino acid type 1 transmembrane protein that is ubiquitously expressed in many cell types (Thomas G. Nat.Rev.Mol.Cell.Biol.2002,3(10),753-766). It consists of a highly conserved domain structure commonly found in PCSKs, including an N-terminal signal peptide, an inhibitory prodomain, a catalytic peptidase S8 / S53 domain, a P domain, a cysteine-rich region, and a cytoplasmic domain (Thomas G. Nat.Rev.Mol.Cell.Biol.2002,3(10),753-766; Turpeinen H, Ortutay Z, Pesu M. Curr.Genomics 2013,14(7),453-467). The prodomain is essential for correct folding, activation, and trafficking of furin, whereas the P domain regulates the enzymatic activity of the catalytic domain by modulating the pH / calcium-dependent autoproteolytic cleavage process (Thomas G. Nat.Rev.Mol.Cell.Biol.2002,3(10),753-766; Turpeinen H, Ortutay Z, Pesu M. Curr.Genomics 2013,14(7),453-467). Finally, the cytoplasmic domain of furin allows both efficient internalization from the plasma membrane and fast retrieval from the plasma membrane to the trans-Golgi network (TGN) (Thomas G. Nat.Rev.Mol.Cell.Biol.2002,3(10),753-766).

[0004] Furin is primarily localized to the trans-Golgi network (TGN) and endosomal systems where it processes most of its diverse substrates in vivo. The endoprotease activity of furin is manifested by the release of its prodomain fragment, which allows furin to functionally process substrates in trans (Thomas G. Nat.Rev.Mol.Cell.Biol.2002,3(10),753-766). The cleavage site at which furin cleaves, located after a carboxy-terminal arginine (Arg) residue, has the sequence: -Arg-X-Lys / Arg-Arg↓- (Lys is lysine, X is any amino acid, and ↓ identifies the cleavage site). Based on this substrate peptide amino acid motif, furin has >400 predicted target protein substrates, including hormones, growth factors, enzymes, receptors, neuropeptides, and infectious agents (Turpeinen H, Ortutay Z, Pesu M. Curr.Genomics 2013,14(7),453-467; Shiryaev SA, Chernov AV, Golubkov VS, Thomsen ER, Chudin E, Chee MS, et al. PLoS One 2013,8(1),e54290) (www.ebi.ac.uk / merops). The importance of the biological role of furin-dependent proteolytic processing can be further illustrated by the phenotypes of various studies in knockout mice.

[0005] Germline furin knockout mouse studies demonstrate a critical role for furin in embryonic development, with embryos becoming lethal between days 10.5 and 11.5. Deficiency in ventral closure and axial rotation, as well as the absence of chorioallantoic membrane fusion, were observed. The effects of furin knockdown in endothelial cells resulted in cardiovascular defects including septal and valvular defects that may be due to impaired processing of TGF-β (Turpeinen H, Ortutay Z, Pesu M. Curr.Genomics 2013,14(7),453-467; Roebroek AJ, Umans L, Pauli IG, Robertson EJ, van Leuven F, Van de Ven WJ, et al. Development 1998,125(24),4863-4876; Seidah NG, Prat A. Nat.Rev.Drug Discov.2012,11(5),367-383; Constam DB, Robertson EJ. Development 2000,127(2),245-254; Susan-Resiga D, Essalmani R, Hamelin J, Asselin MC, Benjannet S, Chamberland A, et al. J.Biol.Chem.2011,286(26),22785-22794). However, knockout of furin (inducible Mx1-Cre transgene) in adult mouse liver was not lethal and typical furin substrates were cleaved, albeit inefficiently, pointing to a possible redundancy of PCSKs (Klein-Szanto AJ, Bassi DE. Biochem.Pharmacol.2017,140,8-15; Roebroek AJ, Taylor NA, Louagie E, Pauli I, Smeijers L, Snellinx A, et al. J.Biol.Chem.2004,279(51),53442-53450).In addition, targeted deletion of furin in T cells caused impaired regulatory and effector T cell function as a result of defective TGFβ1 signaling (Pesu M, Watford WT, Wei L, Xu L, Fuss I, Strober W, et al. Nature 2008,455(7210),246-250). These findings imply a role for furin in TGFβ biology and the potential therapeutic use of furin inhibitors for TGFβ-dependent diseases.

[0006] TGF-β family members play a central role in fibrosis (Dubois CM, Blanchette F, Laprise MH, Leduc R, Grondin F, Seidah NG. Am.J.Pathol.2001,158(1),305-316), and TGF-β1 is elevated in fibrotic organs such as the heart, lung, and kidney (Pohlers D, Brenmoehl J, Loffler I, Muller CK, Leipner C, Schultze-Mosgau S, et al. Biochimica et Biophysica Acta(BBA) - Molecular Basis of Disease 2009,1792(8),746-756; Thomas BJ, Kan OK, Loveland KL, Elias JA, Bardin PG. Am.J.Respir.Cell.Mol.Biol.2016,55(6),759-766). Organ fibrosis is the result of an abnormal wound-healing response, resulting in excessive collagen deposition. Scarring of connective tissue leads to progressive loss of tissue function and ultimately to organ failure (Nanthakumar CB, Hatley RJ, Lemma S, Gauldie J, Marshall RP, Macdonald SJ. Nat.Rev.Drug Discov.2015,14(10),693-720). Pre-pro-TGFβ1 is synthesized by most cells as a single 390 amino acid peptide. A furin-dependent processing event is predicted to occur following an Arg-His-Arg-Arg sequence immediately preceding the NH2-terminal Ala279 residue of the growth factor (Constam DB. Seminars in Cell & Developmental Biology 2014, 32, 85-97).Mature TGFβ forms a 25KDa dimer and is complexed with specific binding proteins, such as the TGFβ latent associated peptide (LAP) (the NH2-terminal part of the precursor sequence) and the large latent binding protein (LTBP), before being secreted into the extracellular matrix (Constam DB. Seminars in Cell & Developmental Biology 2014, 32, 85-97; Robertson IB, Horiguchi M, Zilberberg L, Dabovic B, Hadjiolova K, Rifkin DB. Matrix biology, Journal of the International Society for Matrix Biology 2015,47,44-53). Active mature TGFβ1 must be released from the latent complex before it can exert its biological effects. The biological effects of TGFβ are mediated through canonical SMAD-dependent signaling and noncanonical pathways involving PI3K / ATK, Erk, and p38 upon receptor activation involving upon (Zhang YE. Cell Research 2009,19(1),128-139). TGFβ1 initiates a profibrotic response by promoting the transformation of normal epithelial cells into active fibroblasts and subsequent collagen synthesis and deposition (Biernacka A, Dobaczewski M, Frangogiannis NG. Growth Factors (Chur,Switzerland) 2011,29(5),196-202). Thus, therapeutic intervention using furin inhibitors would provide benefit by preventing the correct processing of pre-pro-TGFβ1 and thus depleting bioactive TGFβ in fibrosis.

[0007] Given the diversity in its substrates, therapeutic intervention of furin could also be beneficial for diseases such as hypertension, cancer, and infectious diseases, respiratory diseases, and neuronal degenerative diseases (Thomas G. Nat.Rev.Mol.Cell.Biol.2002,3(10),753-766; Nakayama K. Biochem.J.1997,327(3),625-635; Shiryaev SA, Chernov AV, Golubkov VS, Thomsen ER, Chudin E, Chee MS, et al. PLoS One 2013,8(1),e54290; Bennett BD, Denis P, Haniu M, Teplow DB, Kahn S, Louis JC, et al. J.Biol.Chem.2000,275(48),37712-37717; Takahashi RH, Nagao T, Gouras GK. Pathology International 2017,67(4),185-193). Hypertension is a disease in which blood exerts increased force against the arterial walls. The renin-angiotensin system and molecules regulating sodium-electrolyte balance can affect blood pressure and are related to furin activity (Turpeinen H, Ortutay Z, Pesu M. Curr.Genomics 2013,14(7),453-467; Cousin C, Bracquart D, Contrepas A, Corvol P, Muller L, Nguyen G. Hypertension 2009,53(6),1077-1082). Two recent large-scale genetic association studies (GWAS) have demonstrated the role of furin genetics as a risk factor for hypertension.One study used a GWAS approach to study over 200,000 subjects of European descent and identified a single nucleotide polymorphism (SNP; rs2521501) in the furin-FES locus associated with elevated systolic and diastolic blood pressure (Ehret GB, Munroe PB, Rice KM, Bochud M, Johnson AD, et al. Nature 2011,478(7367),103-109). Two additional furin polymorphisms, rs2071410 and rs6227, associated with systolic and diastolic blood pressure, respectively, were identified in another multicenter study that genotyped 50,000 SNPs in 2,100 candidate genes (Turpeinen H, Ortutay Z, Pesu M. Curr. Genomics 2013,14(7),453-467; Ganesh SK, Tragante V, Guo W, Guo Y, Lanktree MB, Smith EN, et al. Hum.Mol.Genet.2013,22(8),1663-1678). Given this strong human genetic evidence, modulation of furin activity may be a therapeutic approach to hypertension.

[0008] Cancer is a group of diseases involving abnormal and uncontrolled growth of cells that can spread to other parts of the body (metastasis). Furin substrates are involved in various processes involved in cancer progression, such as proliferation, anti-apoptosis, migration / invasion, metastasis, and angiogenesis. The substrates targeted by furin in these processes are growth factors and their receptors, matrix metalloproteinases, cell adhesion molecules, and angiogenic / lymphangiogenic factors (Shiryaev SA, Chernov AV, Golubkov VS, Thomsen ER, Chudin E, Chee MS, et al. PLoS One 2013,8(1),e54290; Jaaks P, Bernasconi M. Int. J.Cancer 2017,141(4),654-663; Bassi DE, Mahloogi H, Al-Saleem L, Lopez De Cicco R, Ridge JA, Klein-Szanto AJ. Mol.Carcinog.2001,31(4),224-232). Many growth factors and their receptors are important for the balance between apoptotic and pro-survival mechanisms. Thus, dysregulation of growth factors plays a role in cancer development. In addition to uncontrolled growth, extracellular matrix (ECM) degradation is necessary for cancer cells to escape their primary site. Similarly, ECM remodeling is required for the development of metastatic niches that allow disseminated cancer cells to survive, establish, and proliferate at metastatic sites (Bonnans C, Chou J, Werb Z. Nat.Rev.Mol.Cell.Biol.2014,15(12),786-801).Many of these enzymes, such as MMPs and ADAM proteases that mediate ECM degradation, require proteolytic activation by furin (Maquoi E, Noel A, Frankenne F, Angliker H, Murphy G, Foidart JM. FEBS Lett.1998,424(3),262-266; Yana I, Weiss SJ. Mol.Biol.Cell 2000,11(7),2387-2401; Kang T, Nagase H, Pei D. Cancer Res.2002,62(3),675-681; Wang X, Pei DJ Biol.Chem.2001,276(38),35953-35960; Loechel F, Gilpin BJ, Engvall E, Albrechtsen R, Wewer UM. J. Biol. Chem. 1998, 273(27), 16993-16997; Schlondorff J, Becherer JD, Blobel CP. Biochem. J. 2000, 347(1), 131-138). Finally, the process of blood vessel formation, angiogenesis, supports tumor growth. Vascular endothelial growth factors VEGF-C and VEGF-D are processed by furin to promote VEGF signaling, which can stimulate angiogenesis and lymphangiogenesis (Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, et al. EMBO J.1997,16(13),3898-3911; McColl BK, Paavonen K, Karnezis T, Harris NC, Davydova N, Rothacker J, et al. FASEB J.2007,21(4),1088-1098). Thus, therapeutic intervention of furin activity would limit cancer cell growth by blocking multiple key biological processes that promote cancer cell growth and spread.

[0009] Infectious diseases can spread from one person to another and can be caused by pathogenic microorganisms such as bacteria, viruses, parasites, or fungi. Pathogenicity is the ability of a microbial agent to cause disease, and virulence is the degree of pathogenesis of the organism. In order for viruses to enter and replicate in host cells, the envelope glycoproteins must be proteolytically activated (Nakayama K. Biochem.J.1997,327(3),625-635). Processing of the envelope glycoproteins affects the pathogenicity of the virus in some cases (Nakayama K. Biochem.J.1997,327(3),625-635). The glycoprotein precursors of many virulent viruses, such as human immunodeficiency virus (HIV), avian influenza virus, measles virus, respiratory syncytial virus (RSV), Ebola virus, anthrax, and Zika virus (ZIKV), are cleaved at sites characterized by consensus sequences consistent with furin recognition (Thomas G. Nat. Rev. Mol. Cell. Biol. 2002,3(10),753-766;2,36-38). Cleavage of HIV glycoprotein 160 and production of infectious virus is blocked when the furin inhibitor α1-PDX is expressed in cells (Nakayama K. Biochem. J. 1997,327(3),625-635). Furin inhibitors may therefore be useful in pandemic or biological warfare.

[0010] Cystic fibrosis (CF) is a common fatal autosomal recessive genetic disease in Europe and North America (Hoffman LR, Ramsey BW. CHEST 2013,143(1),207-213). A thin film of fluid lines the conducting airways of the lungs facilitating mucociliary clearance and contributing to the innate immune defense by removing inhaled pathogens. This fluid volume is regulated by chloride and sodium transport across the airway epithelium. This regulation is lost in cystic fibrosis due to the absence of the cystic fibrosis transmembrane conductance regulator (CFTR), which mediates chloride secretion across the epithelium and subsequent sodium reabsorption and fluid balance. Hyperabsorption of the epithelial sodium channel (ENaC) is a factor that contributes to the fluid layer deficiency that initiates CF pathophysiology. Channel-activating proteases (CAPs), such as furin, catalyze the intracellular proteolysis of ENaC, increasing sodium channel conductance that would otherwise remain low (Reihill JA, Walker B, Hamilton RA, Ferguson TE, Elborn JS, Stutts MJ, et al. Am.J.Respir.Crit.Care Med.2016,194(6),701-710; Myerburg MM, Harvey PR, Heidrich EM, Pilewski JM, Butterworth MB. Am.J.Respir.Cell.Mol.Biol.2010,43(6),712-719). Furin inhibitors are effective in blocking sodium reabsorption (Reihill JA, Walker B, Hamilton RA, Ferguson TE, Elborn JS, Stutts MJ, et al. Am. J. Respir. Crit. Care Med. 2016, 194(6), 701-710), thus providing proof of concept for the potential use of furin inhibitors in the treatment of CF.

[0011] Alzheimer's disease (AD) is a progressive, multifactorial, and heterogeneous neurodegenerative disorder that leads to progressive cognitive decline. Amyloid-β (Aβ)-containing plaques and neurofibrillary tangles composed of hyperphosphorylated tau in the brain are the neuropathological hallmarks of AD (Takahashi RH, Nagao T, Gouras GK. Pathology International 2017,67(4),185-193; Rangachari V, Dean DN, Rana P, Vaidya A, Ghosh P. Biochimica et Biophysica Acta(BBA) - Biomembranes 2018,https: / / doi.org / 10.1016 / j.bbamem.2018.03.004; Crews L, Masliah E. Human Molecular Genetics 2010,19(R1),R12-R20). The amyloid precursor protein (APP) is an integral membrane protein that contains a single transmembrane domain (Takahashi RH, Nagao T, Gouras GK. Pathology International 2017,67(4),185-193; Rangachari V, Dean DN, Rana P, Vaidya A, Ghosh P. Biochimica et Biophysica Acta(BBA) - Biomembranes 2018,doi.org / 10.1016 / j.bbamem.2018.03.004).Amyloid peptides can be formed by sequential cleavage of APP by aspartyl proteases, β-(BACE), and γ-secretase (Takahashi RH, Nagao T, Gouras GK. Pathology International 2017,67(4),185-193; Rangachari V, Dean DN, Rana P, Vaidya A, Ghosh P. Biochimica et Biophysica Acta(BBA) - Biomembranes 2018,doi.org / 10.1016 / j.bbamem.2018.03.004; Fiala JC. Acta Neuropathologica 2007,114(6),551-571). Proteolytic cleavage of APP leads to the generation of Aβ1-42 monomers, which can assemble in pathological conditions to form potentially toxic oligomers and plaques (Takahashi RH, Nagao T, Gouras GK. Pathology International 2017,67(4),185-193; Rangachari V, Dean DN, Rana P, Vaidya A, Ghosh P. Biochimica et Biophysica Acta(BBA) - Biomembranes 2018,doi.org / 10.1016 / j.bbamem.2018.03.004; Fiala JC. Acta Neuropathologica 2007,114(6),551-571). Amyloid deposition has been suggested to be driven by glia secreting Aβ. The protein spontaneously aggregates into amyloid filaments that activate microglia.Activated microglia then secrete oxidative species and inflammatory cytokines, which lead to axonal dystrophy and cell death (Rangachari V, Dean DN, Rana P, Vaidya A, Ghosh P. Biochimica et Biophysica Acta(BBA) - Biomembranes 2018,doi.org / 10.1016 / j.bbamem.2018.03.004; Crews L, Masliah E. Human Molecular Genetics 2010,19(R1),R12-R20; Fiala JC. Acta Neuropathologica 2007,114(6),551-571). Mutations in APP and presenilins (components of the γ-secretase complex) lead to altered processing of APP by secretases, increasing the production of Aβ peptides that form pro-plaques (Dai MH, Zheng H, Zeng LD, Zhang Y. Oncotarget 2018,9(19),15132-15143), suggesting the importance of secretases in disease progression. Therefore, pharmacological modulation of processing is an outstanding strategy for the treatment of AD, with inhibitors of both BACE and γ-secretase being evaluated in recent clinical trials (Panza F, Seripa D, Solfrizzi V, Imbimbo BP, Lozupone M, Leo A, et al. Expert Opinion on Emerging Drugs 2016,21(4),377-391). The BACE propeptide shares a consensus sequence with furin, and processing of the BACE propeptide has been shown to be dependent on active furin (Bennett BD, Denis P, Haniu M, Teplow DB, Kahn S, Louis JC, et al. J.Biol.Chem.2000,275(48),37712-37717).Thus, selective furin inhibitors could potentially be used for the treatment of AD and neurodegenerative diseases associated with dysregulated furin processing. Summary of the Invention

[0012] overview Typically, potent furin inhibitors are peptide derivatives or peptidomimetics that contain polybasic residues to obtain high inhibitory efficacy. As a result of the inhibitors' high basicity, reactivity, and peptide structure, their chemical and pharmacokinetic properties limit their use as clinical therapeutic agents. However, many small molecule inhibitors of furin have been reported in PCT Publication No. WO 2019 / 215341.

[0013] In one aspect, provided herein is a compound having the formula: [ka] A pharmaceutical composition comprising compound (I) represented by the formula: or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a polymorph thereof; and an organic acid. Preferably, the organic acid is selected from non-aromatic polycarboxylic acids and non-aromatic hydroxylated polycarboxylic acids, more preferably from non-aromatic hydroxylated di- and tricarboxylic acids such as citric acid. In an embodiment, the composition further comprises a pharma- ceutically acceptable excipient (e.g., an isotonicity agent such as a sugar (e.g., dextrose, lactose, trehalose, sucrose), a sugar alcohol (e.g., mannitol), a salt (e.g., sodium chloride, potassium chloride), or a polyol (e.g., propylene glycol, glycerin)). In an embodiment, the isotonicity agent is a sugar. In an embodiment, the isotonicity agent is lactose. In an embodiment, the composition is a solution. In an embodiment, the composition is a powder. In certain embodiments, the composition is a powder obtained by lyophilization of an aqueous solution containing Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a polymorph thereof.

[0014] In another aspect, provided herein is a composition comprising Compound (I) for use in treating a disease (e.g., cystic fibrosis, fibrosis (e.g., pulmonary fibrosis)). In some embodiments, a composition comprising Compound (I) as described herein is formulated for inhalation (e.g., oral and / or nasal inhalation). In other embodiments, a composition comprising Compound (I) is formulated for administration via a nebulizer. In other embodiments, a composition comprising Compound (I) is formulated for administration via an inhaler (e.g., a dry powder inhaler). In some aspects, provided herein is a method of treating a fibrotic disease or condition, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising Compound (I) in a therapeutically effective amount.

[0015] Also provided herein is a compound of the formula: [ka] There are also polymorphs of Compound (I) represented by the formula: or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative. The polymorphic forms of Compound (I) include Freeform Type A, Freeform Type B, Freeform Type C, and Freeform Type D as described herein. Further provided herein are compositions comprising Compound (I) and its polymorphs for use in treating diseases (e.g., cystic fibrosis, fibrosis (e.g., pulmonary fibrosis)). In some embodiments, compositions comprising Compound (I) and its polymorphs as described herein are formulated for inhalation (e.g., oral inhalation and / or nasal inhalation). In other embodiments, compositions comprising Compound (I) and its polymorphs are formulated for administration via a nebulizer. In other embodiments, compositions comprising Compound (I) and its polymorphs are formulated for administration via an inhaler (e.g., a dry powder inhaler). In some aspects, provided herein are methods of treating fibrosis or a fibrotic condition, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a polymorph of Compound (I) or a pharmaceutical composition comprising Compound (I). In another aspect, provided herein are methods of treating cystic fibrosis, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a polymorph of Compound (I) or a pharmaceutical composition comprising Compound (I).

[0016] In certain embodiments, the free form Form D is characterized by at least one of the following: a. an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having three or more peaks selected from 4.07, 10.03, 12.01, 12.53, 14.68, 17.01, 17.27, 18.29, 18.91, 19.89, 20.33, 21.4, 21.62, 22.27, 22.85, 23.25, 24.41, 25.14, 25.65, 26.08, 26.63, 27.18, 28.53, 29.04, 30.45, 32.37, and 35.01 expressed in degrees 2 theta ±0.2°; and / or b. DSC thermogram showing an endotherm at approximately 106.7°C.

[0017] In certain embodiments, free form Form D is characterized by an X-ray powder diffraction (XRPD) pattern substantially identical to the XRPD pattern displayed in FIG.

[0018] In another aspect, provided herein is a pharmaceutical composition comprising a polymorph of Compound (I) (e.g., free form D). Also provided herein is a pharmaceutical composition comprising a polymorph of Compound (I) (e.g., free form D) and a pharmaceutically acceptable excipient (e.g., citric acid) and, optionally, a second pharmaceutically acceptable excipient (e.g., a tonicity agent (e.g., lactose)). Also provided herein is a pharmaceutical composition comprising a polymorph of Compound (I), or a solvate or pharmaceutically acceptable salt thereof (e.g., free form D); a first pharmaceutically acceptable excipient (e.g., citric acid); and a second pharmaceutically acceptable excipient (e.g., a tonicity agent (e.g., lactose)).

[0019] Also disclosed is a method of using a polymorph of Compound (I) or a composition as described herein for treating a disease, e.g., cystic fibrosis or fibrosis, e.g., pulmonary fibrosis, comprising administering to a subject in need thereof a therapeutically effective amount of a polymorph of Compound (I) or a pharmaceutical composition as described herein. In another aspect, the disclosure provides a polymorph of Compound (I), or a solvate or pharma- ceutically acceptable salt thereof, or a composition comprising a polymorph of Compound (I), for use in the manufacture of a medicament for the treatment of a furin-mediated or furin-associated disorder, such as fibrosis.

[0020] Details of certain aspects of the present disclosure are set forth in the Detailed Description of Certain Aspects, as set forth below. Other features, objects, and advantages of the present disclosure will be apparent from the Brief Description of the Drawings, Definitions, Examples, and Claims. [Brief description of the drawings]

[0021] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] Figure 1. XRPD overlay of Compound (I) free form polymorphs.

[0022] [Diagram 2] Figure 2. XRPD pattern of free form Form A.

[0023] [Diagram 3] Figure 3. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) curves of free form A.

[0024] [Figure 4] Figure 4. 1H NMR spectrum of free form A.

[0025] [Diagram 5] Figure 5. Dynamic water vapor sorption (DVS) plot of free form Form A.

[0026] [Figure 6]Figure 6. XRPD overlay of free form Form A before and after DVS testing.

[0027] [Figure 7] Figure 7. XRPD overlay of free form Form B before and after drying.

[0028] [Figure 8] Figure 8. TGA / DSC curve of free form B.

[0029] [Figure 9] Figure 9. 1H NMR spectrum of free form B.

[0030] [Figure 10] Figure 10. XRPD pattern of reconstituted free form Form B.

[0031] [Figure 11] Figure 11. TGA / DSC curve of reconstituted free form B.

[0032] [Figure 12] Figure 12. 1H NMR spectrum of reconstituted free form B.

[0033] [Figure 13] Figure 13. Variable temperature XRPD (VT-XRPD) results of reconstituted free form B.

[0034] [Figure 14] Figure 14. TGA / DSC curves of free form B after VT-XRPD study.

[0035] [Figure 15] Figure 15. DVS plot of reconstituted free form B.

[0036] [Figure 16] Figure 16. XRPD overlay of reconstituted free form B before and after DVS testing.

[0037] [Figure 17] Figure 17. XRPD overlay of free form Form C before and after drying.

[0038] [Figure 18] Figure 18. XRPD pattern of free form Form D.

[0039] [Figure 19] Figure 19. TGA / DSC curve of free form D.

[0040] [Figure 20] Figure 20. 1H NMR spectrum of free form D.

[0041] [Figure 21] Figure 21. DVS plot of free form Form D.

[0042] [Figure 22] Figure 22. XRPD overlay of free form Form D before and after drying.

[0043] [Diagram 23] Figure 23. XRPD overlay of humidity induced experiments on free form Form D.

[0044] [Figure 24] Figure 24. XRPD overlay of slurry competition between free forms A and B.

[0045] [Diagram 25] Figure 25. XRPD overlay of rerun slurry competition between free forms A and B.

[0046] [Figure 26] Figure 26. XRPD overlay of slurry competition between free forms B and D.

[0047] [Figure 27]Figure 27. XRPD overlay of slurry competition between free forms A and D (aw from 0.4 to 1.0).

[0048] [Figure 28] Figure 28. XRPD overlay of slurry competition between free forms A and D (aw from 0.3 to 0.5).

[0049] [Figure 29] Figure 29. Schematic representation of free form chemical species.

[0050] [Diagram 30] Figure 30. Schematic representation of free form chemical species.

[0051] [Diagram 31] Figure 31. Structures of chemical species in the free form.

[0052] [Diagram 32] Figure 32. Solubility curve of free form D in CD solution.

[0053] [Diagram 33] Figure 33. XRPD results of the solid obtained after equilibration in HPβCD solution.

[0054] [Diagram 34] Figure 34. XRPD results of the solid obtained after equilibration in SBECD solution.

[0055] [Diagram 35] Figure 35. XRPD pattern of HCl salt form F.

[0056] [Diagram 36] Figure 36. TGA / DSC curve of HCl salt form F.

[0057] [Figure 37] Figure 37. 1H NMR spectrum of HCl salt form F.

[0058] [Figure 38] Figure 38. DVS plot of HCl salt form F.

[0059] [Figure 39] Figure 39. XRPD overlay of HCl salt Form F before and after DVS.

[0060] [Diagram 40] Figure 40. XRPD pattern of sulfate form B.

[0061] [Diagram 41] Figure 41. TGA / DSC curve of sulfate form B.

[0062] [Diagram 42] Figure 42. 1H NMR spectrum of sulfate type B

[0063] [Diagram 43] Figure 43. DVS plot of sulfate form B.

[0064] [Diagram 44] Figure 44. XRPD overlay of sulfate form B before and after DVS.

[0065] [Diagram 45] Figure 45. XRPD pattern of fumarate salt form A.

[0066] [Figure 46] Figure 46. TGA / DSC curve of fumarate salt form A.

[0067] [Figure 47] Figure 47. 1H NMR spectrum of fumarate salt form A.

[0068] [Figure 48] Figure 48. DVS plot of fumarate form A.

[0069] [Figure 49]Figure 49. XRPD overlay of fumarate Form A before and after DVS.

[0070] [Figure 50] Figure 50. XRPD overlay of free form Form A before and after grinding.

[0071] [Figure 51] Figure 51. XRPD overlay of sulfate form B before and after grinding.

[0072] [Figure 52] Figure 52. XRPD overlay of fumarate Form A before and after grinding.

[0073] [Figure 53] Figure 53. XRPD overlay of HCl salt Form F before and after grinding.

[0074] [Figure 54] Figure 54. XRPD results of free form Form A after solubility assessment.

[0075] [Figure 55] Figure 55. XRPD results of sulfate form B after solubility evaluation (I / III).

[0076] [Figure 56] Figure 56. XRPD results of sulfate form B after solubility evaluation (II / III).

[0077] [Figure 57] Figure 57. XRPD results of sulfate form B after solubility evaluation (III / III).

[0078] [Figure 58] Figure 58. XRPD results of fumarate form A after solubility evaluation (I / II).

[0079] [Figure 59] Figure 59. XRPD results of fumarate form A after solubility evaluation (II / II).

[0080] [Figure 60] Figure 60. XRPD results of HCl salt form F after solubility evaluation (I / II).

[0081] [Figure 61] Figure 61. XRPD results of HCl salt form F after solubility evaluation (II / II).

[0082] [Figure 62] Figure 62. XRPD results of free form Form A after solubility assessment.

[0083] [Figure 63] Figure 63. XRPD results of sulfate form B after solubility evaluation.

[0084] [Figure 64] Figure 64. XRPD results of fumarate Form A after solubility evaluation.

[0085] [Figure 65] Figure 65. XRPD results of HCl salt Form F after solubility evaluation.

[0086] [Figure 66] Figure 66. Chromatogram overlay of in situ salt formation experiment.

[0087] [Figure 67] Figure 67. XRPD results of slurry experiments on amorphous samples.

[0088] [Figure 68] Figure 68. 1H NMR spectrum of free form D.

[0089] [Figure 69] Figure 69. 1H NMR spectrum of amorphous sample.

[0090] [Figure 70]Figure 70. 1H NMR spectrum of free form D mixed with citric acid.

[0091] [Figure 71] Figure 71. 1H NMR overlay of free form Form D and the amorphous sample.

[0092] [Figure 72] Figure 72. 1H NMR overlay of free form D+citric acid with an amorphous sample.

[0093] [Figure 73] Figure 73. XPS overlay of free form D and an amorphous sample.

[0094] [Figure 74] Figure 74. Solubility curve of free form Form D in citrate buffer.

[0095] [Figure 75] Figure 75. XRPD results of solids obtained in 10 mM citrate buffer.

[0096] [Figure 76] Figure 76. XRPD results of solids obtained in 20 mM citrate buffer.

[0097] [Figure 77] Figure 77. XRPD results of solids obtained in 50 mM citrate buffer.

[0098] [Figure 78] Figure 78. XRPD results of solids obtained in 100 mM citrate buffer.

[0099] [Figure 79] Figure 79. Visual findings of stability samples in citrate buffer.

[0100] [Figure 80]Figure 80. Chromatogram overlay of free form Form D after stability evaluation in 10 mM pH=4.3 citrate buffer (1 mg / mL).

[0101] [Figure 81] Figure 81. Chromatogram overlay of free form Form D after stability evaluation in 100 mM pH=4.1 citrate buffer (40 mg / mL).

[0102] [Figure 82] Figure 82. Impurity (RRT approximately 1.23) increase plot for Formulation 1.

[0103] [Figure 83] Figure 83. Impurity (RRT approximately 1.23) increase plot for formulation 2.

[0104] [Figure 84] Figure 84. Impurity (RRT approximately 1.23) increase plot for formulation 3.

[0105] [Figure 85] Figure 85. Impurity (RRT approximately 1.23) increase plot for formulation 4.

[0106] [Figure 86] Figure 86. Impurity (RRT approximately 1.23) increase plot for formulation 5.

[0107] [Figure 87] Figure 87. Chromatogram overlay of solution stability samples in Formulation 1 at 25°C.

[0108] [Figure 88] Figure 88. Chromatogram overlay of solution stability samples in Formulation 1 at 40°C.

[0109] [Figure 89] Figure 89. Chromatogram overlay of solution stability samples in Formulation 1 at 60 °C.

[0110] [Figure 90] Figure 90. Chromatogram overlay of solution stability samples in formulation 2 at 25°C.

[0111] [Figure 91] Figure 91. Chromatogram overlay of solution stability samples in formulation 2 at 40 °C.

[0112] [Figure 92] Figure 92. Chromatogram overlay of solution stability samples in formulation 2 at 60 °C.

[0113] [Figure 93] Figure 93. Chromatogram overlay of solution stability samples in formulation 3 at 25 °C.

[0114] [Figure 94] Figure 94. Chromatogram overlay of solution stability samples in formulation 3 at 40°C.

[0115] [Figure 95] Figure 95. Chromatogram overlay of solution stability samples in formulation 3 at 60 °C.

[0116] [Figure 96] Figure 96. Chromatogram overlay of solution stability samples in formulation 4 at 25°C.

[0117] [Figure 97] Figure 97. Chromatogram overlay of solution stability samples in formulation 4 at 40°C.

[0118] [Figure 98] Figure 98. Chromatogram overlay of solution stability samples in formulation 4 at 60°C.

[0119] [Figure 99]Figure 99. Chromatogram overlay of solution stability samples in formulation 5 at 25°C.

[0120] [Figure 100] Figure 10. Chromatogram overlay of solution stability samples in formulation 5 at 40°C.

[0121] [Figure 101] Figure 101. Chromatogram overlay of solution stability samples in formulation 5 at 60°C.

[0122] [Figure 102] Figure 10 XRPD results of solids obtained in formulations 1 / 2 / 3 / 4 / 5 after stability evaluation at 2.5°C.

[0123] [Figure 103] Figure 10 Chromatogram overlay of solution stability samples in Formulation 1 at 3.5°C.

[0124] [Figure 104] Figure 10 Chromatogram overlay of solution stability samples in formulation 2 at 4.5°C.

[0125] [Figure 105] Figure 10 Chromatogram overlay of solution stability samples in formulation 3 at 5.5°C.

[0126] [Figure 106] Figure 10 Chromatogram overlay of solution stability samples in formulation 4 at 6.5°C.

[0127] [Figure 107] Figure 10 Chromatogram overlay of solution stability samples in formulation 5 at 7.5°C.

[0128] [Figure 108] Figure 108. 1H NMR spectrum of the solid obtained in formulation 1 at 5 °C.

[0129] [Figure 109] Figure 109. 1H NMR spectrum of the solid obtained in formulation 2 at 5 °C.

[0130] [Figure 110] FIG. 11H NMR spectrum of the solid obtained in formulation 3 at 0.5° C.

[0131] [Figure 111] FIG. 11H NMR spectrum of the solid obtained in formulation 4 at 11.5° C.

[0132] [Figure 112] FIG. 11H NMR spectrum of the solid obtained in formulation 5 at 2.5° C.

[0133] [Figure 113] Figure 113. Chromatogram overlay of 40 mg / mL free form + citric acid + lactose formulation stability study.

[0134] [Fig. 114] Figure 114. XRPD results of free form Form D after stability evaluation at 25 °C / 60% RH.

[0135] [Figure 115] Figure 115. XRPD results of free form Form D after stability evaluation at 40 °C / 75% RH.

[0136] [Fig. 116] Figure 116. XRPD results of free form D after stability evaluation at 60 °C.

[0137] [Figure 117] Figure 117. Chromatogram overlay of free form Form D after stability evaluation at 25 °C / 60% RH.

[0138] [Fig. 118]Figure 118. Chromatogram overlay of free form Form D after stability evaluation at 40 °C / 75% RH.

[0139] [Figure 119] Figure 119. Chromatogram overlay of free form D after stability evaluation at 60 °C.

[0140] [Figure 120] Figure 120. XRPD pattern of compound (I) starting material.

[0141] [Figure 121] Figure 121. TGA / DSC curve of compound (I) starting material.

[0142] [Figure 122] Figure 122. LC-MS results for compound (I) starting material.

[0143] [Figure 123] Figure 123. PLM image of compound (I) starting material.

[0144] [Figure 124] Figure 124. 1H NMR spectrum of compound (I) starting material (MeOH-d3).

[0145] [Fig. 125] Figure 125. XRPD overlay of solids obtained during optimization of the free form isolation procedure.

[0146] [Fig. 126] Figure 126. XRPD overlay of solids obtained in step 3 during isolation of the free form on a 7 g scale.

[0147] [Figure 127] Figure 127. XRPD overlay of compound (I) starting material and free form Form D.

[0148] [Figure 128]Figure 128. TGA / DSC curve of compound (I) starting material.

[0149] [Figure 129] Figure 129. 1H NMR spectrum of compound (I) starting material.

[0150] [Fig. 130] Figure 130. PLM image of compound (I) starting material.

[0151] [Fig. 131] Figure 131. DVS plot of compound (I) starting material.

[0152] [Fig. 132] Figure 132. XRPD overlay of Compound (I) starting material before and after DVS testing.

[0153] [Fig. 133] Figure 133. TGA overlay of Compound (I) starting material before and after storage under ambient conditions.

[0154] [Fig. 134] Figure 134. XRPD overlay of the HCl salt form.

[0155] [Fig. 135] Figure 135. TGA / DSC curve of HCl salt form A.

[0156] [Fig. 136] Figure 136. 1H NMR spectrum of HCl salt form A.

[0157] [Fig. 137] Figure 137. TGA / DSC curve of HCl salt form D.

[0158] [Fig. 138] Figure 138. 1H NMR spectrum of HCl salt form D.

[0159] [Figure 139] Figure 139. TGA / DSC curve of HCl salt form E.

[0160] [Fig. 140] Figure 140. 1H NMR spectrum of HCl salt form E.

[0161] [Fig. 141] Figure 141. XRPD overlay of sulfate salt form.

[0162] [Fig. 142] Figure 142. 1H NMR spectrum of sulfate salt form A.

[0163] [Fig. 143] Figure 143. TGA / DSC curve of sulfate form B.

[0164] [Fig. 144] Figure 144. 1H NMR spectrum of sulfate salt form B.

[0165] [Fig. 145] Figure 145. XRPD overlay of the maleate salt form.

[0166] [Fig. 146] Figure 146. TGA / DSC curve of maleate form A.

[0167] [Fig. 147] Figure 147. 1H NMR spectrum of maleate salt form A.

[0168] [Fig. 148] Figure 148. TGA / DSC curve of maleate form B.

[0169] [Figure 149] Figure 149. 1H NMR spectrum of maleate salt form B.

[0170] [Fig. 150]Figure 150. XRPD pattern of tartrate salt form A.

[0171] [Fig. 151] Figure 151. TGA / DSC curve of tartrate salt form A.

[0172] [Fig. 152] Figure 152. 1H NMR spectrum of tartrate salt form A.

[0173] [Fig. 153] Figure 153. XRPD overlay of the fumarate salt form.

[0174] [Fig. 154] Figure 154. TGA / DSC curve of fumarate salt form A.

[0175] [Fig. 155] Figure 155. 1H NMR spectrum of fumarate salt form A.

[0176] [Fig. 156] Figure 156. TGA / DSC curve of fumarate salt form B.

[0177] [Fig. 157] Figure 157. 1H NMR spectrum of fumarate salt form B.

[0178] [Fig. 158] Figure 158. TGA / DSC curve of fumarate salt form C.

[0179] [Fig. 159] Figure 159. 1H NMR spectrum of fumarate salt form C.

[0180] [Fig. 160] Figure 160. XRPD overlay of the succinate salt form.

[0181] [Fig. 161] Figure 161. 1H NMR spectrum of succinate form A.

[0182] [Fig. 162] Figure 162. TGA / DSC curve of succinate salt form B.

[0183] [Fig. 163] Figure 163. 1H NMR spectrum of succinate form B.

[0184] [Fig. 164] Figure 164. TGA / DSC curve of succinate salt form C.

[0185] [Fig. 165] Figure 165. 1H NMR spectrum of succinate form C.

[0186] [Fig. 166] Figure 166. XRPD pattern of triphenylacetate form A.

[0187] [Fig. 167] Figure 167. TGA / DSC curve of triphenylacetate form A.

[0188] [Fig. 168] Figure 168. 1H NMR spectrum of triphenylacetate form A.

[0189] [Fig. 169] Figure 169. XRPD pattern of xinafoate salt form A.

[0190] [Fig. 170] Figure 170. TGA / DSC curve of xinafoate salt form A.

[0191] [Fig. 171] Figure 171. 1H NMR spectrum of xinafoate salt form A.

[0192] [Fig. 172] Figure 172. XRPD pattern of Ca2+ salt form A.

[0193] [Fig. 173] Figure 173. TGA / DSC curve of Ca2+ salt form A.

[0194] [Fig. 174] Figure 174. 1H NMR spectrum of Ca2+ salt form A.

[0195] [Fig. 175] Figure 175. XRPD pattern of the tromethamine salt form.

[0196] [Fig. 176] Figure 176. TGA / DSC curve of tromethamine salt form A.

[0197] [Fig. 177] Figure 177. 1H NMR spectrum of tromethamine salt form A.

[0198] [Fig. 178] Figure 178. TGA / DSC curve of tromethamine salt form B.

[0199] [Fig. 179] Figure 179. 1H NMR spectrum of tromethamine salt form B.

[0200] [Fig. 180] Figure 180. XRPD results of solids obtained in pH = 4.0 citrate / phosphate buffer.

[0201] [Fig. 181] Figure 181. XRPD results of solids obtained in pH = 5.0 citrate / phosphate buffer.

[0202] [Fig. 182] Figure 182. XRPD pattern of form X.

[0203] [Fig. 183] Figure 183. XRPD pattern of form Y.

[0204] [Fig. 184] Figure 184. XRPD pattern of free form Form B.

[0205] [Fig. 185] Figure 185. XRPD pattern of free form Form C.

[0206] [Fig. 186] Figure 186. XRPD pattern of free form Form D.

[0207] [Fig. 187] Figure 187. Single crystal structure of compound (I) trihydrate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0208] definition Terms are used within their ordinary and accepted meanings. The following definitions clarify, but are not intended to limit, the terms defined herein.

[0209] The term "about," as used herein, is used to describe ranges (e.g., of temperature, of molar concentrations, of mass, of weight) and is given its ordinary meaning in the art, typically referring to the error associated with the instrument collecting the measurement or reading. The term "about" can also refer to a 10-20% variation around a given value. In general, the term "about," when referring to temperature, provides for a deviation of ±0-2°C.

[0210] As used herein, the term "salt" refers to an acid or base salt of compound (I). Pharmaceutically acceptable salts can be derived from, for example, mineral acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acids (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.) and quaternary ammonium ions. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0211] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0212] The term "room temperature" or "RT" refers to a temperature in the range of 9 to 26°C.

[0213] The term "solvate" refers to a form of a compound associated with a solvent, usually through a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, dimethylsulfoxide (DMSO), tetrahydrofuran (THF), diethyl ether, and the like. The compounds described herein may be prepared, by way of example, in crystalline form and may be solvated. Suitable solvates include pharma- ceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In some instances, a solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates. In some aspects, the solvates are distinct polymorphs. In some aspects, the solvates are not distinct polymorphs. That is, a defined polymorph with a well-defined crystal structure may contain residual solvent molecules.

[0214] The term "amorphous" or "amorphous form" refers to a solid form ("solid form") that lacks substantial three-dimensional order. In some embodiments, a solid amorphous form is a solid form that is substantially non-crystalline. In some embodiments, the X-ray powder diffraction (XRPD) pattern of the amorphous form includes a broad scattering band with a peak, for example, at 2θ between 20° and 70°, inclusive, using CuKα radiation. In some embodiments, the XRPD pattern of the amorphous form further includes one or more peaks attributable to a crystalline structure. In some embodiments, the maximum intensity of any one of the one or more peaks attributable to a crystalline structure observed at 2θ between 20° and 70°, inclusive, is 300 times or less, 100 times or less, 30 times or less, 10 times or less, or 3 times or less than the maximum intensity of the broad scattering band. In some embodiments, the XRPD pattern of the amorphous form does not include a peak attributable to a crystalline structure.

[0215] The term "polymorph" or "polymorphic form" as used herein refers to a crystalline form of a compound (or its salts, hydrates, or solvates) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms often have different X-ray diffraction patterns, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors may also cause one crystalline form to dominate. Different polymorphs of a compound may be prepared by crystallization under different conditions.

[0216] A "free form" of Compound (I) (e.g., Free Form D) is a polymorphic form of the free base of Compound (I), or a solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof. The free forms of Compound (I) include Free Form A, Free Form B, Free Form C, and Free Form D.

[0217] The term "crystalline" refers to a solid phase in which the material has a regular, ordered internal structure at the molecular level and gives a unique X-ray diffraction pattern with defined peaks. Such materials will also exhibit the properties of a liquid when heated sufficiently, but the change from solid to liquid is characterized by a phase change, typically first order (melting point). The term "crystalline" or "crystalline form" refers to a solid form that exhibits substantial three-dimensional order. In some embodiments, a solid crystalline form is a solid form that is not substantially amorphous. In some embodiments, the X-ray powder diffraction (XRPD) pattern of a crystalline form includes one or more precisely defined peaks.

[0218] When polymorphic forms are described, it is intended to refer to the unidentified polymorph as described herein, which is substantially free of any other polymorph."Substantially free" of another polymorph refers to the molar ratio of two polymorphs being at least 70 / 30, more preferably 80 / 20, 90 / 10, 95 / 5, 99 / 1 or more.In some embodiments, one of the polymorphs will be present in an amount of at least 99%.

[0219] Polymorphs of Compound (I) may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of isotopes may be defined as ranging from the amount found in nature to the amount consisting of 100% of the atom in question. For example, a compound may contain more than 100% of the isotopes of tritium ( 3 H) or carbon 14 ( 14 Radioactive isotopes such as C, or deuterium ( 2 H) or carbon 13 ( 13 Compounds (I) may incorporate non-radioactive isotopes such as C). Such isotopic variations may also provide additional utility to those described elsewhere in this application. By way of illustration, isotopic variants of Compound (I) may find additional utility, including, but not limited to, utility as diagnostic and / or imaging reagents, or as cytotoxic / radiotoxic therapeutic agents. In addition, isotopic variants of Compound (I) may alter pharmacokinetic and pharmacodynamic characteristics that may contribute to enhanced safety, tolerability, or efficacy during treatment. All isotopic variations of Compound (I), whether radioactive or not, are intended to be encompassed within the scope of this disclosure. C 1 ~C 4 When specifically referred to, such as deuteroalkyl - this term refers to an alkyl group having the indicated number of carbon atoms and having hydrogen atoms replaced with deuterium from 1 to per-deutero form, where the replacement of deuterium is greater than the natural abundance of deuterium - typically 50%, 60%, 70%, 80%, 90%, 95% or more replacement of deuterium. 1 ~C 4 An example of a deuterated alkyl is -CD 3 , -CH 2 CD 3 , -CD 2 CD 3 , -CH 2 CH 2 CH 2 D etc.

[0220] As used herein, the term "pharmaceutically acceptable" refers to a material that is compatible with compound (I) and compatible with any other ingredients that are formulated with the compound. Furthermore, a pharmaceutically acceptable material is not toxic to the recipient of the material. The term "pharmaceutically acceptable salt" refers to those salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference).

[0221] Pharmaceutically acceptable salts of compound (I) include those derived from suitable inorganic and organic acids and bases. Examples of pharma-ceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art (such as ion exchange). Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Salts derived from appropriate bases include salts of lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include salts of alkali metal, alkaline earth metal, ammonium, and N + (C 1~4 Alkyl) 4 -Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma-ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0222] As used herein, the term "pharmaceutical composition" refers to a product that includes Compound (I), optionally an excipient and / or a second pharma- ceutically acceptable excipient (e.g., tonicity agent, organic acid), and any other ingredient in specified amounts, as well as any product that results directly or indirectly from the combination of the specified ingredients in specified amounts. In some embodiments, the pharmaceutical composition includes Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof. In some embodiments, the pharmaceutical composition includes a polymorph of Compound (I). In some embodiments, the pharmaceutical composition includes an amorphous form of Compound (I).

[0223] As used herein, the term "excipient" refers to a substance that aids in the administration of an active agent to a subject. Pharmaceutically acceptable excipients useful in the present disclosure include, but are not limited to, those described herein. Those skilled in the art will understand that other excipients may also be useful in the present disclosure.

[0224] As used herein, the term "isotonicity agent" refers to an agent that functions to make a solution similar to physiological fluids in terms of osmotic characteristics. Isotonicity agents include, but are not limited to, sugars (e.g., dextrose, lactose, trehalose, sucrose), sugar alcohols (e.g., mannitol), salts (e.g., sodium chloride, potassium chloride), and polyols (e.g., propylene glycol, glycerin).

[0225] The term "sugar" refers to a monosaccharide, disaccharide, or polysaccharide. Monosaccharides are the simplest carbohydrates in that they cannot be hydrolyzed into smaller carbohydrates. Most monosaccharides have the general formula C y H 2y O y (For example, 6 H 12 O 6 (a hexose, such as glucose), where y is an integer equal to or greater than 3. Certain polyhydric alcohols not represented by the general formula set forth above may also be considered monosaccharides. For example, deoxyribose can be represented by the formula C 5 H 10 O 4Monosaccharides, represented by the general formula (I), are monosaccharides. Monosaccharides are usually composed of 5 or 6 carbon atoms and are called pentoses and hexoses, respectively. If they contain an aldehyde, they are called aldoses; and if they contain a ketone, they are called ketoses. Monosaccharides are also called trioses, tetroses, and heptoses when they consist of 3, 4, or 7 carbon atoms in the aldose or ketose form, respectively. Glyceraldehyde and dihydroxyacetone are considered aldotriose and ketotriose sugars, respectively. Examples of aldotetrose sugars include erythrose and threose; and ketotetrose sugars include erythrulose. Aldopentose sugars include ribose, arabinose, xylose, and lyxose; and ketopentose sugars include ribulose, arabulose, xylulose, and lyxulose. Examples of aldohexose sugars include glucose (e.g., dextrose), mannose, galactose, allose, altrose, talose, gulose, and idose; and ketohexose sugars include fructose, psicose, sorbose, and tagatose. Ketoheptose sugars include sedoheptulose. With the exception of the first and last carbons, each carbon atom of a monosaccharide that bears a hydroxyl group (-OH) is asymmetric, making the carbon atom a stereogenic center, allowing two configurations (R or S). Because of this asymmetry, a number of isomers can exist for any given monosaccharide formula. The aldohexose D-glucose, for example, has the formula C 6 H 12 O 6 Of all six carbon atoms, two are stereogenic, and D-glucose has 16 (i.e., 2 4). The assignment of D or L is made according to the orientation of the asymmetric carbon furthest from the carbonyl group: if the hydroxyl group is to the right in the standard Fischer projection, the molecule is a D sugar, otherwise it is an L sugar. The aldehyde or ketone groups of linear monosaccharides will react reversibly with hydroxyl groups on different carbon atoms to form hemiacetals or hemiketals, forming heterocyclic rings with an oxygen bridge between the two carbon atoms. Rings with five and six atoms are called the furanose and pyranose forms, respectively, and exist in equilibrium with the linear form. During the conversion from the linear to the cyclic form, the carbon atom containing the carbonyl oxygen is called the anomeric carbon and becomes a stereogenic center with two possible configurations: the oxygen atom can be located either above or below the plane of the ring. The resulting possible pair of stereoisomers is called anomers. In the α anomer, the -OH substituent on the anomeric carbon is replaced by -CH 2 The OH side branch is on the opposite side (trans) of the ring. -CH 2 The alternative form in which the OH substituent and the anomeric hydroxyl are on the same side of the ring plane (cis) is called the β anomer. Carbohydrates that include two or more monosaccharide units linked together are called disaccharides or polysaccharides (e.g., trisaccharides), respectively. Two or more monosaccharide units are linked together by a covalent bond known as a glycosidic linkage, which is formed via a dehydration reaction that results in the loss of a hydrogen atom from one monosaccharide and a hydroxyl group from another monosaccharide. Exemplary disaccharides include sucrose, lactulose, lactose, maltose, isomaltose, trehalose, cellobiose, xylobiose, laminaribiose, gentiobiose, mannobiose, melibiose, nigerose, or rutinose. Exemplary trisaccharides include, but are not limited to, isomaltotriose, nigerotriose, maltotriose, melezitose, maltotriulose, raffinose, and kestose. The term carbohydrate also includes other natural or synthetic stereoisomers of the carbohydrates described herein.

[0226] The term "carbohydrate" or "saccharide" refers to aldehyde or ketone derivatives of polyhydric alcohols. Carbohydrates include relatively small molecular compounds (e.g., sugars) as well as macromolecular or polymeric substances (e.g., the polysaccharides starch, glycogen, and cellulose).

[0227] In some embodiments, treatment may be administered after one or more signs or symptoms of disease have developed or been observed. As used herein, the terms "treat", "treating" and "treatment" refer to any evidence of successful treatment or recovery of a pathological condition, injury, disease or symptom related to lung injury, including any objective or subjective parameter, such as abatement; remission; relief of symptoms; making a pathological condition, injury, disease or symptom more tolerable to a patient; reducing the frequency or duration of a pathological condition, injury, disease or symptom; or in some circumstances, preventing the onset of a pathological condition, injury, disease or symptom. Treatment or recovery may be based on any objective or subjective parameter; examples include the results of a physical examination.

[0228] A "subject" to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., a pediatric subject (e.g., an infant, child, or adolescent), or an adult subject (e.g., a young adult, middle-aged adult, or elderly adult)), or a non-human animal. A "patient" refers to a human subject in need of treatment for a disease.

[0229] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing into or onto a subject a polymorphic form of Compound (I) described herein, or a composition thereof.

[0230] The terms "disease," "disease," and "disorder" are used interchangeably.

[0231] An "effective amount" of a polymorphic form described herein refers to an amount sufficient to elicit a desired biological response, i.e., to treat a disease. As will be appreciated by those skilled in the art, an effective amount of a polymorphic form of Compound (I) described herein may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the polymorphic form, the disease being treated, the mode of administration, and the age and health of the subject. In some embodiments, an effective amount is a therapeutically effective amount. In some embodiments, an effective amount is the amount of a polymorphic form of Compound (I) described herein in a single dose. In some embodiments, an effective amount is the combined amount of a polymorphic form of Compound (I) described herein in multiple doses.

[0232] A "therapeutically effective amount" of a polymorphic form of Compound (I) described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a disease or to delay or minimize one or more symptoms associated with a disease. A therapeutically effective amount of a polymorphic form refers to an amount of a therapeutic agent alone or in combination with other treatments that provides a therapeutic benefit in the treatment of a disease. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids symptoms, signs, or causes of a disease, and / or enhances the efficacy of the treatment of another therapeutic agent.

[0233] The terms "prevent", "preventing", or "prevention" refer to prophylactic treatment of a subject who is free of a disease and / or who has not been afflicted but is at risk of developing a disease or at risk of developing a disease. In some embodiments, the subject is at higher risk of developing a disease or at higher risk of developing a disease than the average healthy member of the population.

[0234] The terms "inhibition," "inhibiting," "inhibit," or "inhibitor" refer to the ability of a compound to reduce, slow, stop, or prevent the activity of a specific biological process in a subject (e.g., furin activity, viral infectivity, viral replication, toxin activation and / or activity) relative to a vehicle.

[0235] Detailed Description Provided herein is a compound of the formula: [ka] A pharmaceutical composition comprising compound (I) represented by the formula: or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a polymorph thereof. In some embodiments, the composition comprises compound (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises compound (I), wherein at least a portion of compound (I) is in the form of a fumarate salt. In some embodiments, the composition further comprises a pharma- ceutically acceptable excipient (e.g., a buffer (e.g., an organic acid (e.g., citric acid)). In some embodiments, the composition further comprises a second pharma- cetically acceptable excipient (e.g., an isotonicity agent (e.g., a sugar (e.g., dextrose, lactose, trehalose, sucrose), a sugar alcohol (e.g., mannitol), a salt (e.g., sodium chloride, potassium chloride), and a polyol (e.g., propylene glycol, glycerin)).

[0236] In another aspect, provided herein is a composition comprising Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a polymorph thereof, for use in the treatment of a disease (e.g., cystic fibrosis, fibrosis (e.g., pulmonary fibrosis)). In some embodiments, a composition comprising Compound (I) as described herein is formulated for inhalation (e.g., oral and / or nasal inhalation). In other embodiments, a composition comprising Compound (I), or a pharma-ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a polymorph thereof, is formulated for administration via a nebulizer. In other embodiments, a composition comprising Compound (I), or a pharma-ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a polymorph thereof, is formulated for administration via an inhaler (e.g., a dry powder inhaler). In some aspects, provided herein are methods of treating fibrosis or a fibrotic condition, the methods comprising administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of Compound (I). In another aspect, provided herein are methods of treating cystic fibrosis, the methods comprising administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of Compound (I).

[0237] Also provided herein is a compound having the formula: [ka] or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof. In certain embodiments, compositions comprising Compound (I) as described herein include a polymorph of Compound (I). Polymorphic forms of Compound (I) include Free Form A, Free Form B, Free Form C, Free Form D, HCl Salt Form A, HCl Salt Form B, HCl Salt Form C, HCl Salt Form D, HCl Salt Form E, HCl Salt Form F, Sulfate Form A, Sulfate Form B, Maleate Form A, Maleate Form B, Tartrate Form A, Fumarate Form A, Fumarate Form B, Fumarate Form C, Fumarate Form D, Succinate Form A, Succinate Form B, Succinate Form C, Triphenylacetate Form A, Xinafoate Form A, Ca Salt Form A, Tromethamine Salt Form A, and Tromethamine Salt Form B, as detailed herein.

[0238] The compositions and polymorphs of Compound (I) can be prepared by the methods described in the Examples. Those skilled in the art will understand that the compositions, compounds, and polymorphs thereof of the present disclosure can be prepared using other synthetic methods as an alternative to the transformations provided in the Examples.

[0239] Free form type A The present disclosure provides a polymorph of Compound (I) characterized as free form Form A. In certain embodiments, free form Form A is characterized by at least one of the following: a. an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having three or more peaks selected from 3.96, 7.9, 11.85, 15.83, 16.26, 17.78, 19.82, 20.66, 22.76, 23.83, 24.86, 25.71, 26.83, 27.87, 28.65, 29.36, 30.06, 31.95, 33.92, and 36.07 expressed in degrees 2 theta ±0.2°; and / or b. DSC thermogram showing an endotherm at approximately 110.3°C.

[0240] In certain embodiments, free form Form A is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, having each of the peaks selected from 3.96, 7.9, 11.85, 15.83, 16.26, 17.78, 19.82, 20.66, 22.76, 23.83, 24.86, 25.71, 26.83, 27.87, 28.65, 29.36, 30.06, 31.95, 33.92, and 36.07, expressed in degrees 2-theta ±0.2°. In certain embodiments, free form Form A is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, having each of the peaks selected from 3.96, 7.9, 11.85, 15.83, 16.26, 17.78, 19.82, 20.66, 22.76, 23.83, 24.86, 25.71, 26.83, 27.87, 30.06, 31.95, 33.92, and 36.07, expressed in degrees 2-theta ±0.2°. In certain embodiments, free form Form A is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having each of the peaks selected from 3.96, 7.9, 11.85, 15.83, 16.26, 19.82, 23.83, 26.83, 31.95, and 36.07, expressed in degrees 2-theta ±0.2°. In certain embodiments, free form Form A is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having each of the peaks selected from 3.96, 7.9, 11.85, 15.83, 16.26, 19.82, 23.83, and 31.95, expressed in degrees 2-theta ±0.2°. In certain embodiments, free form Form A is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, having each of the peaks selected from 3.96, 7.9, 11.85, 15.83, and 19.82, expressed in degrees 2-theta ±0.2°.

[0241] In certain embodiments, free form Form A has an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, having at least three peaks selected from 3.96, 7.9, 11.85, 15.83, 16.26, 17.78, 19.82, 20.66, 22.76, 23.83, 24.86, 25.71, 26.83, 27.87, 28.65, 29.36, 30.06, 31.95, 33.92, and 36.07, expressed in degrees 2-theta ±0.2°. In certain embodiments, free form Form A has an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, having at least three peaks selected from 3.96, 7.9, 11.85, 15.83, 16.26, 17.78, 19.82, 20.66, 22.76, 23.83, 24.86, 25.71, 26.83, 27.87, 30.06, 31.95, 33.92, and 36.07, expressed in degrees 2-theta ±0.2°. In certain embodiments, free form Form A has an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα with at least three peaks selected from 3.96, 7.9, 11.85, 15.83, 16.26, 19.82, 23.83, 26.83, 31.95, and 36.07, expressed in degrees 2-theta ±0.2°. In certain embodiments, free form Form A has an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα with at least three peaks selected from 3.96, 7.9, 11.85, 15.83, 16.26, 19.82, 23.83, and 31.95, expressed in degrees 2-theta ±0.2°. In certain embodiments, free form Form A has an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, having at least three peaks selected from 3.96, 7.9, 11.85, 15.83, and 19.82, expressed in degrees 2-theta ±0.2°.In certain embodiments, free form Form A is characterized by 4 or more peaks, 5 or more peaks, 6 or more peaks, 7 or more peaks, 8 or more peaks, 16 or more peaks, or 20 or more peaks, expressed in degrees 2-theta ±0.2°, selected from 3.96, 7.9, 11.85, 15.83, 16.26, 17.78, 19.82, 20.66, 22.76, 23.83, 24.86, 25.71, 26.83, 27.87, 28.65, 29.36, 30.06, 31.95, 33.92, and 36.07.

[0242] In certain embodiments, free form Form A is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks represented by 2 theta degrees ±0.05° at each of 12.0-15.0, 18.0-19.5, and 34.0-36.0. In certain embodiments, free form Form A is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks represented by 2 theta degrees ±0.05° at each of 12.0-15.0 and 18.0-19.5. In certain embodiments, free form Form A is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks represented by 2 theta degrees ±0.05° at each of 12.0-15.0 and 18.0-19.5. In certain embodiments, free form Form A is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, lacking a peak represented in degrees 2 theta ±0.05° between 8.0 and 19.5. In certain embodiments, free form Form A is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, lacking a peak represented in degrees 2 theta ±0.05° between 34.0 and 36.0.

[0243] In certain embodiments, free form Form A is characterized by an X-ray powder diffraction pattern substantially identical to the XRPD pattern shown in FIG.

[0244] In some aspects, Free Form A is characterized by a DSC thermogram essentially the same as that shown in Figure 3. In some aspects, Free Form A is characterized by a DSC thermogram exhibiting an endotherm at about 105°C to about 115°C. In some aspects, Free Form A is characterized by a DSC thermogram exhibiting an endotherm at about 110.3°C.

[0245] In certain aspects of the disclosure, Free Form A is substantially free of other forms (e.g., other polymorphs, amorphous forms) of Compound (I). In certain embodiments, Free Form A is substantially free of Free Form B. In certain embodiments, Free Form A is substantially free of Free Form C. In certain embodiments, Free Form A is substantially free of Free Form D. In certain embodiments, Free Form A is substantially free of Free Form B and Free Form C. In certain embodiments, Free Form A is substantially free of Free Form B and Free Form D. In certain embodiments, Free Form A is substantially free of Free Form B, Free Form C, and Free Form D. In certain embodiments, Free Form A is substantially free of amorphous forms of Compound (I).

[0246] Free form type B The present disclosure provides a polymorph of Compound (I) characterized as free form Form B. In certain embodiments, free form Form B is characterized by at least one of the following: a. an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having three or more peaks selected from 5.21, 5.77, 8.26, 9.37, 11.6, 12.96, 15.65, 16.61, 17.23, 18.51, 19.65, 20.8, 22.03, 23.2, 24.24, 24.63, 25.15, 26.26, 28.37, 29.74, and 34.85, expressed in degrees 2 theta ±0.2°; and / or b. DSC thermogram showing an endotherm at approximately 190.6 °C.

[0247] In certain embodiments, free form Form B is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, having each of the peaks selected from 5.21, 5.77, 8.26, 9.37, 11.6, 12.96, 15.65, 16.61, 17.23, 18.51, 19.65, 20.8, 22.03, 23.2, 24.24, 24.63, 25.15, 26.26, 28.37, 29.74, and 34.85, expressed in degrees 2-theta ±0.2°. In certain embodiments, the free form Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having each of the peaks selected from 5.21, 5.77, 8.26, 9.37, 11.6, 12.96, 15.65, 16.61, 17.23, 18.51, 19.65, 20.8, 22.03, 23.2, 24.24, 24.63, and 26.26, expressed in degrees 2-theta ±0.2°. In certain embodiments, the free form Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having each of the peaks selected from 5.21, 8.26, 11.6, 12.96, 16.61, 17.23, 19.65, 20.8, and 22.03, expressed in degrees 2-theta ±0.2°. In certain embodiments, free form Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having each of the peaks selected from 8.26, 16.61, 17.23, and 22.03 expressed in degrees 2-theta ±0.2°. In certain embodiments, free form Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having each of the peaks selected from 17.23 and 22.03 expressed in degrees 2-theta ±0.2°.

[0248] In certain embodiments, free form Form B has an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, having at least three peaks selected from 5.21, 5.77, 8.26, 9.37, 11.6, 12.96, 15.65, 16.61, 17.23, 18.51, 19.65, 20.8, 22.03, 23.2, 24.24, 24.63, 25.15, 26.26, 28.37, 29.74, and 34.85, expressed in degrees 2-theta ±0.2°. In some embodiments, the free form Form B has an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα with at least three peaks selected from 5.21, 5.77, 8.26, 9.37, 11.6, 12.96, 15.65, 16.61, 17.23, 18.51, 19.65, 20.8, 22.03, 23.2, 24.24, 24.63, and 26.26, expressed in degrees 2 theta ±0.2°. In some embodiments, the free form Form B has an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα with at least three peaks selected from 5.21, 8.26, 11.6, 12.96, 16.61, 17.23, 19.65, 20.8, and 22.03, expressed in degrees 2 theta ±0.2°. In certain embodiments, free form Form B has an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα with at least three peaks selected from 8.26, 16.61, 17.23, and 22.03, expressed in degrees 2 theta ±0.2°. In certain embodiments, free form Form D is characterized by 4 or more peaks, 5 or more peaks, 6 or more peaks, 7 or more peaks, 8 or more peaks, 16 or more peaks, or 20 or more peaks, expressed in degrees 2 theta ±0.2°, selected from 5.21, 5.77, 8.26, 9.37, 11.6, 12.96, 15.65, 16.61, 17.23, 18.51, 19.65, 20.8, 22.03, 23.2, 24.24, 24.63, 25.15, 26.26, 28.37, 29.74, and 34.85.

[0249] In an embodiment, the free form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks represented by 2 theta degrees ±0.05° at each of 0.0-5.0, 20.0-20.5, and 30.0-34.0. In an embodiment, the free form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks represented by 2 theta degrees ±0.05° at each of 0.0-5.0 and 30.0-34.0. In an embodiment, the free form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks represented by 2 theta degrees ±0.05° at 0.0-5.0. In an embodiment, the free form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks represented by 2 theta degrees ±0.05° at 20.0-20.5. In certain embodiments, free form Form B is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, lacking a peak between 30.0 and 34.0 expressed in degrees 2-theta ±0.05°.

[0250] In certain embodiments, free form Form B is characterized by an X-ray powder diffraction pattern substantially identical to the XRPD pattern displayed in FIG.

[0251] In some aspects, Free Form B is characterized by a DSC thermogram essentially the same as that shown in Figure 8. In some aspects, Free Form B is characterized by a DSC thermogram essentially the same as that shown in Figure 11. In some aspects, Free Form B is characterized by a DSC thermogram exhibiting an endotherm at about 185°C to about 195°C. In some aspects, Free Form B is characterized by a DSC thermogram exhibiting an endotherm at about 190.6°C.

[0252] In certain aspects of the disclosure, Free Form B is substantially free of other forms (e.g., other polymorphs, amorphous forms) of Compound (I). In certain embodiments, Free Form B is substantially free of Free Form A. In certain embodiments, Free Form B is substantially free of Free Form C. In certain embodiments, Free Form B is substantially free of Free Form D. In certain embodiments, Free Form B is substantially free of Free Form A and Free Form C. In certain embodiments, Free Form B is substantially free of Free Form A and Free Form D. In certain embodiments, Free Form D is substantially free of Free Form A, Free Form C, and Free Form D. In certain embodiments, Free Form B is substantially free of amorphous forms of Compound (I).

[0253] Free form type C The present disclosure provides a polymorph of Compound (I) characterized as free form Form C. In certain embodiments, free form Form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having three or more peaks selected from 3.9, 12.18, 13.27, 16.16, 17.35, 18.76, 19.37, 19.84, 20.41, 20.74, 21.91, 24.12, 26.07, 27.12, 28.67, 30.45, 31.9, 33.86, and 35.05, expressed in degrees 2-theta ±0.2°.

[0254] In certain embodiments, free form Form C is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, having each of the peaks selected from 3.9, 12.18, 13.27, 16.16, 17.35, 18.76, 19.37, 19.84, 20.41, 20.74, 21.91, 24.12, 26.07, 27.12, 28.67, 30.45, 31.9, 33.86, and 35.05, expressed in degrees 2-theta ±0.2°. In certain embodiments, the free form Form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having each of the peaks selected from 13.27, 16.16, 17.35, 28.67, 30.45, 31.9, 33.86, and 35.05, expressed in degrees 2 theta ±0.2°. In certain embodiments, the free form Form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having each of the peaks selected from 12.18, 18.76, 19.37, 19.84, 21.91, 24.12, 26.07, and 27.12, expressed in degrees 2 theta ±0.2°. In certain embodiments, free form Form C is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, having each of the peaks selected from 3.9, 20.41, and 20.74, expressed in degrees 2-theta ±0.2°.

[0255] In some embodiments, the free form Form C has an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα with at least three peaks selected from 3.9, 12.18, 13.27, 16.16, 17.35, 18.76, 19.37, 19.84, 20.41, 20.74, 21.91, 24.12, 26.07, 27.12, 28.67, 30.45, 31.9, 33.86, and 35.05, expressed in degrees 2-theta ±0.2°. In some embodiments, the free form Form C has an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα with at least three peaks selected from 13.27, 16.16, 17.35, 28.67, 30.45, 31.9, 33.86, and 35.05, expressed in degrees 2-theta ±0.2°. In certain embodiments, free form Form C has an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, having at least three peaks selected from 12.18, 18.76, 19.37, 19.84, 21.91, 24.12, 26.07, and 27.12, expressed in degrees 2-theta ±0.2°. In certain embodiments, free form Form C is characterized by 4 or more peaks, 8 or more peaks, 16 or more peaks, or 20 or more peaks, expressed in degrees 2-theta ±0.2°, selected from 3.9, 12.18, 13.27, 16.16, 17.35, 18.76, 19.37, 19.84, 20.41, 20.74, 21.91, 24.12, 26.07, 27.12, 28.67, 30.45, 31.9, 33.86, and 35.05.

[0256] In certain embodiments, the free form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks represented by 2 theta degrees ±0.05° at each of 4.0-11.0, 22.0-24.0, and 30.0-34.0. In certain embodiments, the free form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks represented by 2 theta degrees ±0.05° at each of 4.0-11.0 and 30.0-34.0. In certain embodiments, the free form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks represented by 2 theta degrees ±0.05° at each of 4.0-11.0 and 30.0-34.0. In certain embodiments, free form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking a peak represented in degrees 2 theta ±0.05° between 22.0 and 24.0. In certain embodiments, free form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking a peak represented in degrees 2 theta ±0.05° between 30.0 and 34.0.

[0257] In certain embodiments, free form Form C is characterized by an X-ray powder diffraction pattern substantially identical to the XRPD pattern displayed in FIG.

[0258] In certain aspects of the disclosure, free form C is substantially free of other forms of Compound (I) (e.g., other polymorphs, amorphous forms). In certain embodiments, free form C is substantially free of free form A. In certain embodiments, free form C is substantially free of free form B. In certain embodiments, free form C is substantially free of free form D. In certain embodiments, free form C is substantially free of free form A and free form B. In certain embodiments, free form C is substantially free of free form A and free form D. In certain embodiments, free form C is substantially free of free form B and free form D. In certain embodiments, free form C is substantially free of free form A, free form B, and free form D. In certain embodiments, free form C is substantially free of amorphous forms of Compound (I).

[0259] Free form type D The present disclosure provides a polymorph of Compound (I) characterized as free form Form D. In certain embodiments, free form Form D is characterized by at least one of the following: a. an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having three or more peaks selected from 4.07, 10.03, 12.01, 12.53, 14.68, 17.01, 17.27, 18.29, 18.91, 19.89, 20.33, 21.4, 21.62, 22.27, 22.85, 23.25, 24.41, 25.14, 25.65, 26.08, 26.63, 27.18, 28.53, 29.04, 30.45, 32.37, and 35.01, expressed in degrees 2 theta ±0.2°; and / or b. DSC thermogram showing an endotherm at approximately 106.7°C.

[0260] In certain embodiments, the free form Form D is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, having each of the peaks selected from 4.07, 10.03, 12.01, 12.53, 14.68, 17.01, 17.27, 18.29, 18.91, 19.89, 20.33, 21.4, 21.62, 22.27, 22.85, 23.25, 24.41, 25.14, 25.65, 26.08, 26.63, 27.18, 28.53, 29.04, 30.45, 32.37, and 35.01, expressed in degrees 2-theta ±0.2°. In certain embodiments, free form Form D is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, having each of the peaks selected from 4.07, 10.03, 12.01, 12.53, 14.68, 17.01, 17.27, 18.29, 18.91, 19.89, 20.33, 21.4, 21.62, 22.27, 22.85, 23.25, 24.41, 25.14, 26.63, 27.18, 28.53, and 30.45, expressed in degrees 2-theta ±0.2°. In certain embodiments, the free form Form D is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having each of the peaks selected from 4.07, 17.27, 21.4, 21.62, 24.41, 25.14, and 28.53, expressed in degrees 2-theta ±0.2°. In certain embodiments, the free form Form D is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having each of the peaks selected from 4.07, 21.62, and 24.41, expressed in degrees 2-theta ±0.2°.

[0261] In certain embodiments, the free form Form D has an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, having at least three peaks selected from 4.07, 10.03, 12.01, 12.53, 14.68, 17.01, 17.27, 18.29, 18.91, 19.89, 20.33, 21.4, 21.62, 22.27, 22.85, 23.25, 24.41, 25.14, 25.65, 26.08, 26.63, 27.18, 28.53, 29.04, 30.45, 32.37, 35.01, expressed in degrees 2-theta ±0.2°. In certain embodiments, the free form Form D has an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, having at least three peaks selected from 4.07, 10.03, 12.01, 12.53, 14.68, 17.01, 17.27, 18.29, 18.91, 19.89, 20.33, 21.4, 21.62, 22.27, 22.85, 23.25, 24.41, 25.14, 26.63, 27.18, 28.53, and 30.45, expressed in degrees 2-theta ±0.2°. In certain embodiments, the free form Form D has an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα with at least three peaks selected from 4.07, 17.27, 21.4, 21.62, 24.41, 25.14, and 28.53, expressed in degrees 2-theta ±0.2°. In certain embodiments, the free form Form D has an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα with at least three peaks selected from 4.07, 17.27, 21.4, 21.62, 24.41, 25.14, and 28.53, expressed in degrees 2-theta ±0.2°. In certain embodiments, free form Form D is characterized by 4 or more peaks, 8 or more peaks, 16 or more peaks, or 20 or more peaks selected from 4.07, 10.03, 12.01, 12.53, 14.68, 17.01, 17.27, 18.29, 18.91, 19.89, 20.33, 21.4, 21.62, 22.27, 22.85, 23.25, 24.41, 25.14, 25.65, 26.08, 26.63, 27.18, 28.53, 29.04, 30.45, 32.37, 35.01, expressed in degrees 2-theta ±0.2°.

[0262] In an embodiment, the free form Form D is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks represented by 2 theta degrees ±0.05° at each of 4.50 to 9.50, 12.1 to 12.3, and 20.40 to 20.60. In an embodiment, the free form Form D is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks represented by 2 theta degrees ±0.05° at each of 12.1 to 12.3, and 20.40 to 20.60. In an embodiment, the free form Form D is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks represented by 2 theta degrees ±0.05° at each of 4.50 to 9.50. In certain embodiments, the free form Form D is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking a peak represented in degrees 2 theta ±0.05° at 12.1 to 12.3. In certain embodiments, the free form Form D is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking a peak represented in degrees 2 theta ±0.05° at 20.40 to 20.60.

[0263] In certain embodiments, free form Form D is characterized by an X-ray powder diffraction pattern substantially identical to the XRPD pattern displayed in FIG.

[0264] In some aspects, Free Form D is characterized by a DSC thermogram essentially the same as that shown in Figure 19. In some aspects, Free Form D is characterized by a DSC thermogram exhibiting an endotherm at about 95°C to about 115°C. In some aspects, Free Form D is characterized by a DSC thermogram exhibiting an endotherm at about 100°C to about 110°C. In some aspects, Free Form D is characterized by a DSC thermogram exhibiting an endotherm at about 106.7°C. In some aspects, Free Form D is characterized by a melting point of 106.7°C ± 2°C.

[0265] In certain embodiments, the free form Form D is characterized by at least one of the following: a. An X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having three or more peaks selected from 4.07, 17.27, 21.4, 21.62, 24.41, 25.14, and 28.53 expressed in degrees theta ±0.2°; and / or b. DSC thermogram showing an endotherm at approximately 106.7°C.

[0266] In certain embodiments, the free form Form D is characterized by at least one of the following: a. An X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having three or more peaks selected from 4.07, 21.62, and 24.41 expressed in degrees theta ±0.2°; and / or b. DSC thermogram showing an endotherm at approximately 106.7°C.

[0267] In certain aspects, the free form D is characterized by the single crystal structure shown in Figure 187. In some aspects, the free form D has a monoclinic crystal system and a P2 1 In one aspect, the free form Form D has unit cell dimensions of a=21.65166(12) Å, b=14.93710(10) Å, c=10.35008(6) Å, α=90°, β=90.5133(5)°, γ=90°, and V=3347.22(3) Å3.

[0268] In certain aspects of the disclosure, Free Form D is substantially free of other forms of Compound (I). In certain embodiments, Free Form D is substantially free of Free Form A. In certain embodiments, Free Form D is substantially free of Free Form B. In certain embodiments, Free Form D is substantially free of Free Form C. In certain embodiments, Free Form D is substantially free of Free Form A and Free Form B. In certain embodiments, Free Form D is substantially free of Free Form A and Free Form C. In certain embodiments, Free Form D is substantially free of Free Form B and Free Form C. In certain embodiments, Free Form D is substantially free of Free Form A, Free Form B, and Free Form C.

[0269] Fumarate type A The present disclosure provides a polymorph of Compound (I) characterized as Fumarate Form A. In certain embodiments, Fumarate Form A is characterized by at least one of the following: a. An X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having three or more peaks selected from 11.67, 17.67, 19.18, 22.45, 23.26, and 27.14 expressed in degrees theta ±0.2°; and / or b. DSC thermogram showing an endotherm at approximately 158.9 °C.

[0270] In some embodiments, fumarate Form A is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having each of the peaks selected from 11.67, 17.67, 19.18, 22.45, 23.26, and 27.14, expressed in degrees 2-theta ±0.2°. In some embodiments, fumarate Form A is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having each of the peaks selected from 17.67, 19.18, 22.45, and 23.26, expressed in degrees 2-theta ±0.2°.

[0271] In some embodiments, fumarate Form A has an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα with at least three peaks selected from 11.67, 17.67, 19.18, 22.45, 23.26, and 27.14, expressed in degrees 2-theta ±0.2°. In some embodiments, fumarate Form A has an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα with at least three peaks selected from 17.67, 19.18, 22.45, and 23.26, expressed in degrees 2-theta ±0.2°.

[0272] In an embodiment, fumarate Form A is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks represented by 2 theta degrees ±0.05° at each of 0 to 11.50, 18.0 to 19.0, and 28.0 to 35.0. In an embodiment, fumarate Form A is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks represented by 2 theta degrees ±0.05° at each of 0 to 11.50 and 18.0 to 19.0. In an embodiment, fumarate Form A is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks represented by 2 theta degrees ±0.05° at each of 0 to 11.50. In one embodiment, fumarate Form A is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, lacking a peak represented in degrees 2-theta ±0.05° from 18.0 to 19.0. In one embodiment, fumarate Form A is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, lacking a peak represented in degrees 2-theta ±0.05° from 0 to 28.0 to 35.0.

[0273] In certain embodiments, the fumarate salt Form A is characterized by an X-ray powder diffraction pattern substantially identical to the XRPD pattern displayed in FIG.

[0274] In some aspects, Free Form D is characterized by a DSC thermogram essentially the same as that shown in Figure 154. In some aspects, Free Form D is characterized by a DSC thermogram exhibiting an endotherm at about 150°C to about 170°C. In some aspects, Free Form D is characterized by a DSC thermogram exhibiting an endotherm at about 155°C to about 165°C. In some aspects, Free Form D is characterized by a DSC thermogram exhibiting an endotherm at about 158.9°C.

[0275] In certain aspects of the disclosure, Fumarate Form A is substantially free of other forms of Compound (I). In certain embodiments, Fumarate Form A is substantially free of Fumarate Form B. In certain embodiments, Fumarate Form A is substantially free of Fumarate Form C. In certain embodiments, Fumarate Form A is substantially free of Fumarate Form D. In certain embodiments, Fumarate Form A is substantially free of Fumarate Form B, Fumarate Form C, and Fumarate Form D.

[0276] Pharmaceutical Compositions, Kits, Uses, and Administration Provided herein are pharmaceutical compositions (also referred to as pharmaceutical formulations) comprising Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a polymorph thereof.

[0277] In some aspects, the pharmaceutical composition as described herein comprises Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a polymorph thereof, and a pharma- ceutically acceptable excipient. In some aspects, the pharmaceutical composition as described herein comprises a polymorph of Compound (I), or a pharma- ceutically acceptable salt, polymorph, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and one or more pharma- ceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises Compound (I), or a pharma- ceutically acceptable salt, polymorph, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, a first excipient, and a second excipient.

[0278] In some embodiments, the excipient is a buffer (e.g., an organic acid (e.g., citric acid)). In some embodiments, the excipient is an organic acid (e.g., citric acid). In some embodiments, in some aspects, the pharmaceutical composition as described herein comprises Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a polymorph thereof, and an organic acid. In some embodiments, the excipient is an organic acid selected from vitamin C, citric acid, fumaric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. In some embodiments, the excipient is citric acid.

[0279] In certain embodiments, in some aspects, the pharmaceutical compositions as described herein comprise Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a polymorph thereof, an organic acid, and a pharma- ceutically acceptable excipient.

[0280] In some embodiments, the excipient is a tonicity adjusting agent. In some embodiments, the tonicity adjusting agent is selected from sugars (e.g., dextrose, lactose, trehalose, sucrose), sugar alcohols (e.g., mannitol), salts (e.g., sodium chloride, potassium chloride), and polyols (e.g., propylene glycol, glycerin). In some embodiments, the tonicity adjusting agent is a sugar. In some embodiments, the tonicity adjusting agent is dextrose. In some embodiments, the tonicity adjusting agent is lactose. In some embodiments, the tonicity adjusting agent is trehalose. In some embodiments, the tonicity adjusting agent is sucrose. In some embodiments, the tonicity adjusting agent is a sugar alcohol. In some embodiments, the tonicity adjusting agent is mannitol. In some embodiments, the tonicity adjusting agent is a salt. In some embodiments, the tonicity adjusting agent is sodium chloride. In some embodiments, the tonicity adjusting agent is potassium chloride. In some embodiments, the tonicity adjusting agent is a polyol. In some embodiments, the tonicity adjusting agent is propylene glycol. In some embodiments, the tonicity adjusting agent is glycerin.

[0281] In some embodiments, the pharmaceutical composition is formulated as an aqueous solution. In some embodiments, the pharmaceutical composition is formulated as a powder. In some embodiments, the aqueous pharmaceutical composition as described herein may be lyophilized to provide a dry composition comprising Compound (I). In some embodiments, the pharmaceutical composition is formulated for inhalation (e.g., oral or nasal inhalation).

[0282] In some aspects, the pharmaceutical composition as described herein comprises Compound (I), or a pharma- ceutically acceptable salt, polymorph, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof; and a pharma- ceutically acceptable excipient (e.g., a buffer or tonicity agent). In some embodiments, the pharmaceutical composition as described herein comprises Compound (I), or a pharma- ceutically acceptable salt, polymorph, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof; and a buffer (e.g., an organic acid). In some embodiments, the pharmaceutical composition as described herein comprises Compound (I), or a pharma- ceutically acceptable salt, polymorph, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof; and a tonicity agent (e.g., a sugar (e.g., lactose)). In some aspects, the pharmaceutical composition as described herein comprises compound (I), or a pharma- ceutically acceptable salt, polymorph, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof; a first pharma- ceutically acceptable excipient (e.g., a buffer); and a second pharma- ceutically acceptable excipient (e.g., an isotonicity agent). In some embodiments, the pharmaceutical composition comprises compound (I), or a pharma- ceutically acceptable salt, polymorph, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, a buffer (e.g., citric acid), and a second pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises compound (I), or a pharma- ceutically acceptable salt, polymorph, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, a pharma- ceutically acceptable excipient (e.g., a buffer), and an isotonicity agent (e.g., lactose). In some embodiments, the pharmaceutical composition comprises Compound (I), or a pharma- ceutically acceptable salt, polymorph, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof; citric acid; and a second pharma-ceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises Compound (I), or a pharma-ceutically acceptable salt, polymorph, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof; lactose; and a second pharma-ceutically acceptable excipient.In certain embodiments, the pharmaceutical composition comprises Compound (I), or a pharma- ceutically acceptable salt, polymorph, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof; citric acid; and lactose.

[0283] In some embodiments, the composition comprises an amorphous form of Compound (I). In some embodiments, the pharmaceutical composition comprises a polymorph of Compound (I). In some embodiments, the pharmaceutical composition comprises a polymorph of Compound (I), or a pharma- ceutically acceptable salt, polymorph, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and one or more excipients. In some embodiments, the pharmaceutical composition comprises a polymorph of Compound (I), or a pharma- ceutically acceptable salt, polymorph, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof; a first excipient; and a second excipient.

[0284] In some embodiments, the polymorph of Compound (I) is free form A, free form B, free form C, or free form D. In some embodiments, the polymorph of Compound (I) is free form A. In some embodiments, the polymorph of Compound (I) is free form B. In some embodiments, the polymorph of Compound (I) is free form C. In some embodiments, the polymorph of Compound (I) is free form D. In some embodiments, the polymorph of Compound (I) is HCl salt form A, HCl salt form B, HCl salt form C, HCl salt form D, HCl salt form E, or HCl salt form F. In some embodiments, the polymorph of Compound (I) is HCl salt form A. In some embodiments, the polymorph of Compound (I) is HCl salt form B. In some embodiments, the polymorph of Compound (I) is HCl salt form C. In some embodiments, the polymorph of Compound (I) is HCl salt form D. In some embodiments, the polymorph of Compound (I) is HCl salt form E. In some embodiments, the polymorph of Compound (I) is HCl Salt Form F. In some embodiments, the polymorph of Compound (I) is Sulfate Form A or Sulfate Form B. In some embodiments, the polymorph of Compound (I) is Sulfate Form A. In some embodiments, the polymorph of Compound (I) is Sulfate Form B. In some embodiments, the polymorph of Compound (I) is Maleate Form A or Maleate Form B. In some embodiments, the polymorph of Compound (I) is Maleate Form A. In some embodiments, the polymorph of Compound (I) is Maleate Form B. In some embodiments, the polymorph of Compound (I) is Tartrate Form A. In some embodiments, the polymorph of Compound (I) is Fumarate Form A, Fumarate Form B, Fumarate Form C, or Fumarate Form D. In some embodiments, the polymorph of Compound (I) is Fumarate Form A. In some embodiments, the polymorph of Compound (I) is Fumarate Form B. In some embodiments, the polymorph of Compound (I) is Fumarate Form C. In some embodiments, the polymorph of Compound (I) is Fumarate Form D. In some embodiments, the polymorph of Compound (I) is Succinate Form A, Succinate Form B, or Succinate Form C. In some embodiments, the polymorph of Compound (I) is Succinate Form A. In some embodiments, the polymorph of Compound (I) is Succinate Form B. In some embodiments, the polymorph of Compound (I) is Succinate Form C.In some embodiments, the polymorph of Compound (I) is triphenylacetate Form A. In some embodiments, the polymorph of Compound (I) is xinafoate Form A. In some embodiments, the polymorph of Compound (I) is Ca salt Form A. In some embodiments, the polymorph of Compound (I) is tromethamine salt Form A or tromethamine salt Form B. In some embodiments, the polymorph of Compound (I) is tromethamine salt Form A. In some embodiments, the polymorph of Compound (I) is tromethamine salt Form B.

[0285] In some embodiments, the pharmaceutical composition comprises free form D in essentially pure form. In some embodiments, the pharmaceutical composition comprises free form D essentially free of other polymorphs. In some embodiments, the pharmaceutical composition comprises free form D at greater than or equal to 90% by weight, as compared to the sum of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises free form D at greater than or equal to 95% by weight, as compared to the sum of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises free form D at greater than or equal to 96% by weight, as compared to the sum of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises free form D at greater than or equal to 97% by weight, as compared to the sum of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises free form D at greater than or equal to 98% by weight, as compared to the sum of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises free form D at greater than or equal to 99% by weight, as compared to the total of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises free form D at greater than or equal to 99.5% by weight, as compared to the total of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises free form D at greater than or equal to 90% by weight, as compared to the total of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises free form D at greater than or equal to 95% by weight, as compared to the total of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises free form D at greater than or equal to 96% by weight, as compared to the total of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises free form D at greater than or equal to 97% by weight, as compared to the total of other polymorphs of Compound (I) in the composition. In certain embodiments, the pharmaceutical composition contains greater than or equal to 98% by weight of free form Form D as compared to the sum of other polymorphs of Compound (I) in the composition.In certain embodiments, the pharmaceutical composition comprises greater than or equal to 99% by weight of free form D, as compared to the sum of other polymorphs of Compound (I) in the composition. In certain embodiments, the pharmaceutical composition comprises greater than or equal to 99.5% by weight of free form D, as compared to the sum of other polymorphs of Compound (I) in the composition.

[0286] In some embodiments, the pharmaceutical composition comprises a polymorph of Compound (I), wherein the molar ratio of the amount of free form D: the sum of the amounts of other forms of Compound (I) is equal to or greater than about 80:20. In some embodiments, the pharmaceutical composition comprises a polymorph of Compound (I), wherein the molar ratio of the amount of free form D: the sum of the amounts of other forms of Compound (I) is equal to or greater than about 90:10. In some embodiments, the pharmaceutical composition comprises a polymorph of Compound (I), wherein the molar ratio of the amount of free form D: the sum of the amounts of other forms of Compound (I) is equal to or greater than about 95:5. In some embodiments, the pharmaceutical composition comprises a polymorph of Compound (I), wherein the molar ratio of the amount of free form D: the sum of the amounts of other forms of Compound (I) is equal to or greater than about 99:1.

[0287] In some embodiments, the polymorph is a polymorph of the fumarate salt of Compound (I). In some embodiments, the polymorph of Compound (I) is Fumarate Form A, Fumarate Form B, Fumarate Form C, or Fumarate Form D. In some embodiments, the polymorph of Compound (I) is Fumarate Form A. In some embodiments, the polymorph of Compound (I) is Fumarate Form B. In some embodiments, the polymorph of Compound (I) is Fumarate Form C. In some embodiments, the polymorph of Compound (I) is Fumarate Form D.

[0288] In some embodiments, the pharmaceutical composition comprises fumarate form A in essentially pure form. In some embodiments, the pharmaceutical composition comprises fumarate form A essentially free of other polymorphs. In some embodiments, the pharmaceutical composition comprises fumarate form A at greater than or equal to 90% by weight, as compared to the sum of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises fumarate form A at greater than or equal to 95% by weight, as compared to the sum of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises fumarate form A at greater than or equal to 96% by weight, as compared to the sum of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises fumarate form A at greater than or equal to 97% by weight, as compared to the sum of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises fumarate form A at greater than or equal to 98% by weight, as compared to the sum of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises fumarate Form A at greater than or equal to 99% by weight, as compared to the sum of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises fumarate Form A at greater than or equal to 99.5% by weight, as compared to the sum of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises fumarate Form A at greater than or equal to 90% by weight, as compared to the sum of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises fumarate Form A at greater than or equal to 95% by weight, as compared to the sum of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition comprises fumarate Form A at greater than or equal to 96% by weight, as compared to the sum of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition contains greater than or equal to 97% by weight of fumarate Form A, as compared to the sum of other polymorphs of Compound (I) in the composition. In some embodiments, the pharmaceutical composition contains greater than or equal to 98% by weight of fumarate Form A, as compared to the sum of other polymorphs of Compound (I) in the composition.In certain embodiments, the pharmaceutical composition contains greater than or equal to 99% by weight of fumarate Form A, as compared to the sum of other polymorphs of Compound (I) in the composition. In certain embodiments, the pharmaceutical composition contains greater than or equal to 99.5% by weight of fumarate Form A, as compared to the sum of other polymorphs of Compound (I) in the composition.

[0289] In some embodiments, the pharmaceutical composition comprises a polymorph of Compound (I), wherein the molar ratio of the amount of Fumarate Form A: the sum of the amounts of other forms of Compound (I) is equal to or greater than about 80:20. In some embodiments, the pharmaceutical composition comprises a polymorph of Compound (I), wherein the molar ratio of the amount of Fumarate Form A: the sum of the amounts of other forms of Compound (I) is equal to or greater than about 90:10. In some embodiments, the pharmaceutical composition comprises a polymorph of Compound (I), wherein the molar ratio of the amount of Fumarate Form A: the sum of the amounts of other forms of Compound (I) is equal to or greater than about 95:5. In some embodiments, the pharmaceutical composition comprises a polymorph of Compound (I), wherein the molar ratio of the amount of Fumarate Form A: the sum of the amounts of other forms of Compound (I) is equal to or greater than about 99:1.

[0290] Typically, the salt of the present disclosure is a pharmaceutically acceptable salt, but this is not necessarily the case.Salt of compound (I) can be prepared by any suitable method known in the art, including the treatment of free base with inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with organic acid such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid (such as glucuronic acid or galacturonic acid), alpha-hydroxy acid (such as citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid or cinnamic acid), sulfonic acid (such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.) or the like.

[0291] Examples of pharma- ceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, and the like. These include benzoates, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, -hydroxybutyrate, glycolate, tartrate, mandelate, and sulfonates such as xylenesulfonate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, and naphthalene-2-sulfonate.

[0292] Salts of compound (I) can be prepared by reacting compound (I) with a suitable base. Such pharma-ceutically acceptable salts may be composed of bases that provide pharma-ceutically acceptable cations, including alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts, and ammonium salts, as well as salts composed of physiologically acceptable organic bases, such as, for example, trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis(2-hydroxyethyl)amine, tri(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acids (lysine and arginine).

[0293] In some embodiments, the pharmaceutically acceptable salt is a salt of hydrochloride, sulfate, phosphoric acid, maleic acid, tartaric acid, fumaric acid, citric acid, succinic acid, acetic acid, methanesulfonic acid, isethionic acid, triphenylacetic acid, or xinafoic acid. In some embodiments, the pharmaceutically acceptable salt is a salt of hydrochloride, sulfate, maleic acid, tartaric acid, fumaric acid, succinic acid, triphenylacetic acid, or xinafoic acid. In some embodiments, the pharmaceutically acceptable salt is a salt of hydrochloride, sulfate, or fumarate.

[0294] In some embodiments, the pharma- ceutically acceptable salt is a calcium hydroxide, sodium hydroxide, or tromethamine salt. In some embodiments, the pharma- ceutically acceptable salt is a calcium hydroxide salt. The present disclosure further provides a pharmaceutical composition (also referred to as a pharmaceutical formulation) comprising Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and one or more excipients. The excipients are acceptable in the sense of being compatible with the other components of the formulation and are not toxic to the recipient thereof (i.e., the patient). In some embodiments, the pharmaceutical composition comprises a polymorph of Compound (I), or a pharma- ceutical acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and one or more excipients. In some embodiments, the pharmaceutical composition comprises Compound (I), or a pharma- ceutical acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, a first excipient, and a second excipient. In certain embodiments, the pharmaceutical composition comprises a polymorph of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, a first excipient, and a second excipient.

[0295] The excipients described herein are acceptable in the sense of being compatible with the other components of the formulation and are not toxic to the recipient (i.e., patient). Suitable pharma- ceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, suitable pharma- ceutically acceptable excipients may be selected for the particular function they may serve in the composition. For example, certain pharma- ceutically acceptable excipients may be selected for their ability to facilitate the production of a uniform dosage form. Certain pharma- ceutically acceptable excipients may be selected for their ability to facilitate the production of a stable dosage form. Certain pharma- ceutically acceptable excipients may be selected for their ability to facilitate the transport or transfer of the compound(s) of the present disclosure from one organ or part of the body to another organ or part of the body once administered to a patient. Certain pharma- ceutically acceptable excipients may be selected for their ability to enhance patient compliance. Certain pharma- ceutically acceptable excipients may be selected for their ability to facilitate the production of a stable dosage form for inhalation. Certain pharma- ceutically acceptable excipients may be selected for their ability to facilitate the production of a stable dosage form for oral inhalation. Certain pharma- ceutically acceptable excipients may be selected for their ability to facilitate the production of a stable dosage form for nasal inhalation. Certain pharma- ceutically acceptable excipients may be selected for their ability to facilitate the production of a stable dosage form for administration in an aerosol. Other pharma- ceutically acceptable excipients may also be selected for their ability to facilitate the production of a stable dosage form for administration in an inhaler (e.g., a dry powder inhaler).

[0296] Suitable pharma- ceutically acceptable excipients include the following types of excipients: isotonicity agents, carriers, diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffers. Those skilled in the art will understand that a pharma-ceutically acceptable excipient may perform more than one function, and may perform alternative functions, depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

[0297] In some aspects, the pharmaceutical composition as described herein comprises a polymorph of Compound (I), or a pharma- ceutically acceptable salt or solvate thereof; a pharma- ceutically acceptable excipient (eg, and organic acid); and a second pharma- ceutically acceptable excipient (eg, isotonicity agent pharma- ceutically acceptable carrier). In some embodiments, the pharmaceutical composition comprises the free form D of Compound (I), a first pharma- ceutically acceptable excipient, and a second pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises the free form D of Compound (I), citric acid, and a second pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises the free form D of Compound (I), a pharma- ceutically acceptable excipient, and lactose. In some embodiments, the pharmaceutical composition comprises a polymorph of Compound (I), or a solvate or pharma- ceutically acceptable salt thereof, citric acid, and a second pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a polymorph of Compound (I), or a solvate or pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable excipient, and lactose. In some embodiments, the pharmaceutical composition comprises a polymorph of Compound (I), or a solvate or pharma- ceutically acceptable salt thereof, citric acid, and lactose. In some embodiments, the pharmaceutical composition comprises the free form D of Compound (I), citric acid, and lactose.

[0298] In some embodiments, the composition comprises 1 molar equivalent of compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a polymorph thereof, and about 1 to about 2 molar equivalents of an organic acid (e.g., citric acid). In some embodiments, the composition comprises 1 molar equivalent of compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1 to about 1.5 equivalents of an organic acid (e.g., citric acid). In some embodiments, the composition comprises 1 molar equivalent of compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 0.8 to about 1.2 molar equivalents, preferably about 0.9 to about 1.1 molar equivalents of an organic acid (e.g., citric acid). In some embodiments, the composition comprises 1 molar equivalent of compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1 to about 1.2 equivalents of an organic acid (e.g., citric acid). In some embodiments, the composition comprises 1 molar equivalent of compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 0.9 to about 1.1 equivalents of an organic acid (e.g., citric acid). In some embodiments, the composition comprises 1 molar equivalent of compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1 to about 1.1 equivalents of an organic acid (e.g., citric acid). In certain embodiments, the composition comprises 1 molar equivalent of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1.05 equivalents of an organic acid.

[0299] In some embodiments, the composition comprises 1 molar equivalent of compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1 to about 5 molar equivalents of a pharma- ceutically acceptable excipient (e.g., a buffer or tonicity agent (e.g., lactose)). In some embodiments, the composition comprises 1 molar equivalent of compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1 to about 5 molar equivalents of a pharma- ceutically acceptable excipient (e.g., a buffer or tonicity agent (e.g., lactose)). In some embodiments, the composition comprises 1 molar equivalent of compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 2 to about 4 equivalents of a pharma- ceutically acceptable excipient. In some embodiments, the composition comprises 1 molar equivalent of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 2 to about 3 equivalents of a pharma- ceutically acceptable excipient. In some embodiments, the composition comprises 1 molar equivalent of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 2.5 to about 3.0 equivalents of a pharma- ceutically acceptable excipient.

[0300] In some embodiments, the composition comprises 1 molar equivalent of compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, about 1 to about 2 molar equivalents of an organic acid (e.g., citric acid), and about 1 to about 5 molar equivalents of an isotonicity agent (e.g., a sugar (e.g., lactose)). In some embodiments, the composition comprises 1 molar equivalent of compound (I), or a pharma-ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, 1 to 2 molar equivalents of an organic acid (e.g., citric acid), and about 2 to about 3 molar equivalents of an isotonicity agent (e.g., lactose). In some embodiments, the composition comprises 1 molar equivalent of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, about 0.8 to about 1.2 molar equivalents of an organic acid (e.g., citric acid), and about 2.5 to about 3.0 molar equivalents of an isotonicity agent (e.g., lactose).

[0301] In some embodiments, the composition comprises 1 molar equivalent of a polymorph of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1 to about 2 molar equivalents of a pharma- ceutically acceptable excipient (e.g., citric acid). In some embodiments, the composition comprises 1 molar equivalent of a polymorph of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1 to about 1.5 equivalents of a pharma- ceutical acceptable excipient. In some embodiments, the composition comprises 1 molar equivalent of a polymorph of Compound (I), or a pharma- ceutical acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1 to about 1.2 equivalents of a pharma- ceutical acceptable excipient. In some embodiments, the composition comprises 1 molar equivalent of a polymorph of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1 to about 1.1 equivalents of a pharma- ceutically acceptable excipient. In some embodiments, the composition comprises 1 molar equivalent of a polymorph of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1.05 equivalents of a pharma- ceutically acceptable excipient.

[0302] In some embodiments, the composition comprises 1 molar equivalent of a polymorph of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1 to about 5 molar equivalents of a pharma- ceutically acceptable excipient (e.g., a buffer or tonicity agent (e.g., lactose)). In some embodiments, the composition comprises 1 molar equivalent of a polymorph of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1 to about 5 equivalents of a pharma- ceutical acceptable excipient. In some embodiments, the composition comprises 1 molar equivalent of a polymorph of Compound (I), or a pharma- ceutical acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 2 to about 4 equivalents of a pharma- ceutical acceptable excipient. In some embodiments, the composition comprises 1 molar equivalent of a polymorph of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 2 to about 3 equivalents of a pharma- ceutically acceptable excipient. In some embodiments, the composition comprises 1 molar equivalent of a polymorph of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 2.5 to about 3.0 equivalents of a pharma- ceutically acceptable excipient.

[0303] In some embodiments, the composition comprises 1 molar equivalent of a polymorph of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, about 1 to about 2 molar equivalents of a first pharma- ceutically acceptable excipient (e.g., citric acid), and about 1 to about 5 molar equivalents of a second pharma- ceutically acceptable excipient (e.g., lactose). In some embodiments, the composition comprises 1 molar equivalent of a polymorph of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, about 1 to about 2 molar equivalents of a first pharma- ceutically acceptable excipient (e.g., citric acid), and about 1 to about 5 molar equivalents of an isotonicity agent (e.g., lactose).

[0304] In some embodiments, the composition comprises 1 molar equivalent of the free form D of Compound (I), about 1 to about 2 molar equivalents of citric acid, and about 1 to about 5 molar equivalents of lactose. In some embodiments, the composition comprises 1 molar equivalent of the free form D, about 1.05 molar equivalents of citric acid, and about 2.5 to about 3 molar equivalents of lactose.

[0305] In some aspects, the compositions described herein are provided as a solution comprising a polymorph of Compound (I), or a pharmaceutically acceptable salt or solvate thereof, a first pharmaceutically acceptable excipient (e.g., citric acid), and a second pharmaceutically acceptable excipient (e.g., lactose). In some aspects, the compositions described herein are provided as a solution comprising a polymorph of Compound (I), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, a first pharmaceutically acceptable excipient (e.g., citric acid), and a second pharmaceutically acceptable excipient (e.g., lactose). In some embodiments, the pharmaceutical composition is an aqueous solution. In some embodiments, the solution contains about 40 mg / mL of a polymorph of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotope-labeled derivative thereof, about 10 to about 20 mg / mL of a first pharma- ceutically acceptable excipient (e.g., citric acid), and about 50 to about 80 mg / mL of a second pharma- ceutically acceptable excipient (e.g., lactose). In some embodiments, the solution contains about 40 mg / mL of a polymorph of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotope-labeled derivative thereof, about 12 to about 13 mg / mL of a first pharma- ceutically acceptable excipient (e.g., citric acid), and about 55 to about 65 mg / mL of a second pharma- ceutically acceptable excipient (e.g., lactose). In some embodiments, the solution comprises about 40 mg / mL of a polymorph of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, about 12 to about 13 mg / mL of citric acid, and about 50 to about 80 mg / mL of lactose.

[0306] In some embodiments, the composition comprises 1 molar equivalent of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1 to about 2 molar equivalents of a pharma- ceutically acceptable excipient (e.g., citric acid). In some embodiments, the composition comprises 1 molar equivalent of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1 to about 1.5 equivalents of a pharma- ceutically acceptable excipient. In some embodiments, the composition comprises 1 molar equivalent of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1 to about 1.2 equivalents of a pharma- ceutically acceptable excipient. In some embodiments, the composition comprises 1 molar equivalent of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1 to about 1.1 equivalents of a pharma- ceutically acceptable excipient. In some embodiments, the composition comprises 1 molar equivalent of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1.05 equivalents of a pharma- ceutically acceptable excipient.

[0307] In some embodiments, the composition comprises 1 molar equivalent of compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1 to about 5 molar equivalents of a pharma- ceutically acceptable excipient (e.g., a buffer or tonicity agent (e.g., lactose)). In some embodiments, the composition comprises 1 molar equivalent of compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 1 to about 5 equivalents of a pharma- ceutically acceptable excipient. In some embodiments, the composition comprises 1 molar equivalent of compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 2 to about 4 equivalents of a pharma- ceutically acceptable excipient. In some embodiments, the composition comprises 1 molar equivalent of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 2 to about 3 equivalents of a pharma- ceutically acceptable excipient. In some embodiments, the composition comprises 1 molar equivalent of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and about 2.5 to about 3.0 equivalents of a pharma- ceutically acceptable excipient.

[0308] In some embodiments, the composition comprises 1 molar equivalent of compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, about 1 to about 2 molar equivalents of a first pharma- ceutically acceptable excipient (e.g., citric acid), and about 1 to about 5 molar equivalents of a second pharma- ceutically acceptable excipient (e.g., lactose). In some embodiments, the composition comprises 1 molar equivalent of compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, about 1 to about 2 molar equivalents of a first pharma- ceutically acceptable excipient (e.g., citric acid), and about 1 to about 5 molar equivalents of an isotonicity agent (e.g., lactose).

[0309] In some embodiments, the composition comprises 1 molar equivalent of the free form D of Compound (I), about 1 to about 2 molar equivalents of citric acid, and about 1 to about 5 molar equivalents of lactose. In some embodiments, the composition comprises 1 molar equivalent of the free form D, about 1.05 molar equivalents of citric acid, and about 2.5 to about 3 molar equivalents of lactose.

[0310] In some aspects, the compositions described herein are provided as a solution comprising Compound (I), or a pharma- ceutically acceptable salt or solvate thereof, a first pharma- ceutically acceptable excipient (e.g., citric acid), and a second pharma- ceutically acceptable excipient (e.g., lactose). In some aspects, the compositions described herein are provided as a solution comprising Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, a first pharma- ceutically acceptable excipient (e.g., citric acid), and a second pharma- ceutically acceptable excipient (e.g., lactose). In some embodiments, the pharmaceutical composition is an aqueous solution. In some embodiments, the pH of the aqueous solution is between about pH 2 and about pH 8. In some embodiments, the pH of the aqueous solution is between about pH 3.5 and about pH 6. In some embodiments, the pH of the aqueous solution is between about pH 4.5 and about pH 5.5.

[0311] In some embodiments, the aqueous solution contains about 40 mg / mL of compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotope-labeled derivative thereof, about 10 to about 20 mg / mL of a first pharma- ceutically acceptable excipient (e.g., citric acid), and about 50 to about 80 mg / mL of a second pharma- ceutically acceptable excipient (e.g., lactose). In some embodiments, the aqueous solution contains about 40 mg / mL of compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotope-labeled derivative thereof, about 12 to about 13 mg / mL of a first pharma- ceutically acceptable excipient (e.g., citric acid), and about 55 to about 65 mg / mL of a second pharma- ceutically acceptable excipient (e.g., lactose). In some embodiments, the aqueous solution comprises about 40 mg / mL of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, about 12 to about 13 mg / mL of citric acid, and about 50 to about 80 mg / mL of lactose.

[0312] In some embodiments, the aqueous solution comprises compound (I) at a concentration between about 10 and about 50 mM. In some embodiments, the aqueous solution comprises compound (I) at a concentration between about 35 and about 45 mM. In some embodiments, the aqueous solution comprises compound (I) at a concentration between about 10 and about 50 mM, and the concentration of citric acid is about 40 mM. In some embodiments, the aqueous solution comprises compound (I) at a concentration between about 10 and about 50 mM, and the concentration of lactose acid is about 173 mM. In some embodiments, the aqueous solution comprises compound (I) at a concentration between about 10 and about 50 mM, and the concentration of citric acid is about 40 mM, and the concentration of lactose acid is about 173 mM. In some embodiments, the concentration of compound (I) is about 40 mM, the concentration of citric acid is about 40 mM, and the concentration of lactose is about 173 mM.

[0313] In some embodiments, the aqueous solution is isotonic with human body fluids (e.g., blood). In some embodiments, the aqueous solution is isotonic with human blood. In some embodiments, the aqueous solution is isotonic with human tissue (e.g., human lung tissue or nasal tissue). In some embodiments, the aqueous solution is isotonic with human lung tissue. In some embodiments, the aqueous solution is isotonic with human nasal tissue.

[0314] The pharmaceutical composition may be adapted for administration by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Such compositions may be prepared by any method known in the art of pharmacy, for example, by combining the active ingredient with the excipient(s). In some embodiments, the composition is an aqueous solution. In some embodiments, the pharmaceutical composition is formulated for oral inhalation. In some embodiments, the pharmaceutical composition is formulated for nasal inhalation. In some embodiments, the pharmaceutical composition is formulated for administration by a nebulizer. In some embodiments, the pharmaceutical composition is formulated for administration by an inhaler (e.g., a dry powder inhaler).

[0315] When suitable for oral administration, the pharmaceutical composition may be in the form of discrete units such as tablets or capsules; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; oil-in-water or water-in-oil liquid emulsions. The compounds or salts thereof or pharmaceutical compositions of the present disclosure may also be incorporated into candy, wafer, and / or tongue tape formulations for administration as "fast dissolving" drugs.

[0316] For illustrative purposes, for oral administration in the form of a tablet or capsule, the active drug component may be combined with an oral, non-toxic, pharma- ceutically acceptable inert carrier, such as ethanol, glycerol, water, and the like. Powders or granules are prepared by pulverizing the compound to a suitable fine size and mixing with a similarly pulverized pharma- ceutically acceptable carrier, such as an edible carbohydrate, such as starch or mannitol. Flavoring agents, preservatives, dispersing agents, and coloring agents may also be present.

[0317] Capsules are made by preparing a powder mixture as described above and filling formed gelatin or non-gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol, etc., can be added to the powder mixture before the filling operation. Disintegrants or solubilizers such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the drug when the capsule is ingested.

[0318] Moreover, suitable binders, lubricants, disintegrating agents, and coloring agents may also be incorporated into the mixture if desired or necessary. Suitable binders include starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic gums (such as acacia), tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrating agents include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

[0319] Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and compressing into tablets. The powder mixture is prepared by mixing the compound (suitably powdered) with a diluent or base as described above, and optionally with a binder (such as carboxymethylcellulose, and alginate, gelatin, or polyvinylpyrrolidone), a dissolution retardant (such as paraffin), a resorption promoter (such as quaternary salts), and / or an absorbent (such as bentonite, kaolin, or dicalcium phosphate). The powder mixture can be granulated by wetting a binder (such as syrup, starch paste, gum arabic, or a solution of cellulosic or polymeric material and forcing it through a screen. As an alternative to granulation, the powder mixture can be passed through a tablet press, which breaks up imperfectly formed slugs into granules. The granules can be made slippery by the addition of stearic acid, stearate salts, talc, or mineral oil to prevent them from sticking to the tablet forming die. The slippery mixture is then compressed into tablets. The compounds or salts of the present disclosure can also be combined with an inert free-flowing carrier and compressed directly into tablets without going through the granulation or smashing steps. A clear or opaque protective coating consisting of a sealing coat of shellac varnish, a coating of sugar or polymeric material, and a polish coating of wax can be provided. Dyes can be added to these coatings to distinguish various dosages.

[0320] 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 active ingredient.Syrups can be prepared by dissolving the polymorph of Compound (I) in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersing the polymorph of Compound (I) in a non-toxic vehicle.Solubilizers and emulsifiers (such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether), preservatives, flavor additives (such as peppermint oil), natural sweeteners, saccharin, or other artificial sweeteners, etc., can also be added.

[0321] Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulations can also be prepared for slow or sustained release, for example, by coating particulate materials or embedding them in polymers, waxes, or the like.

[0322] In another aspect, the polymorph and composition as described herein can be suitable for administration to a patient by inhalation.Inhalation refers to administration into the lungs of a patient, whether inhaled through the mouth or through the nasal passages.For example, the polymorph of Compound (I) can be inhaled into the lungs as dry powder, aerosol, suspension, or solution.

[0323] Dry powder compositions for delivery to the lungs by inhalation typically contain Compound (I) as a fine powder together with one or more pharma- ceutically acceptable excipients as a fine powder. Pharmaceutically acceptable excipients are specifically suitable for use in dry powders and are known to those skilled in the art, including lactose, starch, mannitol, and mono-, di-, and polysaccharides.

[0324] The dry powder may be administered to a patient via a reservoir dry powder inhaler (RDPI) having a reservoir suitable for storing multiple (non-metered) doses of medicament in dry powder form. RDPIs typically include a means for metering each dose of medicament from the reservoir to a delivery location. For example, the metering means may include a metering cup that is movable from a first position (where the cup may be filled with medicament from the reservoir) to a second position (where a metered dose of medicament is made available to the patient for inhalation).

[0325] Alternatively, the dry powder may be presented in a capsule (e.g., gelatin or plastic), cartridge, or blister pack for use in a multi-dose dry powder inhaler (MDPI). MDPIs are inhalers in which the medicament is contained within a multi-dose pack that contains (or otherwise carries) multiple prescribed doses (or portions thereof) of the medicament. When the dry powder is presented as a blister pack, it comprises multiple blisters for containing the medicament in dry powder form. The blisters are typically arranged in an orderly fashion to facilitate release of the medicament from the blisters. For example, the blisters may be arranged in a ring, typically on a disc-shaped blister pack, or the blisters may be in elongated form, including, for example, a strip or tape. Each capsule, cartridge, or blister may contain, for example, between 20 μg and 10 mg of Compound (I).

[0326] The aerosol may be formed by suspending or dissolving the polymorph of Compound (I) in a liquefied propellant. Suitable propellants include halocarbons, hydrocarbons, and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane, and pentane. Aerosols containing the polymorphs of Compound (I) as described herein will typically be administered to a patient via a metered dose inhaler (MDI). Such devices are known to those skilled in the art.

[0327] The aerosol may contain additional pharma- ceutically acceptable excipients typically used with multi-dose inhalers, such as tonicity agents, carriers, surfactants, lubricants, cosolvents, and other excipients to improve the physical stability of the formulation, to improve valve performance, to improve solubility, or to improve taste.

[0328] Suspensions and solutions containing the polymorphs or compositions as described herein may also be administered to patients via a nebulizer. The solvent or suspending agent utilized for nebulization may be any pharma- ceutically acceptable liquid, such as water, aqueous saline, alcohol or glycol, e.g., ethanol, isopropyl alcohol, glycerol, propylene glycol, polyethylene glycol, etc., or mixtures thereof. Saline solutions utilize salts that exhibit little or no pharmacological activity after administration. Both organic and inorganic salts may be used for this purpose.

[0329] Suspensions and solutions comprising the polymorphs or compositions as described herein may also be administered to a patient via an inhaler (eg, a dry powder inhaler).

[0330] Other pharma- ceutically acceptable excipients may also be added to the suspension or solution. The polymorphs of Compound (I) as described herein may be stabilized by the addition of inorganic acids, such as hydrochloric acid, nitric acid, sulfuric acid, and / or phosphoric acid; organic acids, such as ascorbic acid, citric acid, acetic acid, and tartaric acid, and the like, complexing agents such as EDTA, or citric acid and their salts; or antioxidants such as vitamin E or ascorbic acid. These may be used alone or together to stabilize the polymorphs of Compound (I) as described herein. Preservatives such as benzalkonium chloride or benzoic acid and their salts may also be added.

[0331] Also disclosed is a method of using the polymorph or composition described herein to treat a disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a polymorph of Compound (I) or a pharmaceutical composition as described herein.

[0332] In another aspect, the disclosure provides a polymorph of Compound (I), or a pharma- ceutically acceptable salt or solvate thereof, or a composition comprising a polymorph of Compound (I), for use in the manufacture of a medicament for use in the treatment of a disorder mediated by furin, such as fibrosis (e.g., pulmonary fibrosis).

[0333] In another aspect, the disclosure provides a polymorph of Compound (I), or a pharma- ceutically acceptable salt or solvate thereof, or a composition comprising a polymorph of Compound (I), for use in the manufacture of a medicament for use in the treatment of a furin-mediated disorder, such as cystic fibrosis.

[0334] In another aspect, the disclosure provides a polymorph of Compound (I), or a pharma- ceutically acceptable salt or solvate thereof, or a composition comprising a polymorph of Compound (I), for use in the treatment of a disease mediated by furin. In another aspect, the disclosure provides a polymorph of Compound (I), or a pharma- ceutically acceptable salt or solvate thereof, or a composition comprising a polymorph of Compound (I), as an active therapeutic agent for use in the treatment of a disease mediated by or associated with furin.

[0335] In another aspect, the disclosure provides a polymorph of Compound (I), or a pharma- ceutically acceptable salt or solvate thereof, or a composition comprising a polymorph of Compound (I), for use in therapy.

[0336] In another aspect, the disclosure provides a polymorph of Compound (I), or a solvate or pharma- ceutically acceptable salt thereof, or a composition comprising a polymorph of Compound (I), for use in the treatment of fibrosis.

[0337] In another aspect, the disclosure provides a polymorph of Compound (I), or a pharma- ceutically acceptable salt or solvate thereof, or a composition comprising a polymorph of Compound (I), for use in the treatment of pulmonary fibrosis.

[0338] In another aspect, the disclosure provides a polymorph of Compound (I), or a solvate or pharma- ceutically acceptable salt thereof, or a composition comprising a polymorph of Compound (I), for use in the treatment of cystic fibrosis.

[0339] In another aspect, the disclosure provides a method of co-administering a polymorph of Compound (I), or a pharma- ceutically acceptable salt or solvate thereof, or a composition comprising a polymorph of Compound (I), with another active ingredient.

[0340] The present invention also provides methods of treatment in mammals, particularly humans. Conditions that may be treated by the methods and compositions provided herein include, but are not limited to, fibrosis. Fibrosis involves the formation of excessive fibrous connective tissue in an organ or tissue during a repair or reaction process. Diseases include, but are not limited to, pulmonary fibrosis, e.g., idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), Hermansky-Pudlak syndrome, progressive massive fibrosis (a complication of coal worker's pneumoconiosis), fibrosis of the airways in asthma and COPD, fibrosis associated with acute respiratory distress syndrome (ARDS), acute lung injury (e.g., radiation-induced acute lung injury, chemical lung injury), and chronic obstructive pulmonary disease (COPD). interstitial lung disease associated with systemic sclerosis; radiation-induced fibrosis; familial pulmonary fibrosis; pulmonary hypertension; renal fibrosis (e.g., diabetic nephropathy, IgA nephropathy, lupus nephritis, focal segmental glomerulosclerosis (FSGS), transplant nephropathy, autoimmune nephropathy, drug-induced nephropathy, hypertension-related nephropathy, nephrogenic systemic fibrosis); hepatic fibrosis (e.g., viral-induced fibrosis (e.g., hepatitis C or B), autoimmune hepatitis, primary biliary cirrhosis, alcoholic liver disease, nonalcoholic fatty liver disease including nonalcoholic steatohepatitis (NASH), congenital hepatic fibrosis, primary sclerosing cholangitis, drug-induced hepatitis, cirrhosis); dermal fibrosis (e.g., hypertrophic scar, scleroderma, keloids, dermatomyositis, eosinophilic fasciitis) , Dupuytren's contracture, Ehlers-Danlos syndrome, Peyronie's disease, dystrophic epidermolysis bullosa, oral submucous fibrosis); non-cystic fibrosis bronchiectasis (NCFBC); ocular fibrosis (e.g., AMD, diabetic macular edema, dry eye, glaucoma); myocardial fibrosis (e.g., congestive heart failure, endomyocardial fibrosis, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), hypertensive heart disease, cardiac sarcoidosis, and other forms of heart failure), as well as other miscellaneous fibrotic diseases (e.g., mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, Crohn's disease, neurofibromatosis, uterine leiomyomas (uterine fibroids), chronic organ transplant rejection).

[0341] In some embodiments, the disease is cystic fibrosis. In some embodiments, the disease is chronic obstructive pulmonary disease (COPD). In some embodiments, the disease is non-cystic fibrosis bronchiectasis (NCFBC). In some embodiments, the disease is asthma. In some embodiments, the disease is pulmonary fibrosis, including idiopathic pulmonary fibrosis. In some embodiments, the disease is idiopathic pulmonary fibrosis. In some embodiments, the disease is radiation-induced acute lung injury. In some embodiments, the disease is chemical acute lung injury. In some embodiments, the disease is systemic sclerosis-associated interstitial lung disease.

[0342] Additional conditions that may be treated by the methods and compositions provided herein include, but are not limited to, hypertension, cancer, infectious diseases (such as human immunodeficiency virus (HIV), Nipah virus, avian influenza virus, measles virus, respiratory syncytial virus (RSV), Ebola virus, anthrax, and Zika virus (ZIKV)), respiratory diseases (such as cystic fibrosis (CF)), and neurodegenerative diseases (such as Alzheimer's disease (AD)). In some embodiments, the disease is hypertension. In some embodiments, the disease is cancer. In some embodiments, the disease is an infectious disease (such as human immunodeficiency virus (HIV), Nipah virus, avian influenza virus, measles virus, respiratory syncytial virus (RSV), Ebola virus, coronavirus, anthrax, and Zika virus (ZIKV)). In some embodiments, the disease is a respiratory disease (such as cystic fibrosis (CF)), and neurodegenerative diseases (such as Alzheimer's disease (AD)).

[0343] The polymorphs and compositions described herein may be combined with or co-administered with other therapeutic agents, particularly agents that may enhance the activity of the polymorphs. Combination therapy includes the administration of at least one polymorph of Compound (I) as described herein, and the use of at least one other treatment method, including the administration of one or more other therapeutic agents. Other therapeutic agents that may be used in combination with a composition comprising a polymorph or Compound (I) as described herein include, but are not limited to, antigen immunotherapy, antihistamines, corticosteroids (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene modulators (e.g., montelukast, zafirlukast, pranlukast), iNOS inhibitors, tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, elastase inhibitors, beta 2 integrin antagonists, adenosine a2a agonists, chemokine antagonists (such as CCR3 antagonists or CCR4 antagonists), melanoma inhibitors, and the like. mediator release inhibitors (such as sodium cromoglycate), 5-lipoxygenase inhibitors (zyflo), DP1 antagonists, DP2 antagonists, pI3K delta inhibitors, ITK inhibitors, LP (lysophosphatidic acid) inhibitors or FLAP (5-lipoxygenase activating protein) inhibitors (e.g. sodium 3-(3-(tert-butylthio)-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-((5-methylpyridin-2-yl)methoxy)-1H-indol-2-yl)-2,2-dimethylpropanoate), methotrexate, and similar agents; monoclonal antibody treatments such as anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1, and similar agents; receptor treatments, e.g. etanercept and similar agents;Antigen-nonspecific immunotherapy (e.g., interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators, cytokine agonists or antagonists, TLR agonists, and similar agents), inhibitors of TGFβ synthesis (e.g., pirfenidone), tyrosine kinase inhibitors targeting the receptor kinases for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) (e.g., tyrosine kinase inhibitors). For example, intedanib (BIBF-1120) and imatinib mesylate (Gleevec), endothelin receptor antagonists (e.g., ambrisentan or macitentan), antioxidants (such as N-acetylcysteine ​​(NAC or fluimucil)), antibiotics such as tetracyclines (e.g., minocycline hydrochloride), phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil), or alpha; v β 6 Integrin antagonists include, for example, monoclonal antibodies such as those described in WO 2003 / 100033 A2.

[0344] As used herein, the term "co-administration" and its derivatives refer to either simultaneous administration or separate sequential administration in any manner of the furin inhibitor compound as described herein and the additional active ingredient(s).As used herein, the term additional active ingredient(s) includes any compound or therapeutic agent that is known or demonstrates advantageous properties when administered to a patient in need of treatment.Preferably, if administration is not simultaneous, the compounds are administered within a close time period of each other.Furthermore, it does not matter if the compounds are administered in the same dosage form, for example, one compound is administered orally and another compound is administered intravenously.

[0345] The exact amount of polymorph of the composition comprising Compound (I) required to achieve an effective dose will vary from subject to subject, depending on, for example, the species, age, and general condition of the subject, the severity of side effects or disorders, the identity of the specific compound, the mode of administration, etc. The effective amount may be contained in a single dose (e.g., a single oral dose), or multiple doses (e.g., multiple oral doses). In some embodiments, the duration between the first dose and the last dose of the multiple doses is 3 months, 6 months, or 1 year. In some embodiments, the duration between the first dose and the last dose of the multiple doses is the life span of the subject. In some embodiments, the doses described herein (e.g., either a single dose or multiple doses) independently include between 0.1 μg and 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g (inclusive) of the compounds described herein. In some embodiments, the doses described herein include between 1 mg and 3 mg (inclusive) of the compounds described herein. In some embodiments, the doses described herein include between 3 mg and 10 mg (inclusive) of the compounds described herein. In some embodiments, the doses described herein include between 10 mg and 30 mg (inclusive) of the compounds described herein. In certain embodiments, the doses described herein encompass between 30 mg and 100 mg, inclusive, of a compound described herein.

[0346] The dosage ranges provide guidance for administration of the provided pharmaceutical compositions to adults, as described herein. For example, the amount to be administered to a child or adolescent can be determined by a physician or person skilled in the art and can be less than or the same as that administered to an adult.

[0347] The therapeutically effective amount of a compound of the present disclosure will depend on a number of factors, including, for example, the age and weight of the intended recipient, the precise disease requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant prescribing the drug.

[0348] Also covered by the present disclosure are kits (e.g., pharmaceutical packs). In some embodiments, the kits include a polymorph or pharmaceutical composition of Compound (I) as described herein and instructions for using the polymorph or pharmaceutical composition. In some embodiments, the kits include a first container, where the first container includes a polymorph of Compound (I) or a pharmaceutical composition comprising Compound (I). In some embodiments, the kits further include a second container. In some embodiments, the second container includes an excipient (e.g., an excipient for diluting or suspending the compound or pharmaceutical composition). In some embodiments, each of the first or second containers is independently a vial, an ampoule, a bottle, a syringe, a dispenser package, a tube, a nebulizer, or an inhaler (e.g., a dry powder inhaler). In some embodiments, the kit includes a polymorph of Compound (I) or a pharmaceutical composition comprising Compound (I) as described herein, a first pharma- ceutically acceptable excipient (e.g., citric acid), and a second pharma-ceutically acceptable excipient (e.g., lactose).

[0349] In some embodiments, the kits described herein include a first container comprising a polymorph of Compound (I) or a pharmaceutical composition as described herein. In some embodiments, the kits described herein are useful for treating and / or preventing pulmonary fibrosis.

[0350] In some embodiments, the kit comprises a polymorph of Compound (I), or a pharmaceutical composition thereof; and instructions for using the polymorph or pharmaceutical composition as described herein.

[0351] In some embodiments, the kit comprises an amorphous form of Compound (I), or a pharmaceutical composition thereof; and instructions for using the amorphous form or pharmaceutical composition as described herein.

[0352] In some embodiments, the kit further comprises instructions for using the polymorph of Compound (I) or pharmaceutical composition contained in the kit. The kit described herein may also comprise information required by regulatory authorities such as the U.S. Food and Drug Administration (FDA). In some embodiments, the information contained in the kit is prescription information. In some embodiments, the kit and instructions provide for treating pulmonary fibrosis.

[0353] In some embodiments, the instructions are for administering a polymorph or pharmaceutical composition of Compound (I) to a subject (e.g., a subject in need of treatment or prevention of a disease described herein). In some embodiments, the instructions include information required by a regulatory agency, such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). In some embodiments, the instructions include prescribing information. example Table 1-1 Summary of salt and free forms of compound (I) [Table 1-1] Table 1-2 Summary of HPLC purity by area % results in stability evaluation of formulations 1 to 5 [Table 1-2]

[0354] Example 1. Formation and characterization of polymorphs Free Form A and Free Form D of Compound (I) were obtained from free form isolation (Example 7). Using Free Form A of Compound (I) as the starting material, 100 polymorph formation experiments were carried out via slurry at RT / 50° C., slow evaporation, solid / liquid vapor diffusion, temperature cycling, polymer-induced crystallization, and anti-solvent addition. Experimental details are provided in Example 7.

[0355] The two new crystalline forms obtained were designated free form forms B and C. The XRPD overlay of the four forms is shown in Figure 1. The TGA / DSC / 1 H NMR characterization was performed. Detailed characterization results are summarized in Table 2-1 and below. The data show that Free Form A and Free Form D are hydrates, Free Form B is an anhydrate, and Free Form C is a metastable form.

[0356] Thermodynamic relationship studies were performed for free forms A / B / D. w When is less than 0.2, free form B is obtained, and a w Free form D was obtained when β-form is greater than 0.34. Free form D is in its thermodynamic form at ambient conditions. Table 2-1 Summary of polymorphic characterization results for Compound (I) free form [Table 2-1]

[0357] Characterization of free form polymorphs Free form type A The free form A sample was prepared by adding CHCl 3 The detailed preparation procedure is shown in Table 9-3.

[0358] The XRPD pattern of free form Form A is displayed in Figure 2 with the peaks listed below. The TGA / DSC results (Figure 3) show a 7.3% weight loss up to 150°C and one endotherm at 110.3°C (peak). 1 The H NMR spectrum (Figure 4) shows that 3The DVS (Dynamic Water Vapor Sorption) plot of free form A showed a water uptake of 2.3% at 25 °C from 10% RH to 0% RH (Figure 5). The sample weight rapidly decreased when the humidity decreased from 10% to 0%, which may have been caused by the loss of crystal water. No morphological changes were observed after the DVS test (Figure 6, 60% RH to 95% RH to 0% RH to 95% RH). These data indicate that free form A is a hydrate. Table 2-1a: List of XRPD peaks for free form Form A: [Table 2-1a]

[0359] Free form type B A sample of Free Form B obtained by slurrying Free Form A in DMAc / ACN (1:9, v / v) for 7 days was selected for characterization. No morphological changes were observed before and after drying overnight at RT (Figure 7). TGA / DSC results (Figure 8) showed a weight loss of 0.6% up to 170°C and one endotherm at 191.6°C (peak). 1 The 1 H NMR spectrum (Figure 9) showed no signals for ACN and DMAc.

[0360] Free Form B was reconstituted on a 500 mg scale for further characterization and thermodynamic relationship studies. Approximately 595.7 mg Free Form A was dissolved in 1 mL MeOH and 4 mL MTBE was slowly added into the solution under magnetic stirring (1000 rpm). The resulting suspension was stirred at RT for 6 days and the solid was isolated by vacuum filtration. The resulting wet cake was dried under vacuum at RT for 8 hours to give approximately 340 mg Free Form B (Figure 10). The reconstituted Free Form B was analyzed by TGA / DSC / MS ... 1 It was characterized by H NMR / DVS. The TGA / DSC results (FIG. 11) showed a 6.0% weight loss up to 170° C. and one endotherm (peak) at 190.6° C. 1H NMR spectrum (Figure 12) showed no signals of MeOH and MTBE. No morphological change of free form B was observed by VT-XRPD after heating to 160°C (Figure 13). Free form B sample after VT-XRPD study was characterized by TGA / DSC. The results are shown in Figure 14. The TGA / DSC results show a weight loss of 0.9% up to 170°C and one endotherm at 189.5°C (peak). The DVS plot of free form B showed a water uptake of 6.3% at 25°C from 0% RH to 80% RH (Figure 15), indicating that free form B was hygroscopic (European pharmacopoeia 5.0, Example 4). No morphological change was observed after DVS study (Figure 16, 60% RH to 95% RH to 0% RH to 95% RH). These data indicate that the free form, Form B, is anhydrous. Table 2-1b: List of XRPD peaks for free form Form B (dry): [Table 2-1b]

[0361] Free form type C Free form C was obtained via solid vapor diffusion of free form A in EtOH. Approximately 20 mg of free form A was added to a 3-mL vial. The solid was then placed in a 20-mL vial with 4 mL of EtOH. The 20-mL vial was sealed with a cap and kept at RT to allow organic vapors to interact with the solid. Free form C was obtained after solid vapor diffusion at RT for 17 days.

[0362] The XRPD pattern of Free Form C is displayed in Figure 17 with the peaks listed below. The wet cake of Free Form C converted to Free Form A after drying in vacuum at RT for about 3 hours. These data indicate that Free Form C is a metastable form. Table 2-1c: List of XRPD peaks for free form Form C: [Table 2-1c]

[0363] Free form type D CHCl 3 A free form D sample was obtained in an isolation experiment using. The detailed preparation procedure is shown in Table 9-3.

[0364] The XRPD pattern of free form Form D is displayed in Figure 18 and Figure 186 with the peaks for the dry cake listed below. The TGA / DSC results (Figure 19) showed a weight loss of 8.2% up to 120°C and one endotherm at 106.7°C (peak). 1 The H NMR spectrum (Figure 20) shows that 3 The DVS plot of free form D showed a water uptake of 0.3% at 25°C from 10% RH to 80% RH (Figure 21). The sample weight rapidly decreased when the humidity decreased from 10% to 0%, which may have been caused by the loss of crystal water. No morphology change was observed after the DVS test (Figure 22, 40% RH to 95% RH to 0% RH to 95% RH). Single crystal determination of free form D was performed, which demonstrated that free form D was a trihydrate.

[0365] To check the solid-state stability of free form D under various humidity, humidity-induced experiments of free form D under ~7% RH (dessicator with silica gel), ~22% RH, ~43% RH, ~58% RH, and ~84% RH were carried out. Approximately 20 mg of free form D was added to a 3-mL vial. The 3-mL vial was then placed into a 20-mL vial with 4 mL of the corresponding saturated salt solution. The 20-mL vial was sealed with a cap and kept at RT for water vapor to interact with the solid. The XRPD results are shown in Figure 23. No morphological changes of free form D were observed after 6 weeks of exposure to various humidity levels. Table 2-1d: List of XRPD peaks for free form Form D (dry): [Table 2-1d-1] [Table 2-1d-2]

[0366] Thermodynamic Relationship Research Acetone / H2O with various water activities (0.0-1.0) 2 A slurry competition was carried out in the 200 system. An equal mass ratio mixture of hydrated free form A and anhydrous free form B was suspended in a saturated solution (prepared with free form A) and then stirred at RT for 2 days. The solids were isolated and examined by XRPD. The results, summarized in Table 2-2 and shown in Figure 24, show that the acetone and acetone / H2O2 solutions were significantly higher in the acetone / H2O2 solution than in the anhydrous free form B solution. 2 O(a w =0.2), free form B was obtained, and H 2 O and acetone / H 2 O(a w =0.4 / 0.6 / 0.8), indicating that free form A was obtained.

[0367] Acetone / H 2 To measure the solubility of the free form in the O system, w = 0.3 acetone / H 2 The above experiment was repeated with the addition of the 0 system. The suspension samples were centrifuged to obtain a precipitate and a supernatant. The supernatant after filtration was tested for solubility and the isolated precipitate was tested by XRPD. As summarized in Table 2-3 and shown in Figure 25, the solubility of acetone and acetone / H2O was 100%. 2 O(a w =0.2) to obtain free form B, and 2 O(a w =0.3 / 0.4 / 0.6 / 0.8) gave free form A, and H 2 In experiments with acetone / H2O, an additional peak was observed for free form A. 2 O(a w = 0.8), the highest solubility (10.3 mg / mL) was observed. Approximately 5 mg of free form D was added to a slurry competition experiment with free forms A or B, and the samples were stirred again at RT for 10 days. As summarized in Table 2-4 and shown in Figures 26 and 27, the solubility of acetone and acetone / H2 O(a w =0.2), free form B was obtained, and H 2 O and acetone / H 2 O(a w =0.6 / 0.8) to obtain free form D type, and acetone / H 2 O(a w =0.4), a mixture of free forms A and D was obtained.

[0368] a from 0.3 to 0.5 w To determine the thermodynamic relationship between the free forms A and D of the hydrates in the range, acetone / H 2 O(a w A slurry competition was carried out in acetone / H2O (H2O = 0.3 / 0.4 / 0.5). A mixture of the hydrate free form A and the hydrate free form D in equal mass ratios was suspended in the saturated solution and then stirred at RT for 4 days. The solids were isolated and examined by XRPD. As summarized in Table 2-5 and shown in Figure 28, the acetone / H2O 2 O(a w =0.3 / 0.4 / 0.5) gave free form D. 2 O(a w =0.3) The supernatant of the system was checked by KF after the slurry competition experiment, and the KF results showed that the final water activity was about 0.34.

[0369] According to the slurry competition experiment between free forms A and B, w When is less than 0.2, free form B is obtained, and a w When a was greater than 0.3, free form A was obtained. According to the slurry competition experiment between free forms A and D, a w When β-aminobutyric acid was greater than 0.3, free form D was obtained. Free form D is a more stable hydrate form compared to free form A. Table 2-2 Summary of research into the thermodynamic relationship between free forms A and B [Table 2-2] Table 2-3 Summary of thermodynamic relationship studies (including solubility studies) between free forms A and B [Table 2-3] Table 2-4 Summary of the thermodynamic relationship between free forms A, B, and D [Table 2-4] Table 2-5 Thermodynamic relationship study between free forms A and D (a from 0.3 to 0.5) w Overview of [Table 2-5]

[0370] Example 2. Characterization of the free form of Compound (I) pKa testing For pKa testing of the free form of Compound (I), spectrophotometry (UV measured pKa) and potentiometry (pH measured pKa) were used. 1. For UV quantification pKa, pKa values ​​were determined by monitoring the change in UV absorbance with pH as the compound underwent ionization. 2. For pH-metric pKa, pKa values ​​were determined from examination of the shape of the resulting titration curve and fitting a theoretical model appropriate to the ionization behavior of the compound onto the titration data.

[0371] MeOH was used as a co-solvent for pKa testing. psKa represents the apparent pKa value of the compound measured in water / co-solvent mixtures. psKa values ​​were tested at MeOH concentrations of ~30%, ~40% and ~50%. The psKa values ​​were extrapolated to 0% organic content using the Yasuda-Shedlovsky extrapolation procedure for pKa values.

[0372] The tested and calculated pKa results are summarized in Table 3-1. One pKa result (2.21) tested by UV metrology was outside the valid pH range, recommending the pKa result tested by pH metrology. Schematic diagrams of the free form chemical species are shown in Figure 29 (UV metrology) and Figure 30 (pH metrology). The structures of the free form chemical species are shown in Figure 31. Table 3-1 Summary of pKa test results [Table 3-1]

[0373] Log D 7.4 test To determine the distribution coefficient of the free form of compound (I), the Log D of the free form D was determined in n-octanol / aqueous (pH = 7.4) systems at room temperature by the partitioning shake flask method. 7.4 The detailed steps are summarized below. 1. n-octanol and aqueous buffer are pre-equilibrated by adding 10 mL n-octanol and 10 mL aqueous buffer into a glass vial and keeping it rotating for 24 h. Mutually saturated n-octanol and aqueous buffer are obtained after phase separation. 2. Weigh out approximately 1.0 mg sample and place it into a 3-mL glass vial with 1.0 mL of saturated n-octanol (obtained in step 1 above) and sonicate to aid dissolution. 3. Add 1.0 mL of complementary saturated aqueous buffer into the vial. 4. Prepare samples in triplicate. Seal glass vials and mix on a rotating mixer at 25° C. for 24 h. 5. After spinning the phases are separated. 6. Determine the concentration of the compound in each phase by HPLC. Samples in the n-octanol phase are diluted with 100 μL of sample solution and 900 μL of ACN / H 2 Dilute 10-fold by adding O (v / v, 3:1) diluent and mix thoroughly. 7.D ow The distribution coefficient, termed LogD, is calculated as the concentration of the test compound (both ionized and non-ionized) in the n-octanol phase divided by the corresponding concentration in the aqueous phase. 7.4 Based on the three runs, ow The log10 average is calculated. Detailed results are shown in Figure 30. The results are LogD 7.4 It was shown that the σ is 2.23. Table 3-2 LogD 7.4 Summary of test results [Table 3-2]

[0374] Complex formation stability constant test The complex formation stability constant (K 1:1 To determine the solubility of free form D in different concentrations of HPβCD and SBECD solutions at RT, solubility was tested. ~5 mg of solid was suspended in 1 mL of each medium to give a dosing concentration of ~5 mg / mL. Additional solid was added to the sample to produce a suspension if a clear solution was obtained. The suspension was equilibrated via stirring (1000 rpm) for 24 hours. The suspension was centrifuged to obtain a precipitate and a supernatant. Solubility and pH were determined on the supernatant after filtration, and XRPD was obtained on the isolated precipitate.

[0375] The detailed solubility results are summarized in Table 3-3. The solubility curves of free form D in different concentrations of HPβCD and SBECD solutions are shown in Figure 32. The complexation stability constants (K 1:1 ) for HPβCD and SBECD, respectively, 1529M -1 and 3831M -1 (calculated by the Higuchi-Connors phase solubility method). The data are L This suggests that a type complex is formed with HPβCD and SBECD. No morphological changes were observed during the solubility evaluation in HPβCD and SBECD solutions. The XRPD patterns are shown in Figures 33 and 34. Table 3-3 Summary of complex formation stability constant test results [Table 3-3] Table 3-4 Overview of calculation of complex formation stability constants [Table 3-4]

[0376] Example 3. Salt formation and characterization According to the approximate solubility of free form A (Table 9-5) and the simulated pKa of compound (I) (3.00 / carboxylic acid, 4.24 / pyridine, 7.78 / piperazine, and 8.44 / piperidine, simulated with MarvinBeans 5.6.0.2), salt screening was designed and carried out under 96 conditions using 16 counterions in six solvent systems. Free form A was dissolved in 1:1 molar ratio with the corresponding counterions in six solvents (MeOH, THF, EtOAc, acetone, IPA, and ACN / H2O). 2 The salts were mixed in 1:1000 sucrose / hexane (19:1, v / v) and then stirred at RT for 3 days. After centrifugation, the resulting solids were dried under vacuum at RT overnight and then analyzed by XRPD (Table 4-1). For the clear solutions obtained in the salt screening, slurrying and evaporation at 5° C. was applied to induce solid precipitation. Based on the XRPD results, 10 crystalline salts (17 forms) were obtained and characterized. The characterization results are summarized in Table 4-2. The detailed characterization results are shown in Example 7.

[0377] Six additional HCl salt formation experiments with different charge ratios were performed. The experiments and results are summarized in Table 4-3. HCl salt forms B / C / D / E were observed and characterized. Characterization results are summarized in Table 4-2. Detailed characterization results are provided in Example 7. Table 4-1 Summary of salt formation experiments [Table 4-1] Table 4-2. Characterization of salt forms of compound (I) [Table 4-2] Table 4-3 Summary of additional HCl salt formation experiments [Table 4-3]

[0378] Salt preparation and characterization HCl Form D, Fumarate Form B, and Sulfate Form B showed better solid state properties when compared to other salt forms. Three salts were selected for reformulation on 500 mg scale. HCl Form F (new form), Fumarate Form A, and Sulfate Form B were obtained during reformulation experiments and three forms were selected for solubility evaluation. The preparation procedures for the three salts are summarized in Table 4-4. Table 4-4 Preparation procedures for the three salt forms [Table 4-4]

[0379] HCl salt type F During the re-preparation of HCl salt Form D, HCl salt Form F was obtained. The detailed preparation procedure is summarized in Table 4-4. The XRPD pattern of HCl salt Form F is displayed in Figure 35. The TGA / DSC result of the sample (Figure 36) showed a weight loss of 3.4% up to 190°C and two endotherms at 249.5°C (peak) and 288.1°C (peak). 1 The H NMR spectrum (FIG. 37) showed no ACN signal. HPLC / IC results showed Cl - The molar ratio of water to free form was 2.2:1.0. The DVS plot of HCl salt Form F showed a water uptake of 2.3% at 25° C. from 0% RH to 80% RH (FIG. 38). No morphological changes were observed after the DVS study (FIG. 39).

[0380] Sulfate type B Sulfate Form B was obtained during the salt formation experiment in acetone and this form was selected for reconstitution on a 500 mg scale. The detailed preparation procedure of Sulfate Form B is summarized in Table 4-4. The XRPD pattern of the reconstituted Sulfate Form B is displayed in Figure 40. The TGA / DSC results of the sample (Figure 41) showed a weight loss of 4.8% up to 200°C and three endotherms at 86.4°C (peak), 255.3°C (peak), and 279.7°C (peak). 1The H NMR spectrum (FIG. 42) showed no acetone signals. HPLC / IC results showed that SO 4 2- The molar ratio of sulfate to free form was 1.0:1.0. The DVS plot of sulfate Form B showed a water uptake of 7.2% at 25° C. from 0% RH to 80% RH (FIG. 43). Two additional peaks (marked with arrows) were observed after the DVS test (FIG. 44).

[0381] Fumarate type A A sample of fumarate Form B was obtained during the salt formation experiment in THF / EtOAc / acetone. This form was selected for re-preparation on a 500 mg scale. The detailed preparation procedure of fumarate Form B is summarized in Table 4-4, while fumarate Form A was obtained. The XRPD pattern of fumarate Form A is displayed in Figure 45. The TGA / DSC result of the sample (Figure 46) showed a 6.6% weight loss up to 170°C and one endotherm at 158.9°C (peak). 1 H NMR spectrum (Figure 47) showed that the molar ratio of acetone:free form in fumarate form A was about 0.01:1.0 (~0.08%) and the molar ratio of fumaric acid:free form was 1.0:1.0. The DVS plot of fumarate form A showed a water uptake of 6.1% at 25°C from 0% RH to 80% RH (Figure 48). The crystallinity of fumarate form A decreased after the DVS study (Figure 49).

[0382] Example 4. Evaluation of salt and free forms HCl salt form F, fumarate salt form A, and sulfate salt form B were selected as salt forms to compare the grinding stability and solubility of various salts with the free form A.

[0383] Grinding stability To compare the grinding stability of Free Form A, Sulfate Form B, Fumarate Form A, and HCl Form F, approximately 30 mg of each solid sample was added to a mortar and then manually ground for about 5 minutes. The crystallinity of Free Form A, Sulfate Form B, Fumarate Form A, and HCl Form F decreased after grinding. The results are shown in Figures 50-53.

[0384] Equilibrium solubility in pH buffers (3.0-8.0), 20% Captisol, and water Equilibrium solubility of free form Form A, sulfate Form B, fumarate Form A, and HCl salt Form F in 50 mM pH buffer (pH=3.0, 4.0, 5.0, 6.0, 7.0, 8.0), 20% Captisol (pH=5.0, w / v), and water was performed at RT (approximately 21° C.) with a sampling time of 24 hours. ∼5 mg of solid was suspended in 1 mL of each medium to give a dosing concentration of ∼5 mg / mL. When a clear solution was obtained, additional solid was added to the sample to form a suspension. The suspension was equilibrated via stirring (1000 rpm). The suspension was centrifuged to obtain a precipitate and a supernatant.

[0385] Solubility and pH were tested on the supernatant after filtration and the isolated precipitate was tested by XRPD. The equilibrium solubility results are summarized in Table 5-1. The XRPD results are shown in Figures 54-61. 1. For the free form A, no morphological changes were observed after 24 hours of equilibration in all media (clear solutions were obtained in pH=4.0 buffer). For the three salt forms, morphological changes were observed after 24 hours of equilibration in all media (except for sulfate form B in water). 2. Free form A showed the highest solubility in pH=4.0 buffer (>17.9 mg / mL, 50 mM citrate buffer, final pH=4.8). Fumarate form A showed the highest solubility in pH=6.0 buffer (20.6 mg / mL, 50 mM citrate buffer, final pH=5.1). HCl salt form F and sulfate salt form B showed low solubility in pH buffer (<8 mg / mL). Table 5-1 Summary of equilibrium solubility results at RT [Table 5-1]

[0386] Equilibrium solubility in pH-adjusted pH buffers (pH 4.0-6.0) Free form Form A and fumarate Form A showed higher solubility in 50 mM pH=4.0 and pH=6.0 buffers. To distinguish the solubility under different pH ranging from pH 4.0 to 6.0, the solubility of all four materials was tested in 50 mM pH=4.0, 5.0, and 6.0 citrate buffers and pH adjusted pH=6.0 phosphate buffer. In detail, ~5 mg of solid was suspended in 1 mL of each medium to give a dosing concentration of ~5 mg / mL. If a clear solution was obtained, additional solid was added into the sample to form a suspension. The suspension was equilibrated via stirring (1000 rpm) for 24 hours. The pH of the suspension was adjusted when the final pH shifted above 0.3, and the sample was stirred for another 1.5 hours after pH adjustment. The suspension was centrifuged to obtain the precipitate and supernatant. Solubility, purity, and pH were tested on the supernatant after filtration, and the isolated precipitate was tested by XRPD. The equilibrium solubility results are summarized in Table 5-2. The XRPD results are shown in Figures 62-65. 1. For the free form A, no morphological changes were observed after 24 hours of equilibration in all media (clear solutions were obtained in pH=4.0 buffer). For the three salt forms, morphological changes were observed after 24 hours of equilibration in all media (sulfate form B showed no morphological changes in water). 2. Free form A showed the highest solubility in pH=4.0 buffer (>36.9 mg / mL, 50 mM citrate buffer, final pH=4.2). Fumarate form A showed the highest solubility in pH=5.0 buffer (19.3 mg / mL, 50 mM citrate buffer, final pH=4.9). HCl salt form F and sulfate salt form B showed low solubility in pH buffer (<6.8 mg / mL). Table 5-2 Summary of equilibrium solubility results at RT in pH=4.0 / 5.0 / 6.0 buffers [Table 5-2]

[0387] Example 5. Pre-formulation development In Situ Salt Solubility Test The free form showed high solubility in pH=4.0 buffer (>36.9 mg / mL, 50 mM citrate buffer, final pH=4.2) and fumarate Form A showed high solubility in pH=5.0 buffer (19.3 mg / mL, 50 mM citrate buffer, final pH=4.9). Citric and fumaric acids were selected for in situ salt solubility testing with free form Form D.

[0388] For the in situ salt formation of citric acid, ~50mg free form D and 1.1 equivalents of citric acid were added in a 5mL vial and 1.1mL water was added to dissolve the sample. The sample was almost clear (almost no solids were observed). It was filtered for solubility testing. The concentration of free form D tested with 1.1 equivalents of citric acid in water was 39.3mg / mL (final pH=3.4).

[0389] For the in situ salt formation of fumaric acid, ~5mg free form D and 1.1 equivalents of fumaric acid were added in a 5mL vial and 4.2mL water was added to dissolve the sample. The sample was almost clear (almost no solids were observed). It was filtered for solubility testing. The concentration of free form D tested with 1.1 equivalents of fumaric acid in water was 1.1mg / mL (final pH=4.0).

[0390] The small amount of solid observed during sample preparation may be an insoluble impurity according to the data from the in situ salt formation sample (Figure 66). The results showed that one impurity with a retention time of approximately 9 minutes in the free form D form disappeared in solutions with citric acid and fumaric acid, so the impurity may have been filtered out prior to purity and concentration testing.

[0391] The results of the in situ salt formation and solubility evaluation are summarized in Table 6-1. In situ salt formation with citric acid showed higher solubility and citric acid was selected for further in situ salt formation and further preformulation studies. Table 6-1 Summary of in situ salt solubility test results [Table 6-1]

[0392] Preparation of solid citrate samples Approximately 35 mg free form D and 9.6 mg citric acid (~1 equiv.) were dissolved in 1 mL water (~50 mM), the sample was slightly turbid and filtered to obtain the supernatant. The resulting supernatant was dried under vacuum at RT to obtain an amorphous sample. The amorphous sample was stirred in EtOH and EtOAc for 9 days, respectively. XRPD results showed that the sample was still amorphous after stirring in the solvents (Figure 67).

[0393] of free form D, amorphous sample, and mixture of free form D + 1 equivalent of citric acid 1 H NMR was obtained and the results are shown in Figures 68-72. 1 H NMR signals were observed. XPS (Figure 73) of the free form D and amorphous sample shows that the nitrogen peak of the two samples is shifted, indicating potential salt formation.

[0394] Solubility profile of free form D in citrate buffer To understand the solubility profile of free form D in citrate buffers of different concentrations and pH, the equilibrium solubility of free form D in citrate buffers was tested at RT at different buffer concentrations (10 / 20 / 50 / 100 mM) and different pH (2.8-5.5). ~5 mg of solid was suspended in 1 mL of each medium to give a dosing concentration of ~5 mg / mL. If a clear solution was obtained, additional solid was added to the sample to form a suspension. The suspension was equilibrated via stirring (1000 rpm) for 24 hours. The suspension was centrifuged to obtain a precipitate and a supernatant. The solubility and pH were tested on the supernatant after filtration and the isolated precipitate was tested by XRPD. The equilibrium solubility results are summarized in Table 6-2 and the solubility curve of free form D in citrate buffers is shown in Figure 74. The XRPD results are shown in Figures 75-78. No conformational change was observed in free form D after equilibration for 24 hours in all buffers. The solubility of the free form D increased when the pH was decreased or the buffer concentration was increased. The highest solubility tested was 56.8 mg / mL (100 mM citrate buffer, final pH=4.9). Table 6-2 Summary of equilibrium solubility results at RT in citrate buffers [Table 6-2]

[0395] Example 6. Free form stability assessment Solution stability in citrate buffer Solution stability of free form D in 10 mM citrate buffer (pH 4.3, 1 mg / mL) and 100 mM citrate buffer (pH 4.1, 40 mg / mL) was determined. The stock solution of 40 mg / mL free form D in 100 mM pH=4.1 citrate buffer was slightly turbid and the stability study was initiated after filtering the suspension through a 0.45 μm PTFE filter. The stock solution of 1 mg / mL free form D in 10 mM pH=4.3 citrate buffer was clear and was not filtered before initiating the stability study. The stability samples were stored at 5° C. and 25° C. for 28 days, respectively. After 28 days of storage, the stability samples were taken for HPLC and pH testing.

[0396] Free form D at 1 mg / mL in 10 mM citrate buffer, pH 4.3, became cloudy and yellow for 28 days at 25° C. and became a yellow solution for 28 days at 5° C. Free form D at 40 mg / mL in 100 mM citrate buffer, pH 4.1, became cloudy for 28 days at 5° C. and remained a clear solution for 28 days at 25° C. The visual findings are shown in FIG. The stability results are summarized in Table 7-1. The assay of 1 mg / mL free form D in citrate buffer decreased to 68.4% and 11.6% after storage at 5° C. and 25° C. for 28 days. No significant degradation was observed for 40 mg / mL free form D in 100 mM citrate buffer at 5° C. and 25° C. for 28 days. The assay of the stability samples decreased (95.0% and 98.9% for the 5° C. and 25° C. stability samples). Chromatogram overlays of the stability samples are shown in FIG. 80 and FIG. 81. Table 7-1 Summary of solution stability experiments in citrate buffer [Table 7-1]

[0397] Formulation solution stability The solution stability of free form Form D in five formulations was tested at 5° C., 25° C., 40° C., and 60° C. The five formulations are shown in Table 7-2 and the characterization results are summarized in Example 7. The procedures are summarized below. 1. Weigh approximately 544 mg free form Form D into a 25 mL volumetric flask and prepare 5 copies (designated Formulations 1 / 2 / 3 / 4 / 5). 2. Add approximately 149 mg Citric Acid to the Formulation 1 / 2 / 3 / 4 volumetric flask. 3. Add approximately 2037 mg of the corresponding sugar into the volumetric flask of formulation 2 / 3 / 4. (The solubility of free form D in the presence of sugar is shown in Example 7) 4. For formulations 1 / 2 / 3 / 4, Dilute to volume with water. 5. For Formulation 5, dilute the volume with pH=4.0 citrate / phosphate buffer. (The solubility of free form D in citrate / phosphate buffer is shown in Example 7.) 6. Sonicate the sample for approximately 2 minutes and filter through a 0.45 μm filter to obtain a clear solution. 7. Pour approximately 0.7 mL of solution into 32 separate HPLC vials for each formulation, seal and store under corresponding conditions.

[0398] Stability samples were stored for 28 days at 5° C., 25° C., 40° C., and 60° C. After 1, 3, 7, 14, and 28 days of storage, stability samples at 25° C., 40° C., and 60° C. were removed for HPLC and pH testing. After 28 days of storage, stability samples at 5° C. were removed for HPLC and pH testing. Table 7-2 Summary of the five formulations used for stability studies [Table 7-2]

[0399] Stability tests at 25℃, 40℃, and 60℃ All stability samples at 25° C., 40° C., and 60° C. remained clear solutions. The stability results of the free form in Formulations 1 to 5 at 25° C., 40° C., and 60° C. are summarized in Tables 7-3 to 7-7. 1. In all five formulations, no significant degradation was observed after storage for 28 days at 25°C. 2. In all five formulations, decomposition of 1.3% to 2% was observed after storage at 40°C for 28 days. 3. In all five formulations, ~7% degradation was observed after 16 days of storage at 60°C.

[0400] The impurity with RRT around 1.23 was the major growth impurity. The impurities increased with increasing temperature and time. The impurity growth plots for formulations 1-5 are shown in Figures 82-86. The chromatogram overlays of the stability samples are shown in Figures 87-101. The results show that the presence of sugar in the formulations does not affect the stability. Table 7-3. Summary of solution stability evaluation experiment for formulation 1 [Table 7-3] Table 7-4. Summary of solution stability evaluation experiment for formulation 2 [Table 7-4] Table 7-5. Summary of solution stability evaluation experiment for formulation 3 [Table 7-5] Table 7-6 Summary of solution stability evaluation experiment for formulation 4 [Table 7-6] Table 7-7 Summary of solution stability evaluation experiment for formulation 5 [Table 7-7]

[0401] Stability study at 5℃ Some of the stability samples at 5° C. became suspended after 37 days of storage. The samples were then stirred (1000 rpm) at 5° C. for 2 days, at which point all samples became suspended. Three samples were characterized under each condition to determine the identity of the precipitate, the solubility of the citrate salt at 5° C., and the stability at 5° C. 1. Sample 1 of formulations 1 / 2 / 3 / 4 / 5 after mixing was isolated and analyzed by XPRD / MS of the solid. 1 H NMR was obtained and the supernatant was tested for purity / assay / concentration / pH. 2. Sample 2 of Formulations 1 / 2 / 3 / 4 / 5 after mixing was stored at RT for approximately 1 hour to allow the solids to dissolve. The solution was tested for purity / assay / concentration. 3. Sample 3 of Formulations 1 / 2 / 3 / 4 / 5 after stirring was sonicated at RT for approximately 2-3 minutes to dissolve solids.

[0402] Characterization of the stability samples at 5° C. for formulations 1-5 is summarized in Tables 7-8-7-12. XRPD results showed that the solids obtained at 5° C. for formulations 1 / 2 / 3 / 4 / 5 were amorphous (FIG. 102). 1 H NMR showed that the precipitate in all cases could be citrate salt with the molar ratio of citric acid:free form in the solids being about 0.8:1 to 1:1 (Figures 108-112). The amount of solids obtained in formulations 1 and 5 was less than that in formulations 2-4 as confirmed by the supernatant concentration results shown in Tables 7-8 and 7-12, suggesting that the presence of sugars reduces the solubility of citrate salt at 5°C from 16.9 mg / ml to as low as 10.4 mg / mL. For formulations 1-5, no significant degradation was observed after 37 days of storage at 5°C. All formulations were allowed to warm to room temperature once to dissolve all solids, suggesting that the solubility of citrate salt at RT is greater than 20 mg / mL. Chromatogram overlays of the stability samples are shown in Figures 103-107. Table 7-8 Summary of solution stability evaluation experiments for Formulation 1 at 5°C [Table 7-8] Table 7-9 Summary of solution stability evaluation experiments for Formulation 2 at 5°C [Table 7-9] Table 7-10 Summary of solution stability evaluation experiments for formulation 3 at 5°C [Table 7-10] Table 7-11 Summary of solution stability evaluation experiments for formulation 4 at 5°C [Table 7-11] Table 7-12 Summary of solution stability evaluation experiments for Formulation 5 at 5°C [Table 7-12]

[0403] Solution stability in formulation with lactose (dosage concentration 40mg / mL) The physical and chemical stability of formulation 2 in Example 6 was tested at 40 mg / mL concentration. A 40 mg / mL free form + citric acid + lactose formulation was prepared by transferring 217.5 mg free form sample (equivalent to ∼200 mg API), 62.5 mg citric acid, and 297 mg lactose into a 5 mL volumetric flask and diluting the volume with water. The resulting sample was sonicated for about 2 minutes and filtered through a 0.22 um filter. The tested concentration was 39.3 mg / mL and the pH of the solution was 3.6. About 5 mg of amorphous wet sample (solid obtained at 5°C in formulation 2, Example 6) was added into 1 mL of the 40 mg / mL formulation and the solid was dissolved after stirring for 1 hour. Another 5 mg of amorphous wet sample was added into the 40 mg / mL formulation and the solid was dissolved after stirring for 1 hour. The tested concentration of the resulting solution was 41.6 mg / mL and the pH of the solution was 3.6. Approximately 5 mg of the wet cake was added to a 40 mg / mL formulation (~41.6 mg / mL) and the sample was stirred overnight at 5°C to give a suspension. The suspension was stirred at RT for 1 hour to give a clear solution. The pH of the resulting solution was 3.7 and the concentration of the solution was 42.8 mg / mL. This result suggests that the formulation at the 40 mg / mL concentration is physically stable and not supersaturated. No precipitation of the citrate salt is expected when the solution is stored at room temperature.

[0404] Another 1 mL of the 40 mg / mL free form + citric acid + lactose formulation was stored at RT for 1 week (covered with aluminum foil). The purity of the 1 week stability sample was 99.01% and the pH was 3.7. No significant degradation was observed. A chromatogram overlay of the stability sample is shown in Figure 113.

[0405] Solid State Stability The solid state stability of free form Form D was determined: Approximately 30 mg of each solid sample was added to an HPLC vial (sealed with Parafilm® and punctured with several pinholes) and then stored at 25° C. / 60% RH, 40° C. / 75% RH, and 60° C. for 28 days.

[0406] After storage for 1 / 3 / 7 / 14 / 28 days, the solids were taken for HPLC and XRPD to assess the chemical and physical stability, respectively.

[0407] The stability results are summarized in Tables 7-13. No significant decomposition or morphological changes were observed after 28 days of storage at 25° C. / 60% RH, 40° C. / 75% RH, and 60° C. XRPD overlays of the stability samples are shown in Figures 114-116, and chromatogram overlays of the stability samples are shown in Figures 117-119. Table 7-13 Overview of solid-state stability evaluation experiments [Table 7-13]

[0408] In summary, the free form isolation and 100 polymorphic and salt formation experiments of Compound (I) free form were carried out by various crystallization methods. Four crystalline forms of the free form (designated as free forms A, B, C, and D) and 10 crystalline salts (19 forms) were obtained. The pKa, Log D of free form D in HPβCD and SBECD were 7.4 , and the complex formation stability constants were also determined.

[0409] Equilibrium solubility evaluations were performed for free form Form A, HCl salt Form F, fumarate salt Form A, and sulfate salt Form B. Free form Form A showed high solubility in pH=4.0 buffer (>36.9 mg / mL, 50 mM citrate buffer, final pH=4.2). The free form was selected for further development. According to the solubility results, the free form and citric acid were selected for further preformulation studies. Solubility, stability (solid and solution), and preformulation experiments of free form Form D with citric acid were performed. A formulation of Compound (I) free form with 1.05 equivalents citric acid and 173 mM lactose (40 mg / mL) was selected for further development, and the formulation showed no degradation after 7 days of storage at RT.

[0410] The trihydrate free form D was selected for further development. During the thermodynamic relationship study, w The free form D was obtained when RH was >0.3 and was kinetically stable for at least 6 weeks under a wide range of RH (7%-84%). The citrate salt offers significant aqueous solubility enhancement (>50 mg / mL vs. 0.02 mg / mL free form) and good solution stability. In addition, it can be conveniently prepared in situ by simply mixing citric acid and the free form in water. As a result, a solution of 40 mg / mL Compound (I) free form (adjusted for weight), 1.05 equivalents citric acid, and 173 mM lactose (QS to make isotonic) was identified as the formulation to be employed in the toxicology studies.

[0411] Example 7. Characterization of starting materials Compound (I) starting material was analyzed by XRPD, TGA, DSC, LC-MS, PLM, and 1The sample was characterized by H NMR. The XRPD pattern (Figure 120) showed that the sample was low crystallinity. In Figure 121, the TGA curve showed a 6.1% weight loss up to 130°C, followed by a continuous weight loss of 10.9% from 130°C to 280°C, and the DSC curve showed five endotherms at 72.4°C (peak), 140.7°C (peak), 159.8°C (peak), 187.7°C (peak), and 194.3°C (peak). The LC-MS result (Figure 122) showed that the m / z of the sample was 641.2. The PLM (Figure 123) showed that the sample was aggregated and irregular particles. 1 1 H NMR (Figure 124) showed that the molar ratio of isopropylamine:free form in the sample was approximately 0.8:1.0.

[0412] Free form isolation of starting material The free form isolation procedure is summarized below: 1. The starting material (SM) is dissolved or dispersed in a corresponding solvent. 2. Add the corresponding acid (in the ratio given in the summary table) to the solution or suspension. 3. The experiment was stirred at 5° C. for about 10 min to 1 h and the solid was collected by centrifugation or filtration followed by rinsing with water. The solid was dried in vacuum and characterized.

[0413] Four free form isolation experiments were carried out in different solvents with various acids. The solid was dissolved in DCM / HCl and CHCl 3 The solid was analyzed by XRPD / 1 Characterized by H NMR / IC, two samples were found to contain isopropylamine and residual Cl - The resulting crystal sample was free of any crystalline components (designated free form A). The experiments and results are summarized in Table 9-1. The approximate solubility of the starting material and free form A was tested at RT. The starting material was CHCl 3 The free form, Form A, is more soluble in CHCl 3 (Table 9-2).

[0414] Residual Cl -Considering that CHCl was detected in the free form A and that HCl may have reacted with the free form during isolation, the ratio between the free form and HCl was adjusted. 3 Four other free form isolation experiments were performed with different charge ratios of acid to starting material in the HCl:starting material. The experiments and results are summarized in Table 9-3. 3 The solid obtained in the reaction mixture was isopropylamine and Cl. - The XRPD results showed that the solid was free form Form A.

[0415] All solids obtained in the free form isolation procedure are shown in Figure 125. CHCl 3 The solid obtained in CHCl (0.5 eq. HCl) and DCM (1 eq. HCl) was consistent and was designated free form Form A. 3 (0.9 equivalent HCl), CHCl 3 (0.8 equiv. HCl), and CHCl 3 At (1 equiv. HCl) additional diffraction peaks were observed, which could be attributed to partial formation of the HCl salt.

[0416] CHCl 3 was selected as the final free form isolation solvent, and HCl with a charge ratio of 0.5:1 was selected as the final acid. The free form isolation was carried out on an 8 g scale. The detailed procedure is summarized in Table 9-4. No residual isopropylamine but Cl - The free form A was obtained with a concentration of 0.35% (Cl in the solid). - (The calculated molar ratio of :free form was about 0.06:1.) Characterization results of 8 g free form A are shown in Example 1. The sample was used for polymorphism and salt formation.

[0417] Free form isolation was re-performed using 8 g free form A for the formation experiment. The detailed procedure is summarized in Table 9-4. The wet cake obtained in step 3 of the procedure was the new crystalline form. The new crystalline form was transferred to the low crystallinity sample after vacuum drying (Figure 126). The IC results showed that the Cl in the sample was 0.01%. -The weight percentage of Cl in the solid was about 1.6%. - The calculated molar ratio of the solid to the free form was approximately 0.3:1. 2 The mixture was stirred in 20:1 O / acetone (10:1, v / v) for 3 days to remove potential HCl salts, and then dried in vacuum. - Another new crystalline form was finally obtained, which was named Free Form D. The characterization results of Free Form D are shown in Example 1. Samples were used for solubility and stability evaluation. Table 9-1 Free form isolation experiments and results (I / II) [Table 9-1] Table 9-2 Approximate solubility results in solvents for free form isolation [Table 9-2] Table 9-3 Free form isolation experiments and results (II / II) [Table 9-3] Table 9-4. Free form isolation procedures [Table 9-4]

[0418] Characterization of starting materials Starting materials were analyzed by XRPD, TGA, DSC, PLM, 1 It was characterized by H NMR, DVS, and KF. The XRPD pattern (Figure 127) showed that the diffraction peaks of the starting material were similar to the free form D, but some of the diffraction peaks were shifted. In Figure 128, the TGA curve showed a weight loss of 7.1% up to 130°C, and the DSC curve showed one endotherm at 85.8°C (onset). 1H NMR results are shown in Figure 129. PLM (Figure 130) showed the sample as rod-like particles. DVS results (Figure 131) showed 0.7% water uptake when humidity varied from 10% RH to 80% RH and no morphology change was observed after DVS test (Figure 132). KF results showed that the water content in the sample was 2.7%. As the KF results did not match the TGA results, some experiments were performed. Approximately 100 mg of starting material was stored under ambient conditions in open and closed bottles over the weekend. TGA and KF tests were performed on two samples (Figure 133). As per the characterization results the water content of the sample correlates with the ambient humidity. Single crystal determination was performed to confirm the water content.

[0419] Approximate solubility and solvent abbreviations The approximate solubility of Compound (I) free form A (Table 9-5) was tested at RT to guide polymorph and salt formation experiments. Approximately 2 mg solid was added to a 3-mL glass vial. The solvents in the table below were then added stepwise (50-50- 200-700-1000 μL per step) to the vial and stirred until the solid was dissolved or the total volume reached 1 mL. The solubility results were used to guide solvent selection in polymorph formation. Table 9-5 Approximate solubility of free form A at RT [Table 9-5] Table 9-6 List of solvent abbreviations [Table 9-6]

[0420] Polymorphism of Compound (I) in free form Polymorphism experiments using Compound (I) free form Form A as the starting material were carried out under 100 conditions. The methods utilized and the crystalline forms identified are summarized in Table 9-7. Table 9-7 Summary of free form polymorph formation [Table 9-7]

[0421] Slurry at RT Slurry experiments were performed in 19 different solvent systems at RT. ∼20 mg of Free Form A was suspended in 0.5 mL of the corresponding solvent in an HPLC vial. The suspension was magnetically stirred (∼1000 rpm) at RT for approximately 7 days, after which the remaining solid was isolated for XRPD analysis. The results, summarized in Tables 9-8, indicate that Free Form A and Free Form B were produced. Table 9-8 Summary of slurry conversion experiments at RT [Table 9-8]

[0422] Slurry at 50℃ Slurry experiments were performed in 18 different solvent systems at 50° C. Approximately 20 mg of Free Form A was suspended in 0.5 mL of the corresponding solvent in an HPLC vial. After the suspension was magnetically stirred (~1000 rpm) at 50° C. for approximately 3 days, Free Form A and Free Form B were observed. The results are summarized in Table 9-9. Table 9-9 Summary of slurry conversion experiments at 50°C [Table 9-9]

[0423] Slow evaporation Slow evaporation experiments were carried out under nine conditions. Approximately 20 mg free form A was dissolved in the corresponding solvent in a 3-mL glass vial. All samples were filtered using a PTFE membrane (0.45 μm pore size) and the filtrate was used for the follow-up step. The vial was sealed with Parafilm® (with a few pinholes) and allowed to slowly evaporate at RT. Free form A was observed. The results are summarized in Tables 9-10. Table 9-10 Summary of slow evaporation experiments [Table 9-10]

[0424] Liquid Vapor Diffusion Liquid vapor diffusion was performed under 10 conditions. Approximately 20 mg of free form A was dissolved in 0.5-1.2 mL of the appropriate solvent in a 3-mL vial. The solution was filtered to obtain a clear solution. This solution was then placed in a 20-mL vial containing 4 mL of the corresponding volatile solvent. The 20-mL vial was sealed with a cap and kept at RT for a sufficient time to allow the organic vapor to interact with the solution. Free form A and free form B were observed. The results are summarized in Tables 9-11. Table 9-11 Summary of liquid vapor diffusion experiments [Table 9-11]

[0425] Temperature Cycling Temperature cycling experiments were performed in 12 different solvent systems from 50°C to 5°C (0.1°C / min, 3 cycles). Approximately 20 mg of Free Form A was suspended in 0.5 mL of the corresponding solvent in an HPLC vial. After the suspension was magnetically stirred (~1000 rpm) for approximately 5 days, Free Form A and Free Form B were observed. The results are summarized in Tables 9-12. Table 9-12. Overview of temperature cycle experiment [Table 9-12]

[0426] Polymer-induced crystallization Polymer-induced crystallization was carried out under four conditions. Approximately 20 mg free form Form A was dissolved in the corresponding solvent in a 3-mL glass vial. All samples were filtered using a PTFE membrane (0.45 μm pore size) and the filtrate was used for the follow-up step. Approximately 2 mg of the corresponding polymer was added into the filtrate, and then the vial was sealed by Parafilm® (with a few pinholes) and allowed to evaporate slowly at RT. Free form Form A was observed. The results are summarized in Tables 9-13. Table 9-13 Summary of polymer-induced crystallization experiments [Table 9-13]

[0427] Solid Vapor Diffusion Solid vapor diffusion was carried out under 12 conditions. Approximately 20 mg of Free Form A was added to a 3-mL vial. The solid was then placed in a 20-mL vial containing 4 mL of the corresponding volatile solvent. The 20-mL vial was sealed with a cap and kept at RT for a sufficient time to allow the organic vapor to interact with the solid. After 20 days of evaporation, Free Form A and Free Form B were observed. The results are summarized in Tables 9-14. Table 9-14 Summary of solid vapor diffusion experiments [Table 9-14]

[0428] Antisolvent addition Anti-solvent addition was performed under 16 conditions. Approximately 20 mg of Free Form A was dissolved in the corresponding solvent. The solution was filtered to obtain a clear solution, and the solution was stirred magnetically (~1000 rpm). Following this, anti-solvent was added slowly until either the precipitate disappeared or the total volume of anti-solvent reached 5 mL. The resulting precipitate was isolated for XRPD analysis. The results in Tables 9-15 showed that Free Form A and Free Form B were produced. Table 9-15 Summary of antisolvent addition experiments [Table 9-15]

[0429] Characterization of Salt Hits HCl salt Six HCl salt forms, designated HCl salt forms A, B, C, D, E, and F, were obtained during the salt formation and rearrangement experiments. The XRPD overlays of the forms are displayed in Figure 134. Samples of HCl salt forms A, B, and C were obtained by reaction of the free forms with 1 equivalent of HCl in MeOH or THF, EtOAc, and ACN, respectively. After drying in vacuum at RT for 5 hours, HCl salt forms B / C were converted to HCl salt form E. HCl salt form D was obtained by reaction of the free forms with 2 equivalents of HCl in ACN. HCl salt form F was obtained during the rearrangement of HCl salt form D. TGA / DSC / MS spectra of HCl salt forms A, D, E, and F were analyzed by NMR, NMR, and NMR. 1 H NMR / HPLC / IC were performed.

[0430] The TGA / DSC curve for the HCl salt Form A in Figure 135 showed a 3.6% weight loss up to 140°C, with three endotherms at 70.9°C (peak), 98.5°C (peak), and 221.2°C (onset). 1 The H NMR spectrum (Figure 136) showed no THF signal. HPLC / IC results showed Cl - The molar ratio of the soluble form to the free form was 0.3:1.0.

[0431] The TGA / DSC curve for the HCl salt Form D in Figure 137 showed a 4.4% weight loss up to 200°C, and three endotherms at 231.6°C (peak), 263.0°C (peak), and 286.6°C (onset). 1 The H NMR spectrum (Figure 138) showed that the molar ratio of ACN:free form in the sample was 0.1:1 (0.8%). HPLC / IC results showed that Cl - The molar ratio of HCl salt to free form was 1.8:1.0. The TGA / DSC curve for the HCl salt Form E in Figure 139 shows a 3.2% weight loss up to 200°C, and two endotherms at 272.4°C (peak) and 281.2°C (peak). 1 The H NMR spectrum (Figure 140) showed no EtOAc signals. HPLC / IC results showed Cl - The molar ratio of the α-tocopherol to the free form was 2.4:1.0.

[0432] Characterization results for the HCl salt Form F are summarized in Example 3.

[0433] Sulfate Two sulfate salt forms, designated sulfate Form A and sulfate Form B, were obtained during the salt formation experiments. XRPD overlays of the forms are displayed in Figure 141. Samples of sulfate Form A and Form B were obtained by reaction of the free form with one equivalent of sulfuric acid in MeOH and EtOAc, respectively. TGA / DSC / MS of sulfate Form A and Form B were analyzed. 1 H NMR / HPLC / IC were performed.

[0434] Sulfate type A 1 The 1 H NMR spectrum (Figure 142) showed no MeOH signal. The amount of sample of sulfate Form A was not sufficient for TGA / DSC / HPLC / IC studies.

[0435] The TGA / DSC curve for the Sulfate Salt Form B in Figure 143 showed a 2.6% weight loss up to 200°C, with three endotherms at 66.7°C (peak), 259.5°C (peak), and 280.0°C (peak). 1 The H NMR spectrum (Figure 144) showed no acetone signals. HPLC / IC results showed that SO 4 2- The molar ratio of the :free form was 1.0:1.0.

[0436] Maleate Two maleate salt forms, designated maleate forms A and B, were obtained during the salt formation experiments. XRPD overlays of the forms are displayed in Figure 145. Samples of maleate forms A and B were dissolved in THF and ACN / H, respectively. 2 The maleate forms A and B were obtained by reaction of the free form with one equivalent of maleic acid in 2H2O (19:1, v / v). 1 H NMR was performed.

[0437] The TGA / DSC curve for the maleate salt Form A in Figure 146 showed a 7.3% weight loss up to 130°C, with three endotherms at 66.1°C (peak), 116.4°C (peak), and 140.9°C (peak). 1 The H NMR spectrum (Figure 147) showed that the molar ratio of THF:free form was approximately 0.3:1.0 (-2.6%) and the molar ratio of maleic acid:free form was 1.1:1.0.

[0438] The TGA / DSC curve for the maleate salt Form B in Figure 148 showed a weight loss of 10.3% up to 140°C, with two endotherms at 56.0°C (onset) and 193.6°C (peak). 1 The 1 H NMR spectrum (Figure 149) showed no signal for ACN, indicating that the molar ratio of maleic acid:free form was 1.0:1.0.

[0439] Tartrate During the salt formation experiments, a form of tartrate salt, designated as Tartrate Form A, was obtained. The XRPD pattern of the form is displayed in Figure 150. The Tartrate Form A sample was obtained by reaction of the free form with 1 equivalent of tartaric acid in ACN / H2O (19:1, v / v). TGA / DSC / 1 H NMR was performed.

[0440] The TGA / DSC curve for the tartrate salt Form A in Figure 151 showed a weight loss of 16.1% up to 160°C, and four endotherms at 89.5°C (peak), 124.0°C (peak), 141.9°C (peak), and 209.8°C (peak). 1 The 1 H NMR spectrum (Figure 152) showed no signal for ACN, indicating that the molar ratio of tartaric acid:free form was 1.2:1.0.

[0441] Fumarate Four fumarate forms, designated Fumarate Forms A, B, C, and D, were obtained during salt formation and reconstitution. XRPD overlays of the forms are displayed in Figure 153. Samples of Fumarate Forms A, B, and C were obtained by reaction of the free forms with one equivalent of fumaric acid in MeOH, THF or EtOAc or acetone, and ACN / H2O (19:1, v / v), respectively. Fumarate Form D was observed during reconstitution of Fumarate Form B in acetone, which shifted to a mixture of Fumarate Forms A and B after drying in vacuum overnight. TGA / DSC / MS of Fumarate Forms A, B, and C 1 H NMR was performed.

[0442] The TGA / DSC curve for the fumarate salt Form A in Figure 154 showed a 6.2% weight loss up to 175°C, with three endotherms at 72.6°C (peak), 165.1°C (peak), and 214.4°C (peak). 1 The H NMR spectrum (Figure 155) showed that the molar ratio of fumaric acid:free form was 1.1:1.0. The TGA / DSC curve for Fumarate Salt Form B in Figure 156 showed a 7.3% weight loss up to 160°C, with three endotherms at 107.2°C (onset), 134.1°C (onset), and 218.5°C (peak). 1 The 1 H NMR spectrum (Figure 157) showed no THF signals, indicating that the molar ratio of fumaric acid:free form was 0.9:1.0.

[0443] The TGA / DSC curve for the fumarate salt Form C in Figure 158 showed a 9.9% weight loss up to 170°C, with two endotherms at 70.8°C (peak) and 167.0°C (peak). 1 The 1 H NMR spectrum (Figure 159) showed no signal for ACN, indicating that the molar ratio of fumaric acid:free form was 1.2:1.0.

[0444] Succinate Three succinate forms, designated succinate forms A, B, and C, were obtained during the salt formation experiments. XRPD overlays of the forms are displayed in Figure 160. Samples of succinate forms A, B, and C were dissolved in THF, IPA, and ACN / H, respectively. 2 The free form was obtained by reaction with one equivalent of succinic acid in 2H2O (19:1, v / v). 1 H NMR was performed.

[0445] Succinate type A 1 The 1 H NMR spectrum (Figure 161) showed that the molar ratio of THF:free form was approximately 0.03:1.0, and the molar ratio of succinic acid:free form was 1.0:1.0.

[0446] The TGA / DSC curve for succinate salt Form B in Figure 162 showed a 5.4% weight loss up to 130°C, three endotherms at 76.0°C (peak), 117.6°C (peak), and 179.0°C (peak), and one exotherm at 147.8°C (peak). 1 The H NMR spectrum (Figure 163) showed that the molar ratio of IPA:free form was approximately 0.3:1.0 (~2.6%) and the molar ratio of succinic acid:free form was 0.3:1.0.

[0447] The TGA / DSC curve for succinate Form C in Figure 164 showed a 6.4% weight loss up to 150°C and five endotherms at 72.9°C (peak), 102.4°C (peak), 119.3°C (peak), 130.7°C (peak), and 205.3°C (peak). 1 The 1 H NMR spectrum (Figure 165) showed no signal for ACN, indicating that the molar ratio of succinic acid:free form was 0.8:1.0.

[0448] Triphenylacetate A form of triphenylacetate, designated triphenylacetate form A, was obtained during the salt formation experiment. The XRPD pattern of the form is displayed in Figure 166. A sample of triphenylacetate form A was obtained by reaction of the free form with one equivalent of triphenylacetate in THF. TGA / DSC / MS of triphenylacetate form A 1 H NMR was obtained.

[0449] The TGA / DSC curve for triphenylacetate Form A in Figure 167 showed a 6.1% weight loss up to 140°C, with three endotherms at 58.4°C (peak), 148.8°C (peak), and 222.5°C (peak). 1 The H NMR spectrum (Figure 168) showed that the molar ratio of THF:free form was approximately 0.5:1.0 (-3.7%) and the molar ratio of triphenylacetic acid:free form was 1.0:1.0.

[0450] Xinafoate A form of xinafoate salt, designated xinafoate form A, was obtained during the salt formation experiment. The XRPD pattern of the form is displayed in Figure 169. The xinafoate form A sample was obtained by reaction of the free form with one equivalent of xinafoic acid in THF. TGA / DSC / MS of xinafoate form A 1 H NMR was obtained.

[0451] The TGA / DSC curve for xinafoate salt Form A in Figure 170 showed a 3.8% weight loss up to 130°C, and four endotherms at 67.9°C (peak), 180.4°C (peak), 213.6°C (peak), and 243.6°C (peak). 1 The 1 H NMR spectrum (Figure 171) showed no THF signals, indicating that the molar ratio of xinafoic acid:free form was 1.1:1.0.

[0452] Ca 2+ salt During the salt formation experiment, Ca 2+ Ca salt was named A-type 2+ A salt form was obtained, the XRPD pattern of which is shown in Figure 172. Ca 2+Salt A samples were prepared in the free form and in ACN / H 2 It was obtained by reaction with 1 equivalent of calcium hydroxide in 20:20 (19:1, v / v). 2+ TGA / DSC / 1 H NMR / HPLC / IC were obtained.

[0453] Ca in Figure 173 2+ The TGA / DSC curve for salt form A showed a weight loss of 5.6% up to 150° C. and two endotherms at 76.2° C. (peak) and 171.4° C. (peak). 1 The H NMR spectrum (Figure 174) showed no ACN signal. HPLC / IC results showed that Ca + The molar ratio of the soluble form to the free form was 0.4:1.0.

[0454] Tromethamine salts Two tromethamine salt forms, designated tromethamine salt forms A and B, were obtained during the salt formation experiments. The XRPD patterns of the forms are displayed in Figure 175. Samples of tromethamine salt forms A and B were dissolved in IPA and ACN / H, respectively. 2 The TGA / DSC / MS spectra of tromethamine salt forms A and B were obtained by reaction of the free form with one equivalent of tromethamine in 2H2O (19:1, v / v). 1 H NMR was obtained.

[0455] The TGA / DSC curve for tromethamine salt Form A in Figure 176 showed a 3.6% weight loss up to 140°C and six endotherms at 65.3°C (peak), 77.8°C (peak), 86.2°C (peak), 110.5°C (peak), 124.7°C (peak), and 203.7°C (peak). 1 The 1 H NMR spectrum (Figure 177) showed that the molar ratio of IPA:free form was approximately 0.2:1.0 (1.4%) and the molar ratio of tromethamine:free form was 1.8:1.0.

[0456] The TGA / DSC curve for the tromethamine salt Form B in Figure 178 showed a 9.2% weight loss up to 150°C, with three endotherms at 90.2°C (peak), 104.6°C (peak), and 127.9°C (peak). 1 The 1 H NMR spectrum (Figure 179) showed no ACN signals, indicating that the molar ratio of tromethamine:free form was 1.3:1.0.

[0457] Solubility of free form D-type with sugar To determine the effect of various sugars on the solubility of free form D, the equilibrium solubility of free form D in the presence of sugar (lactose or sucrose) at pH=5.0 was tested at RT. Two samples were prepared by suspending ~35 mg of free form D solid and 9.6 mg citric acid in 1 mL water. The samples were sonicated for about 2 minutes and the samples were nearly clear (almost no solids were observed). Filtered until a clear solution was obtained. The pH of the solution was 3.5. About 68.5 mg lactose and sucrose were added to the two solutions, respectively. The two samples were clear after the sugars were added. The pH of the two samples remained at 3.5. The pH of the two solutions was adjusted to 5.1 by adding 1 M NaOH. No solids precipitated after the pH adjustment. Another sample was also prepared without sugar. ~21 mg of free form D solid and 5.8 mg citric acid were suspended in 1 mL water.

[0458] The three solutions were stored at 5° C. for three days. No solids precipitated after cooling. Concentration and pH were tested for each sample. The results are summarized in FIG. 136. Table 9-16 Summary of equilibrium solubility results in citrate / phosphate buffers at RT [Table 9-16]

[0459] Solubility of free form D in pH=4.0 and 5.0 citrate / phosphate buffers The equilibrium solubility of free form Form D in pH=4.0 and 5.0 citrate / phosphate was evaluated at RT. 35 mg of solid was suspended in 1 mL of each medium to give a dosing concentration of 35 mg / mL. The suspension was equilibrated via stirring (1000 rpm) for 24 hours. The suspension was centrifuged to obtain a precipitate and a supernatant. Solubility and pH were tested on the supernatant after filtration, and the isolated precipitate was tested by XRPD. Equilibrium solubility results are summarized in Tables 9-17, and XRPD results are shown in Figures 180 and 181. A low crystallinity sample was obtained after 24 hours of equilibration in pH=4.0 citrate / phosphate. No morphological change of free form Form D was observed after 24 hours of equilibration in pH=5.0 citrate / phosphate. Table 9-17 Summary of equilibrium solubility results at RT in citrate / phosphate buffers [Table 9-17]

[0460] Formulation development with NaCl NaCl was chosen to adjust the osmolality of the formulation before sugar was chosen. ~35 mg free form D was combined with ~9.6 mg citric acid + ~6.1 mg NaCl in water and stirred for 24 hours to obtain a suspension. The concentration of the free form in the suspension was 0.60 mg / mL (pH 3.8). The resulting solid was a new form (designated as Form X, Figure 182). HPLC / IC results showed Cl - The molar ratio of the API to the free form was 1.0:1.0. The data suggests that the sample is the HCl salt. The experiment was repeated and after adding 1 mL water to ~32 mg / mL API + 9.6 mg / mL citric acid, a clear solution (slightly cloudy) was obtained immediately. A solid precipitated after addition of NaCl. The resulting solid was another new form (designated Form Y, Figure 183). After drying in vacuum, Form Y transformed into a low crystallinity sample. HPLC / IC results showed that Cl - The molar ratio of the α-to-β-form to the free form was 1.2:1.0.

[0461] Preparation of pH buffers 1. pH=3.0 buffer (50mM HCl+KCl): Weigh 365.39 mg KCl into a 100 mL volumetric flask (VF) and add 0.1 mL 1M HCl into the VF and dilute the volume with water. 2. pH=4.0 Buffer (50mM Citrate): Weigh 56.74 mg citric acid and 60.18 mg sodium tricitrate into a 10 mL volumetric flask and dilute the volume with water. 3. pH=5.0 buffer (50mM citrate) Weigh 11.12 mg citric acid and 95.38 mg sodium tricitrate into a 10 mL volumetric flask and dilute the volume with water. 4. pH=6.0 buffer (50mM citrate) Weigh 11.04 mg citric acid and 130.2 mg sodium tricitrate into a 10 mL volumetric flask and dilute the volume with water. 5. pH=6.0 buffer (50mM phosphate) 8.7mg Na 2 HPO 4 and 52.6 mg NaH 2 PO 4 into a 10 mL volumetric flask and dilute the volume with water. 6. pH=7.0 buffer (50mM phosphate) 23.47mg Na 2 HPO 4 and 43.34 mg NaH 2 PO 4 into a 10 mL volumetric flask and dilute the volume with water. 7. pH=8.0 buffer (50mM phosphate) 31.64mg Na 2 HPO 4 and 67.18 mg NaH 2 PO 4 into a 10 mL volumetric flask and dilute the volume with water.

[0462] Apparatus and Method XRPD A PANalytical X'Pert3 X-ray powder diffractometer was used for XRPD analysis. The XRPD parameters used are listed in Tables 9-18. Table 9-18 Parameters for XRPD testing [Table 9-18]

[0463] TGA and DSC TGA data was collected using a TA Discovery5500 / Q5000 TGA from TA Instruments. DSC was performed using a TA Discovery2500 / Q2000 DSC from TA Instruments. Detailed parameters used are listed in Tables 9-19. Table 9-19 Parameters for TGA and DSC testing [Table 9-19]

[0464] DVS DVS was measured via SMS (Surface Measurement Systems) DVS Intrinsic. The parameters for DVS testing are listed in Table 9-20. Table 9-20 Parameters for DVS testing [Table 9-20]

[0465] I C ThermoFisher ICS-1100 was used for Ionic Chromatography (IC) analysis of stoichiometry. The detailed method is shown in Tables 9-21. Table 9-21 Parameters for IC testing [Table 9-21]

[0466] UPLC Waters H-class UPLC (ultra performance liquid chromatography) was used for purity, solubility, assay, and stability testing. Detailed methods are shown in Table 9-22, Table 9-23, and Table 9-24. Table 9-22 Chromatographic conditions and parameters for stability determination (Example 6) [Table 9-22] Table 9-23 Chromatographic conditions and parameters for stability determination (Example 6) [Table 9-23] Table 9-24 Chromatographic conditions and parameters for solubility testing [Table 9-24]

[0467] KF A Metrohm 870 KF Titrinoplus was used for the KF test. The instrument was calibrated using purified water. The titration reagent was Hydranal® R-Composite 5 provided by Sigma-Aldrich. HPLC grade methanol was used to dissolve the samples.

[0468] 1 H NMR on a Bruker 400M NMR spectrometer using MeOH-d6 as the solvent. 1 1 H NMR was collected.

[0469] microscope Images of single crystal samples were taken using a Shanghai Cewei PXS9-T stereo microscope. PLM images were taken using an Axio Scope A1 microscope from Carl Zeiss German.

[0470] Example 8. PK study of compound (I). material and method animal Fifty (50) inbred 6-8 week old, Sigmodon hispidus female and male cotton rats (source: Sigmovir Biosystems, Inc., Rockville MD) were maintained and handled under veterinary supervision and in accordance with National Institutes of Health guidelines and Sigmovir Institutional Animal Care and Use Committee approved animal research protocols (IACUC Protocol #15). Fifteen animals were used in Phase I and 35 animals in Phase II of the study. Each group of five animals contained three females (first three animals in each group) and two males (last two animals in each group). Groups of even numbers of animals contained equal numbers of males and females. Cotton rats were housed in clear polycarbonate cages and provided with standard rodent chow (Harlan #7004) and tap water ad libitum.

[0471] Preparation of Compound (I) Vehicle Solutions To prepare the excipient solution, 125 mg of anhydrous citric acid and 972 mg of anhydrous lactose were dissolved in water by adding 6 ml to the powder. The solution was vortexed. The final volume was adjusted to 10 mL with water to give a final concentration of 65 mM anhydrous citric acid and 284 mM anhydrous lactose. The solution was stored at 4±2° C.

[0472] Experimental study design Phase I.PK study. Day 0

[0473] Step 1. Fifteen juvenile S. hispidus (6-8 weeks old) were divided into three groups (three females and two males per group). All animals were ear tagged, weighed and eye bled under isoflurane anesthesia for serum and plasma. All animals were treated intranasally (administered into both nostrils) with the solutions indicated in Table 8-1 below, 50 μl / 100 g animal. Table 8-1: Intranasal treatment plan [Table 8-1]

[0474] Day 1

[0475] Step 2. Weights were measured, clinical findings (e.g., changes in appearance, movement, posture) were collected, and treatments were repeated as in step 1 for all animals.

[0476] Day 2

[0477] Step 3. Weights were measured, clinical findings (e.g., changes in appearance, movement, posture) were collected, and treatments were repeated as in step 1 for all animals.

[0478] Day 3

[0479] Step 4. Weights were measured, clinical findings (e.g., changes in appearance, movement, posture) were collected, and treatments were repeated as in step 1 for all animals.

[0480] Day 4

[0481] Step 5. Weights were measured, clinical findings were collected, and procedures were repeated as in step 1 for all animals. Step 6, 1 h later, one animal from each group was extremly bled, followed by necropsy with examination for gross morbidity, and collection of BAL (right lung) and lung samples (left lung) for PK assessment. Step 7, 3 h later, the second animal from each group was extremly bled, followed by necropsy with examination for gross morbidity, and collection of BAL and lung samples for PK assessment.

[0482] Step 8. A third animal from each group was extremly bled and subsequently necropsied with examination for gross morbidity and collection of BAL and lung samples for PK assessment.

[0483] Step 9. The fourth animal from each group was extremly bled and subsequently necropsied with examination for gross pathology, and collection of BAL and lung samples for PK assessment.

[0484] Day 5

[0485] Step 10. The remaining animals were weighed and clinical findings were collected. Animals were extremly bled followed by necropsy with examination for gross morbidity, and BAL and lung samples were collected for PK assessment. Table 8-2. Summary of sample collection timing and procedures [Table 8-2] Table 8-3. Determination of dose volume (for intranasal delivery). [Table 8-3]

[0486] Phase I.PK study. In a Phase I study, three different doses of Compound (I): 0.1 mg / kg, 0.3 mg / kg, and 1 mg / kg per day were tested in young cotton rats S. hispidus when administered via intranasal route once a day (QD). Treatments were given for 5 consecutive days. After the last treatment, lungs, BAL, and plasma were collected for PK analysis 1 h, 3 h, 6 h, 12 h, and 24 h after the last dose of Compound (I) and shipped to AIT Bioscience as requested. In general, treatment with Compound (I) was well tolerated by the cotton rats. The only notable effect was an apparent increase in blood clotting time in one of the animals treated with the highest dose of Compound (I) (1 mg / kg / day). Blood clotted too rapidly to be effectively collected from that animal during terminal bleeding.

[0487] Results of the PK analysis showed that Compound (I) was detectable in the plasma and lungs (but significantly less in BALF) of cotton rats treated with Compound (I). A dose-dependent effect on Compound (I) concentrations in plasma and lungs was observed, with 1 mg / kg treatment resulting in the highest levels of Compound (I) detected in plasma and lungs 1 hr after treatment, followed by 0.3 and 0.1 mg / kg doses of Compound (I). Detectable levels of Compound (I) in plasma and lungs of treated animals remained elevated for several hours (depending on the dose of treatment).

[0488] Equivalents and Scope In the claims, unless indicated to the contrary or otherwise clear from the context, articles such as "a," "an," and "the" can mean one or more than one. Unless indicated to the contrary or otherwise clear from the context, a claim or description including "or" between one or more members of a group is considered to be satisfied if one, more than one, or all of the members of the group are present in, used in, or otherwise involved in a given product or process. The present disclosure includes embodiments in which exactly one member of a group is present in, used in, or otherwise involved in a given product or process. The present disclosure includes embodiments in which more than one or all of the members of a group are present in, used in, or otherwise involved in a given product or process.

[0489] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that is dependent on another claim may be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented in the Markush group format as an example list, each subgroup of elements is also disclosed, and any element(s) may be removed from the group. In general, where the disclosure or aspects of the disclosure are said to include certain elements and / or features, it should be understood that certain aspects of the disclosure or aspects of the disclosure consist of or consist essentially of such elements and / or features. For purposes of simplicity, those aspects have not been specifically submitted as such in the application. It is also noted that the terms "comprise" and "contain" are intended to be open-ended, permitting the inclusion of additional elements or steps. Where ranges are given, the endpoints are included. Furthermore, unless otherwise indicated or otherwise apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can, in different aspects of this disclosure, take any particular value or subrange within the claimed range to one tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0490] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. In addition, any specific aspects of this disclosure that are in the prior art may be expressly excluded from any one or more of the claims. Such aspects may be excluded even if the exclusion is not expressly stated in this application, since they are deemed to be known to those of ordinary skill in the art. Any specific aspects of this disclosure may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0491] Those skilled in the art will recognize, or be able to ascertain, many equivalents to the specific embodiments described herein, at most using routine experimentation. The scope of the embodiments described herein is not intended to be limited to the above specification, but rather is set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications of this description can be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Claims

1. formula: 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a polymorph thereof; and It is characterized in that it contains an organic acid; and a pharma- ceutically acceptable excipient, The pharmaceutical composition, wherein the organic acid is selected from the group consisting of vitamin C, citric acid, fumaric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, phytic acid, and any combination thereof.

2. 2. The pharmaceutical composition of claim 1, wherein the organic acid is citric acid.

3. 3. The pharmaceutical composition according to claim 2, wherein citric acid is present in a molar ratio relative to compound (I) of between about 0.8 and about 1.2, preferably between about 0.9 and about 1.

1.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharma- ceutically acceptable excipient is an isotonicity agent.

5. 5. The pharmaceutical composition of any one of claims 1 to 4, wherein the pharma- ceutically acceptable excipient is selected from the group consisting of dextrose, mannitol, sodium chloride, potassium chloride, lactose, trehalose, propylene glycol, glycerin, and any combination thereof.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharma- ceutically acceptable excipient is lactose.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the composition is an aqueous solution.

8. 8. The pharmaceutical composition of claim 7, wherein the pH of the aqueous solution is between about 2 and about 8, preferably between about 3.5 and about 6.

9. 9. The pharmaceutical composition according to claim 7 or 8, wherein the concentration of compound (I) in the aqueous solution is between 10 mM and 50 mM, preferably between 35 mM and 45 mM.

10. 10. The pharmaceutical composition according to any one of claims 7 to 9, wherein the concentration of compound (I) is 40 mM, the concentration of citric acid is 40 mM, and the concentration of lactose is 173 mM.

11. 7. The pharmaceutical composition of any one of claims 1 to 6, wherein at least a portion of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, is in a polymorphic form.

12. 12. The pharmaceutical composition according to any one of claims 1 to 6 and 11, wherein at least a portion of compound (I) is in polymorphic form, wherein the polymorph is free form Form D or fumarate Form A.

13. 13. The pharmaceutical composition according to claim 11 or 12, wherein the polymorph is greater than or equal to 95% by weight of free form D or greater than or equal to 95% by weight of fumarate form A, or wherein the polymorph is greater than or equal to 99% by weight of free form D or greater than or equal to 99% by weight of fumarate form A.

14. 14. The pharmaceutical composition of claim 12 or 13, wherein the polymorph comprises the free form Form D in essentially pure form or comprises the fumarate Form A in essentially pure form.

15. 7. The pharmaceutical composition according to any one of claims 1 to 6, comprising an amorphous form of Compound (I), or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the composition is formulated for oral or nasal inhalation.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the composition is formulated for administration in a nebulizer or a dry powder inhaler.

18. A pharmaceutical composition according to any one of claims 1 to 17 for use in therapy.

19. A pharmaceutical composition according to any one of claims 1 to 17 for use in the treatment of fibrosis or cystic fibrosis.

20. 20. The pharmaceutical composition of claim 19, wherein the fibrosis is pulmonary fibrosis.

21. A pharmaceutical composition according to any one of claims 1 to 17; and Instructions for using said pharmaceutical composition Including the kit.

22. 22. The kit of claim 21, wherein the kit comprises a nebulizer or a dry powder inhaler.

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