Forms of 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

Abstract

The present disclosure relates to forms (e.g., salt forms and / or crystalline forms) of a compound of structure (I): Formula (I), and pharmaceutical compositions comprising the forms, methods of preparing the forms, and methods for using the forms, e.g., to treat diseases, such as cancer, or conditions involving dysregulated immune response or other disorders associated with aberrant AhR signaling.

Description

FORMS OF AHR INHIBITORSRELATED APPLICATION

[0001] This application claims the benefit of US Provisional Application No. 63 / 605,265, filed December 1, 2023. The entire teachings of this application are incorporated herein by reference.BACKGROUND

[0002] The compound 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one is a potent aryl hydrocarbon receptor (AhR) inhibitor disclosed in International Publication No. WO 2021 / 102288.

[0003] There is a need for forms of 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6- (6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one that are suitable for use in pharmaceutical compositions and methods for treating diseases associated with aberrant expression of AhR.SUMMARY

[0004] The present disclosure provides forms e.g., salt forms and / or crystalline forms, such as crystalline salt forms) of 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, which are, for example, suitable for use in pharmaceutical compositions and / or methods for treating diseases associated with aberrant expression of AhR.

[0005] In some embodiments, the present disclosure provides an unsolvated hydrochloride salt of a compound of structure (I):

[0006] In some embodiments, the present disclosure provides a crystalline form of an unsolvated hydrochloride salt of a compound of structure (I), e.g., a crystalline form of anunsolvated hydrochloride salt of a compound of structure (I) having an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 6.

[0007] The present disclosure also provides in some embodiments a method of making an unsolvated hydrochloride salt of a compound of structure (I), or a crystalline form thereof, comprising: a) providing a compound of structure (I):in a polar organic solvent; and b) adding HC1 to the polar organic solvent under conditions sufficient to induce reactive precipitation of the salt or crystalline form from the polar organic solvent, thereby making the unsolvated hydrochloride salt of a compound of structure (I), or crystalline form thereof.

[0008] Also provided herein in some embodiments is a pharmaceutical composition comprising a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), and at least one pharmaceutically acceptable excipient.

[0009] Provided herein in some embodiments is a pharmaceutical combination comprising a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), or a pharmaceutical composition thereof and an additional therapeutic agent.

[0010] In some embodiments of the present disclosure, methods of using a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), are provided, e.g., to treat a disease or condition mediated by AhR signaling, a disease or condition associated with aberrant AhR signaling, or a cancer, or to inhibit cancer cell proliferation mediated by AhR signaling or tumor cell invasion or metastasis mediated by AhR signaling in a subject in need thereof. In some embodiments, the methods comprise administering to the subject a therapeutically effective amount of a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), or a pharmaceutical composition thereof.

[0011] Some embodiments of the present disclosure provide a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), or a pharmaceutical composition thereof for a use described herein (e.g., treating a disease or condition mediated by aryl hydrocarbon receptor (AhR) signaling, a disease or condition associated with aberrant AhR signaling, or a cancer, or inhibiting cancer cell proliferation mediated by AhR signaling or tumor cell invasion or metastasis mediated by AhR signaling).

[0012] Some embodiments of the present disclosure provide use of a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), or a pharmaceutical composition thereof for, e.g., treating a disease or condition mediated by aryl hydrocarbon receptor (AhR) signaling, a disease or condition associated with aberrant AhR signaling, or a cancer, or inhibiting cancer cell proliferation mediated by AhR signaling or tumor cell invasion or metastasis mediated by AhR signaling.

[0013] Some embodiments of the present disclosure provide use of a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), or a pharmaceutical composition thereof for the manufacture of a medicament, e.g., for the treatment of a disease or condition mediated by AhR signaling, a disease or condition associated with aberrant AhR signaling, or a cancer, or inhibition of cancer cell proliferation mediated by AhR signaling or tumor cell invasion or metastasis mediated by AhR signaling.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The foregoing will be apparent from the following more particular description of example embodiments.

[0015] FIG. 1 shows x-ray powder diffraction (XRPD) patterns for Free Base Types 1-4 (A-D, respectively).

[0016] FIG. 2 shows XRPD patterns for HC1 Salt Types 1, 2, and 3 (C, B, and A, respectively) and Phosphate Salt Types 1 (E) and 2 (D).

[0017] FIG. 3 shows XRPD patterns for the L-tartrate (A), benzoate (B), and nicotinate (C) salts.

[0018] FIG. 4 shows XRPD patterns for Maleate Salt Types 1-8 (H-A, respectively).

[0019] FIG. 5 shows a differential scanning calorimetry (DSC) thermogram (B) and thermogravimetric analysis (TGA) thermal curve (A) for HC1 Salt Type 3.

[0020] FIG. 6 shows an XRPD pattern for HC1 Salt Type 3 collected according to the conditions given in Table 7 of Example 8.

[0021] FIG. 7 shows a dynamic vapor sorption (DVS) plot for HC1 Salt Type 3 when analyzed by a 40-95-0-95% relative humidity (RH) method conducted at 25.6 °C over 60 minutes.

[0022] FIG. 8 shows the particle size distribution (PSD) for HC1 Salt Type 3 when crystallized and collected using the conditions of Scale-up Experiment 2 in Example 14.

[0023] FIG. 9A is a polarized light microscopy (PLM) image of particles resulting from Scale-Up Experiment 2 described in Example 14 at 1.5-hour time point at 60 °C.

[0024] FIG. 9B is a PLM image of particles resulting from Scale-Up Experiment 2 described in Example 14 at 4-hour time point after cool down to 20 °C.

[0025] FIG. 10A shows Hepal-6 tumor growth kinetics in C57BL / 6 mice from Example 16 for 36 days post treatment.

[0026] FIG. 10B shows Hepal-6 tumor volume on the final day of the study described in Example 16. Significance analyses were performed using unpaired t-test comparing the compound of structure (I) to vehicle QD and anti-PD-1 to isotype (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001; error in SEM).

[0027] FIG. 11 shows a differential scanning calorimetry (DSC) thermogram (B) and thermogravimetric analysis (TGA) thermal curve (A) for HC1 Salt Type 3.DETAILED DESCRIPTION

[0028] A description of example embodiments follows.

[0029] The aryl hydrocarbon receptor (AHR) is a ligand- activated transcription factor, belonging to the basic helix-loop-helix / Per-Amt-Sim (bHLH / PAS) family that is located in the cytosol. Upon ligand binding, the AHR translocates to the nucleus where it heterodimerizes with AHR nuclear translocator (ARNT) and interacts with dioxin response elements (DREs) of AHR-responsive genes to regulate their transcription. The AHR is best known for binding to environmental toxins and inducing the metabolic machinery, such as cytochrome P450 enzymes (e.g., CYP1A1, CYP1A2 and CYP1B1), required for their elimination (Reyes et al., Science, 1992, 256(5060): 1 193-5). Activation of AHR by xenobiotics has demonstrated its role in numerous cellular processes such as embryogenesis, tumorigenesis and inflammation.

[0030] AHR is expressed in many cells of the immune system, including dendritic cells (DCs), macrophages, T cells and NK cells, and plays an important role inimmunoregulation (Nguyen et al., Front. Immunol., 2014, 5:551). The classic exogenous AHR ligands TCDD and 3-methylcholanthrene, for example, are known to induce profound immunosuppression, promote carcinogenesis and induce tumor growth (Gramatzki et al., Oncogene, 2009, 28(28):2593- 605; Bui et al., Oncogene, 2009, 28(41):3642-51; Esser et al., Trends Immunol., 2009, 30:447- 454). In the context of immunosuppression, AHR activation promotes regulatory T cell generation, inhibits Thl and Thl7 differentiation, directly and indirectly, and decreases the activation and maturation of DCs (Wang et al., Clin. Exp. Immunol., 2014, 177(2):521-30; Mezrich et al., J. Immunol., 2010, 185(6):3190-8; Wei et al., Lab. Invest., 2014, 94(5):528-35; Nguyen et al., PNAS, 2010, 107(46): 19961-6). AHR activation modulates the innate immune response, and constitutive AHR expression has been shown to negatively regulate the type-1 interferon response to viral infection (Yamada et al., Nat. Immunol., 2016, 17(6):687-94). Additionally, mice with constitutively active AHR spontaneously develop tumors (Andersson et al., PNAS, 2002, 99(15):9990-5).

[0031] In addition to xenobiotics, the AHR can also bind metabolic products of tryptophan degradation. Tryptophan metabolites, such as kynurenine and kynurenic acid, are endogenous AHR ligands that activate the AHR under physiological conditions (DiNatale et al., Toxicol. Sci., 2010, 115(l):89-97; Mezrich et al., J. Immunol., 2010, 185(6):3190-8; Opitz et al., Nature, 2011, 478(7368): 197-203). Other endogenous ligands are known to bind the AHR, although their physiological roles are currently unknown (Nguyen & Bradfield, Chem. Res. Toxicol., 2008, 21(1): 102-116).

[0032] The immunosuppressive properties of kynurenine and tryptophan degradation are well described and are implicated in cancer-associated immunosuppression. The enzymes indoleamine-2,3-dioxygenases 1 and 2 (IDO1 / IDO2) as well as tryptophan-2,3- dioxygenase 2 (TDO2) are responsible for catalyzing the first and rate-limiting step of tryptophan metabolism. IDOl / 2-mediated degradation of tryptophan in tumors and tumordraining lymph nodes reduces anti-tumor immune responses and inhibition of IDO can suppress tumor formation in animal models (Uyttenhove et al., Nat. Med., 2003, 9(10): 1269-74; Liu et al., Blood, 2005, 115(17): 3520-30; Muller et al., Nat. Med., 11(3):312-9; Metz, Cancer Res., 2007, 67(15):7082-7).

[0033] TDO2 is also strongly expressed in cancer and can lead to the production of immunosuppressive kynurenine. In glioma, activation of the AHR by kynurenine, downstream of TDO-mediated tryptophan degradation, enhances tumor growth as aconsequence of inhibiting anti-tumor immune responses as well as directly promoting tumor cell survival and motility (Opitz et al., Nature, 2011, 478(7368): 197-203). AHR ligands generated by tumor cells therefore act in both an autocrine and paracrine fashion on tumor cells and lymphocytes, respectively, to promote tumor growth.

[0034] Additional therapies may be useful in the treatment of cancer in combination with AhR modulation. Immune checkpoint inhibitors (ICIs) have been used in cancer treatment to enhance the immune response of the host. Non-limiting examples of ICI targets include programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4). PD-1 is highly expressed by activated T cells, B cells, dendritic cells (DC), and natural killer cells (NK), whereas PD-L1 can be expressed on several types of tumor cells.

[0035] ICIs are currently approved by the Food and Drug Administration to treat melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, Hodgkin's lymphoma, urothelial carcinoma, small cell lung cancer, esophageal squamous cell carcinoma, cervical cancer, primary mediastinal large B-cell lymphoma, MSI-H / dMMR colorectal cancer, hepatocellular carcinoma, Merkel cell carcinoma, triplenegative breast cancer, and cutaneous squamous cell carcinoma.Definitions

[0036] As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the relevant contents of which are incorporated herein by reference.

[0037] Unless specified otherwise within this specification, the nomenclature used in this specification generally follows the examples and rules stated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated by reference herein for its chemical structure names and rules on naming chemical structures. Optionally, a name of a compound may be generated using a chemical naming program (e.g., CHEMDRAW®, version 17.0.0.206, PerkinElmer Informatics, Inc.).

[0038] When introducing elements disclosed herein, unless indicated otherwise, e.g., expressly or by context, the articles “a,” “an,” “the,” and “said” are intended to mean that there are one or more of the elements. Further, the one or more elements may be the same or different.

[0039] As used herein, the term “form of a compound of structure (I)” refers to a compound of structure (I) depicted herein, such as an unsolvated salt of a compound of structure (I), as well as isotopologues, salts, and inherently formed moieties (e.g., polymorphs and / or solvates, such as hydrates) thereof, as well as combinations of the foregoing. When the compound of structure (I) is in salt form, pharmaceutically acceptable salts are preferred.

[0040] Certain atoms naturally occur in various isotopic forms. Natural isotopic abundance describes the relative abundance of the various naturally-occurring isotopes of a given atom. The term “isotopologue” refers to a molecule that differs from a reference molecule only in its isotopic composition. Thus, it will be understood that a population of molecules represented by a particular chemical structure will typically contain isotopologues of the particular chemical structure. The relative amount of such isotopologues will depend upon a number of factors, such as relative natural isotopic abundance, the isotopic purity of reagents used to make the compound and the efficiency of incorporation of isotopic atoms in the various synthetic steps used to prepare the compound. In certain embodiments, the amount of such isotopologues in toto will be less than 49.9%, for example, less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5%.

[0041] Structures depicted herein are meant to allow for such natural isotopic abundance, as well as replacement of one or more atoms in a structure with an isotope thereof or an isotopically enriched counterpart, e.g., at a non-natural isotopic abundance. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a13C or14C are within the scope of this disclosure. In some embodiments, a hydrogen atom in a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), is replaced or enriched with D. In some embodiments, a methyl group in form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), is replaced or enriched with -CD3.Isotopologues can be useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.

[0042] The term “pharmaceutically acceptable,” as used herein in “pharmaceutically acceptable salt,” “pharmaceutically acceptable excipient,” and elsewhere refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio.

[0043] As used herein, the term “pharmaceutically acceptable salt” refers to a salt that is pharmaceutically acceptable as defined herein and that has the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge el al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the relevant teachings of which are incorporated herein by reference in their entirety. Non-limiting examples of pharmaceutically acceptable salts include those derived from inorganic acids, non-limiting examples of which include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and those derived from organic acids, non-limiting examples of which include acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, nicotinic acid, oxalic acid, stearic acid, malic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, and lactic acid. Either the mono-, di- or tri-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form.

[0044] Additional non-limiting examples of pharmaceutically acceptable salts include those formed when an acidic proton in a parent compound is replaced by a metal ion, nonlimiting examples of which include an alkali metal ion and an alkaline earth metal ion, and those formed when an acidic proton present in a parent compound is replaced by an ammonium ion, a primary ammonium ion, a secondary ammonium ion, a tertiary ammonium ion, or a quaternary ammonium ion. Non-limiting examples of alkali metals and alkaline earth metals include sodium, potassium, lithium, calcium, aluminum, magnesium, copper, zinc, iron, and manganese. Additional non-limiting examples of pharmaceutically acceptable salts include those comprising one or more counterions and zwitterions.

[0045] As used herein, “solvent” refers to the substance or mixture of two or more substances in which a material is dissolved, suspended, emulsified, or slurred. Typically, a solvent is a liquid. A solvent may be organic, such as ethyl acetate, tetrahydrofuran, and isopropyl alcohol, or it may be inorganic, such as water. Solvents which are primarily composed of water are referred to herein as aqueous. Solvents may be further categorized by their dielectric constant as a measure of the solvent’s polarity. Solvents with a high dielectric constant, and therefore considered polar solvents, include water, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, isopropyl alcohol, tetrahydrofuran and the like. Solvents with a low dielectric constant, and therefore considered nonpolar solvents, include hexane, ethyl acetate, dichloromethane, and the like.

[0046] Experimental measurements, results, or observations, such as XRPD patterns, DSC thermograms, DVS isotherms or TGA thermal curves, are said to be “substantially in accordance” with another XRPD pattern, DSC thermogram, DVS isotherm or TGA thermal curve when one skilled in the art would consider them to represent the same single crystalline form of the same compound. Thus, an XRPD pattern, DSC thermogram, DVS isotherm or TGA thermal curve that is substantially in accordance with one or more figures provided herein may be identical or, more likely, may be somewhat different. For example, an XRPD pattern that is somewhat different from one or more of the figures may not necessarily show each of the lines of the diffraction pattern presented herein and / or may show a slight change in appearance or intensity of the lines or a shift in the position of the lines. These differences typically result from differences in the conditions involved in obtaining the data or differences in the purity of the sample used to obtain the data. A person skilled in the art is capable of determining if a sample of a crystalline compound is of the same form as or a different form from a form disclosed herein by comparison of the XRPD pattern, DSC thermogram, DVS isotherm, or TGA thermal curve of the sample and the corresponding XRPD pattern, DSC thermogram, DVS isotherm or TGA thermal curve disclosed herein.

[0047] It is to be understood that, unless otherwise indicated, any XRPD peak specified herein, with the exception of the XRPD peaks in the figures or examples, means the specified value ± 0.2 or less. For example, unless otherwise indicated, when an embodiment or a claim specifies a peak, in terms of 2-theta, at 20.0, this is to be understood to mean 20.0° ± 0.2° or less, that is a 2-theta angle of from 19.8° to 20.2°. Inpreferred embodiments, a 2-theta angle is the specified value ± 0.1° or less, in more preferred embodiments, ± 0.05° or less.

[0048] The crystalline forms provided herein can also be identified on the basis of differential scanning calorimetry (DSC). DSC is a thermoanalytical technique in which the difference in the amount of heat required to increase the temperature of a sample is measured as a function of temperature. DSC can be used to detect physical transformations, such as phase transitions, of a sample. For example, DSC can be used to detect the temperature(s) at which a sample undergoes crystallization, melting or glass transition. It is to be understood that any temperature associated with DSC specified herein, with the exception of the DSC temperatures in the figures or examples, means the specified value ± 10 °C or less. For example, when an embodiment or a claim specifies an endothermic peak at 264 °C, this is to be understood to mean 264 °C ± 10 °C or less, that is a temperature of from 254 °C to 274 °C. In preferred embodiments, a DSC is the specified value ± 5 °C or less, in more preferred embodiments, ± 3 °C or less, in yet more preferred embodiments, ± 2 °C or less.

[0049] The crystalline forms provided herein may also be identified or characterized on the basis of dynamic vapor sorption (DVS). DVS is a gravimetric technique in which the mass change of a substance is measured as a function of solvent vapor (e.g. water vapor) present within the test chamber. Varying the vapor concentration surrounding the sample and measuring the change in mass it produces allows for the analysis of the hygroscopicity of a sample. Data from DVS experiments may be presented as kinetic data, showing the change in solvent vapor and sample mass over time, or as isotherms, wherein the equilibrium mass is plotted against the vapor concentration. It is to be understood that any mass change (e.g., loss, gain) associated with DVS specified herein, with the exception of mass changes in the figures or examples, means the specified mass change ± 0.02%. For example, when an embodiment or a claim specifies 0.2% mass gain over a specified solvent vapor concentration or time range, this is to be understood to mean 0.2% ± 0.02%, that is mass gain of from 0.18% to 0.22%. In preferred embodiments, a mass change is the specified value ± 0.01%, in more preferred embodiments, the specified value ± 0.005%, in yet more preferred embodiments, the specified value ± 0.0025%. In some embodiments, a mass change is the specified value ± 0.002%, for example, ± 0.001% or ± 0.0005%.

[0050] The crystalline forms provided herein may also be identified on the basis of thermogravimetric analysis (TGA). TGA is a thermoanalytical technique in which themass change of a substance is measured as a function of temperature or time in a controlled atmosphere. The record is a thermogravimetric curve which is a plot of the mass of the substance versus time or temperature, with the mass loss on the ordinate plotted downward and mass gains plotted upward relative to a baseline. The technique can be used to characterize weight loss or gain due to the sorption / desorption of volatiles, decomposition, oxidation and / or reduction. It is to be understood that any mass change (e.g., loss, gain) associated with TGA specified herein, with the exception of mass changes in the figures or examples, means the specified mass change ± 0.2%. For example, when an embodiment or a claim specifies 3.2% mass loss over a specified temperature range, this is to be understood to mean 3.2% ± 0.20%, that is mass loss of from 3.0% to 3.4%. In preferred embodiments, a mass change is the specified value ± 0.1%, in more preferred embodiments, the specified value ± 0.05%, in yet more preferred embodiments, the specified value ± 0.025%. In some embodiments, a mass change is the specified value ± 0.02%, for example, ± 0.01% or ± 0.005%.

[0051] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. The same rule applies for any other ranges described herein, even if the values within the range are not specifically called out in this disclosure.

[0052] ‘ ‘About” means within an acceptable error range for the particular value, as determined by one of ordinary skill in the art. Typically, an acceptable error range for a particular value depends, at least in part, on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean within an acceptable standard deviation, per the practice in the art. Alternatively, “about” can mean a range of ± 20%, e.g., ± 15%, ± 10%, ± 5%, ± 2.5%, ± 1.5%, or ± 1% of a given value. It is to be understood that the term “about” can precede any particular value specified herein, except for particular values used in the examples provided herein.

[0053] As used herein, the term “crystalline” refers to a homogeneous solid formed by a repeating, three-dimensional pattern of atoms, ions or molecules having fixed distances between constituent parts. The unit cell is the simplest repeating unit in this pattern. Notwithstanding the homogeneous nature of an ideal crystal, a perfect crystal rarely, if ever,exists. “Crystalline,” as used herein, encompasses crystalline forms that include crystalline defects, for example, crystalline defects commonly formed by manipulating (e.g., preparing, purifying) the crystalline forms described herein. A person skilled in the art is capable of determining whether a sample of a compound is crystalline notwithstanding the presence of such defects. Crystalline forms can be characterized by analytical methods such as x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance spectroscopy (NMR), single crystal x-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR), and / or any other suitable analytical techniques. A “pseudopolymorph” refers to a form of a chemical structure. Pseudopolymorphs of a compound may or may not be crystalline, and include, but are not limited to, crystalline forms, anhydrous forms, hydrates, salts and solvates of the compound.

[0054] The term “polymorph” refers to different crystal structures into which a compound, or a salt or solvate thereof, can crystallize. Polymorph refers to a crystalline form of a compound characterized by a distinct arrangement of its molecules in a crystal lattice. Polymorphs can be characterized by analytical methods such as x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA).

[0055] As used herein, “solvate” or “solvated” refers to a form of a substance which contains solvent. The terms "hydrate" and "hydrated" refer to a solvate wherein the solvent comprises water. “Ansolvate,” “ansolvated,” and “unsolvated” refer to a form of a substance or compound that is not solvated, i.e. substantially free of solvent. The terms “anhydrous” and “anhydrate” similarly refer to forms of a substance substantially free of water. Solvent may still be present in a given sample of an ansolvate compound form, but any solvent present is not included in the crystal lattice and is instead randomly distributed outside the crystal lattice.

[0056] “Substantially pure,” when used without further qualification, means the compound has a purity greater than 90 weight percent, for example, greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 weight percent, and also including a purity equal to about 100 weight percent, based on the weight of the compound. The remaining material may comprise other form(s) of the compound and / or reaction impurities and / or processing impurities arising from its preparation. Purity can be assessed using techniques known in the art, for example, using an HPLC assay. “Substantially pure” can also be qualified, as inAttorney Docket No. 01374-0001-00PCT “substantially pure of other physical forms of the compound having the indicated structure.” When qualified, “substantially pure” means that the indicated compound contains less than 10%, preferably less than 5%, more preferably less than 3%, most preferably, less than 1% by weight of the indicated impurity. Similarly, the phrase “substantially free of” means that the compound contains no significant amount of the referenced contaminant. For example, a substance substantially free of water may contain less than 3% water by weight, more preferably less than 1%, yet more preferably, less than 0.1%, most preferably, less than 0.01%.

[0057] “Particle size distribution,” as used herein, refers to a list of values or a mathematical function that defines the relative amount, typically by mass or volume, of particles present in a sample according to size. Particle size distribution can be characterized by one or more values, such as D90, D50 and / or D10, or a ratio of any of the foregoing, or by the shape of the mathematical function, when graphed. Exemplary shapes of a particle size distribution graph include unimodal, bimodal, normal and Gaussian.

[0058] “D90,” as used herein, describes the value of particle size at which 90% of the total volume of particles is comprised of particles no larger than the indicated size. In some embodiments, when “about” precedes a D90 value specified herein, it means the specified value ±10% or less of the specified value, e.g., preferably ±5%, more preferably, ±2.5%, yet more preferably, ±1.5%. For example, when an embodiment or a claim specifies a D90 of about 46 µm, this is to be understood to mean 46 µm ± 4.6 µm, that is from 41.4 µm to 50.6 µm.

[0059] “D50,” as used herein, describes the value of particle size at which 50% of the total volume of particles is comprised of particles no larger than the indicated size. D50 is typically the median of the particle size distribution. In some embodiments, when “about” precedes a D50 value specified herein, it means the specified value ±10% or less of the specified value, e.g., preferably ±5%, more preferably, ±2.5%, yet more preferably, ±1.5%.

[0060] “D10,” as used herein, describes the value of particle size at which 10% of the total volume of particles is comprised of particles no larger than the indicated size. In some embodiments, when “about” precedes a D10 value specified herein, it means the specified value ±30% or less of the specified value, e.g., preferably ±15%, more preferably, ±5%, yet more preferably, ±3%.

[0061] “Pharmaceutically acceptable carrier” refers to a non-toxic carrier that does not destroy the pharmacological activity of the agent with which it is formulated and isAttorney Docket No. 01374-0001-00PCT nontoxic when administered in doses sufficient to deliver a therapeutic amount of the agent. The pharmaceutically acceptable carrier may be an excipient, where “excipient” as used herein refers to a pharmaceutically acceptable material chosen from a solvent, dispersion media, diluent, dispersion, suspension aid, surface active agent, isotonic agent, thickening or emulsifying agent, preservative, polymer, peptide, protein, cell, hyaluronidase, and mixtures thereof. Pharmaceutically acceptable carriers that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. In some embodiments, the solvent is an aqueous solvent. Pharmaceutically acceptable carriers and excipients are well-known to persons having ordinary skill in the art and are described in, as a non-limiting example, Remington: The Science and Practice of Pharmacy, 22nd Edition, Lippincott Williams & Wilkins, Philadelphia, Pa. (2013) and any other editions, which are hereby incorporated by reference.

[0062] “Treating,” as used herein, refers to taking steps to deliver a therapy to a subject, such as a mammal, in need thereof (e.g., as by administering to a mammal one or more therapeutic agents). “Treating” includes inhibiting the disease or condition (e.g., as by slowing or stopping its progression or causing regression of the disease or condition), and relieving the symptoms resulting from the disease or condition.

[0063] The terms “disease” and “disorder” are used interchangeably herein and refer to any alteration in state of the body or of some of the organs, interrupting or disturbing the performance of the functions and / or causing symptoms such as discomfort, dysfunction, distress, or even death to the person afflicted or those in contact with a person. A disease or disorder can also relate to a distemper, ailing, ailment, malady, sickness, illness, complaint, indisposition, or affection.

[0064] As used herein, “subject” includes humans, domestic animals, such as laboratory animals (e.g., dogs, monkeys, pigs, rats, mice, etc.), household pets (e.g., cats, dogs,Attorney Docket No. 01374-0001-00PCT rabbits, etc.) and livestock (e.g., pigs, cattle, sheep, goats, horses, etc.), and non-domestic animals. In some embodiments, the subject is a mammal. In some embodiments, a subject is a human.

[0065] An “effective amount” is an amount effective, at dosages and for periods of time necessary, to achieve a desired result (e.g., a desired therapeutic result, a desired in vitro result).

[0066] The term “therapeutically effective amount” as used herein refers to an amount of an agent that produces a desired effect for which it is administered (e.g., improvement in symptoms of a disease or condition mediated by AhR signaling, lessening the severity of such a disease or condition or a symptom thereof, and / or reducing progression any one of the foregoing). The exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0067] As used herein, the term “resistant” refers to conditions, diseases, or cancers that show a diminished therapeutic response to a given treatment. Resistant may refer to conditions, diseases, or cancers that are tolerant, insensitive, or refractory. The diminished therapeutic response may be due to intrinsic resistance in the condition, disease, or cancer, or it may be acquired as a result of one or more previous treatments. The diminished therapeutic response may be less than expected by the treatment provider, less than the result of a previous administration of the same or different treatment, or no response at all.

[0068] One of ordinary skill in the art would recognize that when an amount of a compound is disclosed, the relevant amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the amount of the free base of the compound. The amounts of the compounds and pharmaceutically acceptable salts disclosed herein are based upon the free base form of the relevant compound. For example, “10 mg of a form of a compound of structure (I) or a pharmaceutically acceptable salt thereof” refers to 10 mg of a form of a compound of structure (I) or an amount of a pharmaceutically acceptable salt of a compound of structure (I) equivalent to 10 mg of the compound of structure (I). Forms of Compound of Structure (I)

[0069] It has been found that compounds having structure (I) can exist in various salt and / or crystalline (e.g., polymorphic) forms.

[0070] Disclosed herein is an anhydrous hydrochloride salt of a compound of structure (I):Attorney Docket No. 01374-0001-00PCTIn some embodiments, the hydrochloride salt of the compound of structure (I) is unsolvated. In some embodiments, the salt of the compound of structure (I) is in crystalline form. In some embodiments, the crystalline form comprises HCl salt type 3. In certain embodiments, the crystalline form consists or consists essentially of HCl salt type 3. In some embodiments the salt or crystalline form of the compound of structure (I) is substantially pure.

[0071] In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) is characterized by an x-ray powder diffraction pattern comprising at least three peaks at 2- theta angles selected from the group consisting of 10.1±0.2°, 11.6±0.2°, 14.5±0.2°, 16.0±0.2°, 16.6±0.2°, 19.8±0.2°, and 20.3±0.2°. In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) is characterized by an x-ray powder diffraction pattern comprising at least four peaks at 2-theta angles selected from the group consisting of 10.1±0.2°, 11.6±0.2°, 14.5±0.2°, 16.0±0.2°, 16.6±0.2°, 19.8±0.2°, and 20.3±0.2°. In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) is characterized by an x-ray powder diffraction pattern comprising at least five peaks at 2-theta angles selected from the group consisting of 10.1±0.2°, 11.6±0.2°, 14.5±0.2°, 16.0±0.2°, 16.6±0.2°, 19.8±0.2°, and 20.3±0.2°. In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) is characterized by an x-ray powder diffraction pattern comprising at least six peaks at 2-theta angles selected from the group consisting of 10.1±0.2°, 11.6±0.2°, 14.5±0.2°, 16.0±0.2°, 16.6±0.2°, 19.8±0.2°, andAttorney Docket No. 01374-0001-00PCT 20.3±0.2°. In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) is characterized by an x-ray powder diffraction pattern comprising peaks at the 2-theta angles 10.1±0.2°, 11.6±0.2°, and 14.5±0.2°. In further embodiments, the crystalline form further comprises a peak at the following 2-theta angle: 16.0±0.2°.

[0072] In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 6.

[0073] In any of the foregoing embodiments, the crystalline form may be characterized by an x-ray powder diffraction pattern measured by x-ray powder diffraction using an x- ray wavelength of 1.5406 Å.

[0074] In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak at 234 °C. In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) is characterized by a differential scanning calorimetry thermogram substantially in accordance with that depicted in FIG. 5. In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) is characterized by a melting temperature of 221 °C. In any of the foregoing embodiments, the crystalline form may be characterized by a differential scanning calorimetry thermogram measured by differential scanning calorimetry over a range of 30 °C to 300 °C using a scanning rate of 10 ºC / minute.

[0075] In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) is characterized by a differential scanning calorimetry thermogram comprising anAttorney Docket No. 01374-0001-00PCT endothermic peak at 249 °C. In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) is characterized by a melting temperature of 239 °C. In any of the foregoing embodiments, the crystalline form may be characterized by a differential scanning calorimetry thermogram measured by differential scanning calorimetry over a range of 30 °C to 300 °C using a scanning rate of 10 ºC / minute.

[0076] In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak at 247 °C. In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) is characterized by a melting temperature of 232 °C. In any of the foregoing embodiments, the crystalline form may be characterized by a differential scanning calorimetry thermogram measured by differential scanning calorimetry over a range of 30 °C to 300 °C using a scanning rate of 10 ºC / minute.

[0077] In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) is characterized by a thermogravimetric analysis thermal curve with a 0.07% weight loss over the range of about 30 °C to about 156 °C. In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) is characterized by a thermogravimetric analysis thermal curve substantially in accordance with that shown in FIG. 5. In any of the foregoing embodiments, the crystalline form may be characterized by a thermogravimetric analysis thermal curve measured using a heating rate of 10 ºC / minute.

[0078] In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) is characterized by a thermogravimetric analysis thermal curve with a 0.16% weight lossAttorney Docket No. 01374-0001-00PCT over the range of about 30 °C to about 148 °C. In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) is characterized by a thermogravimetric analysis thermal curve with a 0.03% weight loss over the range of about 30 °C to about 153 °C. In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) is characterized by a thermogravimetric analysis thermal curve substantially in accordance with that shown in FIG. 11. In any of the foregoing embodiments, the crystalline form may be characterized by a thermogravimetric analysis thermal curve measured using a heating rate of 10 ºC / minute.

[0079] In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) exhibits no detectable form conversion after storage (e.g., in an open vial, in a closed vial) for four weeks at 25 °C and 60% relative humidity. In further embodiments, the crystalline form of a hydrochloride salt of the compound of structure (I) exhibits no detectable form conversion after storage for four weeks at 40 °C and 75% relative humidity. In some embodiments, a crystalline form of a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)) exhibits no detectable form conversion after slurrying for 24 hours in ethanol at 40 °C or 50 °C.

[0080] In some embodiments, a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)), exhibits greater than 90% (e.g., greater than 95%, greater than 98%) of its initial purity after slurrying for 24 hours in ethanol at 40 °C or 50 °C.

[0081] In some embodiments, a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)), has a molar ratio of hydrochloric acid to the compound of structure (I) of from about 0.5 to 1 to about 4 to 1, e.g., about 0.5 to 1 to about 1 to 1, or about 0.5 to 1, about 0.6 to 1, about 0.7 to 1, about 0.8 to 1, about 0.9 to 1,Attorney Docket No. 01374-0001-00PCT or about 1 to 1. In some embodiments, the molar ratio of hydrochloric acid to compound of structure (I) is about 0.8 to 1.

[0082] In some embodiments, a hydrochloride salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)), is in the form of particles having a D90 of less than about 50 µm, e.g., from about 40 µm to about 50 µm, from about 41 µm to about 47 µm, about 41 µm, about 42 µm, about 43 µm, about 44 µm, about 45 µm, about 46 µm, or about 47 µm. Additionally or alternatively, in some embodiments, a salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)), is in the form of particles having a D50 of less than about 25 µm, e.g., less than about 20 µm, from about 10 µm to about 20 µm, from about 14 µm to about 20 µm, about 14 µm, about 15 µm, about 16 µm, about 17 µm, about 18 µm, about 19 µm, or about 20 µm. Additionally or alternatively, in some embodiments, a salt of the compound of structure (I) (e.g., anhydrous and / or unsolvated hydrochloride salt of the compound of structure (I); HCl salt type 3 of the compound of structure (I)), is in the form of particles having a D10 of less than about 10 µm, e.g., from about 5 µm to about 10 µm, about 5 µm, about 6 µm, about 7 µm, about 8 µm, about 9 µm, or about 10 µm.

[0083] The compound of structure (I) is also referred to herein as: 3-(2-hydroxy-2- methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one. Preparation of Compounds of Structure (I), And Forms Thereof

[0084] Methods of making the compound of structure (I) are described herein and in International Publication No. WO 2021 / 102288, the entire content of which is incorporated herein by reference.

[0085] In some embodiments, described herein is a method of making a hydrochloride salt of a compound of structure (I), or a crystalline form thereof, comprising: a. providing a compound of structure (I) in a polar organic solvent; and b. adding HCl to the polar organic solvent under conditions sufficient to induce reactive precipitation of the salt or crystalline form from the polar organic solvent, thereby making the hydrochloride salt of a compound of structure (I), or a crystalline form thereof.Attorney Docket No. 01374-0001-00PCT

[0086] In some embodiments, the polar organic solvent is an alcohol. In some embodiments, the alcohol is methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n- butanol, sec-butanol, isobutanol, or tert-butanol. In some embodiments, the polar organic solvent is ethanol, isopropyl alcohol, or tetrahydrofuran. In some embodiments, the polar organic solvent is ethanol.

[0087] In some embodiments, HCl is concentrated HCl. In some embodiments, HCl is aqueous HCl. In some embodiments, a molar excess of HCl is added (where molar excess is measured with respect to the compound of structure (I)). For example, in some embodiments, HCl is added in a molar excess of from about 1% to about 100%, e.g., from about 5% to about 75%, from about 25% to about 75%, from about 15% to about 25%, about 50%, or about 20%.

[0088] In some embodiments, the method of making the salt or crystalline form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), further comprises heating the polar organic solvent to or above a clear point, e.g., at or above about 40 °C, such as about 40 °C or about 60 °C. Additionally or alternatively, in some embodiments, the method of making the salt or crystalline form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), further comprises seeding the polar organic solvent at or above a clear point with seeds of the salt or crystalline form, e.g., less than about 10 weight percent, less than about five weight percent, about 5 weight percent, about four weight percent, about three weight percent, about two weight percent, about one weight percent, or about 0.5 weight percent seeds (where weight percent is indicated with respect to weight of the free base form in the polar organic solvent). It will be appreciated that it is preferable not to heat the polar organic solvent above a temperature at which it or the compound of structure (I), e.g., in free base form, or salt or crystalline form, becomes unstable.

[0089] As used herein, “clear point” refers to a temperature at which a solid solute in a solvent dissolves to produce a solution. Typically, in the embodiments and examples described herein, the solute comprises a compound of structure (I), e.g., the solute is the compound of structure (I) in free base form or a salt or crystalline form of the compound of structure (I) described herein. It will be appreciated that “clear point” is a function of, for example, the identities of the solute and solvent, the concentration of the solute in the solvent, and the temperature of the solvent. A person skilled in the art can determine clearAttorney Docket No. 01374-0001-00PCT point in accordance with the present disclosure at least in view of the examples provided herein.

[0090] Additionally or alternatively, in some embodiments, the method of making the salt or crystalline form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), further comprises cooling the polar organic solvent to or below a cloud point, e.g., to less than or about 40 °C, such as about 25 °C or less or about 20 °C or less. In some embodiments, cooling is at a rate of less than or about 10 °C / hour. Additionally or alternatively, in some embodiments, cooling is to a temperature of less than or about 25 °C. Additionally or alternatively, in some embodiments, cooling is to a temperature of greater than freezing temperature of the polar organic solvent. It will be appreciated that it is preferable not to cool to or below the freezing point of the polar organic solvent.

[0091] As used herein, “cloud point” refers to a temperature at which a solution undergoes a liquid-liquid or liquid-solid phase transition to form a mixture that is not a solution. Typically, in the embodiments and examples described herein, a solution at its cloud point undergoes a liquid-solid phase transition whereby a salt of a compound of structure (I) forms a precipitate, such as a crystalline precipitate. It will be appreciated that “cloud point” is a function of, for example, the identities of the components of the solution, the concentration of the solute in the solution, and the temperature of the solution. A person skilled in the art can determine cloud point in accordance with the present disclosure at least in view of the examples provided herein.

[0092] Additionally or alternatively, in some embodiments, the method of making the salt or crystalline form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), further comprises collecting the salt or crystalline form.

[0093] Additionally or alternatively, in some embodiments, the method of making the salt or crystalline form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), further comprises formulating the salt or crystalline form into a pharmaceutical composition, including any of the pharmaceutical compositions described herein. Compositions and Combinations of Forms of a Compound of Structure (I)

[0094] Typically, for administration to a subject, a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), is formulated with one or more pharmaceutically acceptable carriers (e.g. a pharmaceutically acceptable excipient). TheAttorney Docket No. 01374-0001-00PCT disclosure provides such compositions, including pharmaceutical compositions. Thus, one embodiment is a composition (e.g., pharmaceutical composition) comprising a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), and a pharmaceutically acceptable carrier. The compositions described herein can be used in accordance with the uses and / or methods described herein, e.g., to supply a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), for administration to a subject.

[0095] Compositions described herein and, hence, forms of the compound of structure (I), may be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously and intradermally), by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The terms “parenteral” and “parenterally,” as used herein, include subcutaneous, intracutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-arterial, intra-synovial, intrasternal, intrathecal, intralesional, intrahepatic, intraperitoneal, intralesional and intracranial injection or infusion techniques. In some embodiments, a composition described herein is administrable intravenously and / or intraperitoneally. In some embodiments, a composition described herein is administrable orally. Preferably, a composition described herein is administered orally, subcutaneously, intraperitoneally or intravenously.

[0096] The compound salts, additional therapies, and / or pharmaceutical compositions can be administered in unit forms of administration to mammalian subjects, including human beings. Suitable non-limiting examples of unit forms of administration include orally administered forms and forms administered via a parenteral / systemic route, non- limiting examples of which including inhalation, subcutaneous administration, intramuscular administration, intravenous administration, intradermal administration, and intravitreal administration.

[0097] In some embodiments, pharmaceutical compositions suitable for oral administration can be in the form of tablets, pills, powders, hard gelatin capsules, soft gelatin capsules, and / or granules. In some embodiments of such pharmaceutical compositions, a form of a compound of structure (I) and / or a pharmaceutically acceptable salt of a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), is (or are) mixed with one or more inert diluents, non-limiting examples of which including starch, cellulose, sucrose, lactose, and silica. In some embodiments, such pharmaceutical compositions may further comprise one or more substances other thanAttorney Docket No. 01374-0001-00PCT diluents, such as (as non-limiting examples), lubricants, coloring agents, coatings, or varnishes. In some embodiments, such pharmaceutical compositions may further comprise at least one at least one additional therapy.

[0098] In some embodiments, an oral formulation is formulated for immediate release or sustained / delayed release.

[0099] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium salts, (g) wetting agents, such as acetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0100] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol (ethanol), isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

[0101] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.Attorney Docket No. 01374-0001-00PCT

[0102] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0103] A form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), can also be in micro-encapsulated form with one or more excipients, as noted above. In such solid dosage forms, the compound can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.

[0104] Compositions for oral administration may be designed to protect the active ingredient against degradation as it passes through the alimentary tract, for example, by an outer coating of the formulation on a tablet or capsule.

[0105] In another aspect, a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), can be provided in an extended (or “delayed” or “sustained”) release composition. This delayed-release composition comprises the form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), and a delayed-release component. Such a composition allows targeted release of the compound, for example, into the lower gastrointestinal tract, for example, into the small intestine, the large intestine, the colon and / or the rectum. In certain aspects, a delayed- release composition further comprises an enteric or pH-dependent coating, such as cellulose acetate phthalates and other phthalates (e.g., polyvinyl acetate phthalate, methacrylates (Eudragits)). Alternatively, the delayed-release composition can provide controlled release to the small intestine and / or colon by the provision of pH sensitive methacrylate coatings, pH sensitive polymeric microspheres, or polymers which undergo degradation by hydrolysis. The delayed-release composition can be formulated with hydrophobic or gelling excipients or coatings. Colonic delivery can further be provided by coatings which are digested by bacterial enzymes such as amylose or pectin, by pHAttorney Docket No. 01374-0001-00PCT dependent polymers, by hydrogel plugs swelling with time (Pulsincap), by time-dependent hydrogel coatings and / or by acrylic acid linked to azoaromatic bonds coatings.

[0106] Compositions described herein can also be administered in the form of suppositories for rectal administration. These can be prepared by mixing a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and, therefore, will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0107] Compositions described herein can also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0108] Topical application for the lower intestinal tract can be affected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches can also be used.

[0109] For other topical applications, the compositions can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of a compound described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water and penetration enhancers. Alternatively, compositions can be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in one or more pharmaceutically acceptable carriers. Alternatively, the composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol, water and penetration enhancers.

[0110] For ophthalmic use, compositions can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the compositions can be formulated in an ointment such as petrolatum.Attorney Docket No. 01374-0001-00PCT

[0111] Compositions can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents. Without wishing to be bound by any particular theory, it is believed that local delivery of a composition described herein, as can be achieved by nasal aerosol or inhalation, for example, can reduce the risk of systemic consequences of the composition, for example, consequences for red blood cells.

[0112] In some embodiments, pharmaceutical compositions for parenteral administration can be in the form of aqueous solutions, non–aqueous solutions, suspensions, emulsions, drops, or any combination(s) thereof. In some embodiments, such pharmaceutical compositions may comprise one or more of water, pharmaceutically acceptable glycol(s), pharmaceutically acceptable oil(s), pharmaceutically acceptable organic esters, or other pharmaceutically acceptable solvents. In some embodiments, such pharmaceutical compositions may further comprise at least one at least one additional therapy.

[0113] Compositions described herein can also be administered subcutaneously, intraperitoneally or intravenously, e.g., in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, dextrose, water, Ringer’s solution, lactated Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation ofAttorney Docket No. 01374-0001-00PCT pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and / or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.

[0114] Other pharmaceutically acceptable carriers that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, and γ- cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives can also be advantageously used to enhance delivery of agents described herein.

[0115] In some embodiments, a composition described herein further includes one or more additional therapeutic agents, e.g., for use in combination with a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I).

[0116] Some embodiments provide a combination (e.g., pharmaceutical combination) comprising a form of a compound of structure (I) (e.g., a composition described herein comprising a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I)) and one or more additional therapeutic agents (e.g., one or more compositions comprising one or more additional therapeutic agents). Such combinations are particularly useful as, for example, when the compound of structure (I), such as an unsolvated salt of a compound of structure (I), and the one or more additional therapeutic agents are to be administered separately. In a combination provided herein,Attorney Docket No. 01374-0001-00PCT the compound of structure (I) and the one or more additional therapeutic agents can be administrable by the same route of administration or by different routes of administration.

[0117] Some embodiments provide a kit comprising a form of a compound of structure (I) (e.g., a composition described herein comprising a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I)) and an additional therapeutic agent(s) (e.g., a composition comprising an additional therapeutic agent(s)). In one embodiment, the kit comprises a therapeutically effective amount of the form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), to treat a disease, disorder or condition described herein, and a therapeutically effective amount of the one or more additional therapeutic agents to treat the disease, disorder or condition. In some embodiments, the kit further comprises written instructions for administering the form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), and / or the additional agent(s) to a subject to treat a disease, disorder or condition described herein.

[0118] Additional therapeutic agents for use in the compositions, combinations and / or kits provided herein include any of those discussed herein with respect to combination therapies.

[0119] In some embodiments, the at least one additional therapy is chosen from anti- CTLA-4 compounds, anti-PD-1 compounds, and anti-PD-L1 compounds. In some embodiments, the at least one additional therapy is chosen from Pembrolizumab (Keytruda); Nivolumab (Opdivo); Ipilimumab (Yervoy); Avelumab (Bavencio); Atezolizumab (Tecentriq); Durvalumab (Imfinzi); Cemiplimab (LBTAYO); Sintilimab (Tyvyt); Toripalimab (Tuoyi); Camrelizumab (AiRuiKa); Spartalizumab; and Tislelizumab. In some embodiments, the at least one additional therapy is chosen from anti-LAG-3 (lymphocyte activation gene-3) compounds; anti-TIM-3 (T-cell immunoglobulin and mucin-domaincontaining-3) compounds; anti-TIGIT (T-cell immunoglobulin and ITIM domain) compounds; anti-VISTA (V-domain Ig suppressor of T-cell activation) compounds; or a combination thereof. Non-limiting examples of anti- LAG-3 compounds include IMP321 (Eftilagimod alpha), Relatlimab (BMS-986016), LAG525, MK-4280, REGN3767, TSR-033, BI754111, Sym022, FS118, and MGD013. Non-limiting examples of anti-TIM-3 compounds include TSR-022, MBG453, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, RO7121661. Non-limitingAttorney Docket No. 01374-0001-00PCT examples of anti-TIGIT compounds include MK-7684, Etigilimab (OMP-313), Tiragolumab (MTIG7192A, RG-6058), BMS-986207, AB-154, and ASP-8374. Non- limiting examples of anti-VISTA compounds include JNJ-61610588 and CA-170.

[0120] In some embodiments, a form of the compound of structure (I) is present in a pharmaceutical composition (e.g., a unit dosage form) in an amount ranging from 5 µg to 2,000 mg. In some embodiments, a form of the compound of structure (I) is present in a pharmaceutical composition (e.g., a unit dosage form) in an amount ranging from 5 µg to 1,000 mg. In some embodiments, a form of the compound of structure (I) is present in a pharmaceutical composition (e.g., a unit dosage form) in an amount ranging from 5 µg to 500 mg. In some embodiments, a form of the compound of structure (I) is present in a pharmaceutical composition (e.g., a unit dosage form) in an amount ranging from 5 µg to 250 mg. In some embodiments, a form of the compound of structure (I) is present in a pharmaceutical composition (e.g., a unit dosage form) in an amount ranging from 5 µg to 100 mg. In some embodiments, a form of the compound of structure (I) is present in a pharmaceutical composition (e.g., a unit dosage form) in an amount ranging from 5 µg to 50 mg.

[0121] In some embodiments, a form of compound of structure (I) is present in a pharmaceutical composition (e.g., a unit dosage form) in an amount ranging from 1 mg to 5,000 mg. In some embodiments, a form of the compound of structure (I) (e.g., a unit dosage form) is present in a pharmaceutical composition in an amount ranging from 1 mg to 3,000 mg. In some embodiments, a form of the compound of structure (I) is present in a pharmaceutical composition (e.g., a unit dosage form) in an amount ranging from 1 mg to 2,000 mg. In some embodiments, a form of the compound of structure (I) is present in a pharmaceutical composition (e.g., a unit dosage form) in an amount ranging from 1 mg to 1,000 mg. In some embodiments, a form of the compound of structure (I) is present in a pharmaceutical composition (e.g., a unit dosage form) in an amount ranging from 1 mg to 500 mg. In some embodiments, a form of the compound of structure (I) is present in a pharmaceutical composition (e.g., a unit dosage form) in an amount ranging from 1 mg to 250 mg. In some embodiments, a form of the compound of structure (I) is present in a pharmaceutical composition (e.g., a unit dosage form) in an amount ranging from 1 mg to 100 mg. In some embodiments, a form of the compound of structure (I) is present in a pharmaceutical composition (e.g., a unit dosage form) in an amount ranging from 1 mg to 50 mg.Attorney Docket No. 01374-0001-00PCT

[0122] In some embodiments, a form of the compound of structure (I) is present in a pharmaceutical composition (e.g., a unit dosage form) in an amount of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1,000 mg, 1,100 mg, 1,200 mg, 1,300 mg, 1,400 mg, 1,500 mg, 1,600 mg, 1,700 mg, 1,800 mg, 1,900 mg, 2,000 mg, 2,100 mg, 2,200 mg, 2,300 mg, 2,400 mg, 2,500 mg, 2,600 mg, 2,700 mg, 2,800 mg, 2,900 mg, 3,000 mg, 3,100 mg, 3,200 mg, 3,300 mg, 3,400 mg, 3,500 mg, 3,600 mg, 3,700 mg, 3,800 mg, 3,900 mg, 4,000 mg, 4,100 mg, 4,200 mg, 4,300 mg, 4,400 mg, 4,500 mg, 4,600 mg, 4,700 mg, 4,800 mg, 4,900 mg, or 5,000 mg.

[0123] In some embodiments, the concentration of one or more therapeutic agents provided in a composition (e.g., a form of the compound of structure (I)) is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v or v / v; and / or greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125% , 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v.

[0124] In some embodiments, the concentration of one or more therapeutic agents provided in a composition (e.g., a form of the compound of structure (I)) is in the range from about 0.0001% to about 50%, about 0.001% to about 40 %, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%,Attorney Docket No. 01374-0001-00PCT about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, w / v or v / v. In some embodiments, the concentration of one or more therapeutic agents provided in a pharmaceutical composition (e.g., a form of the compound of structure (I)) is in the range from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, w / v or v / v. Uses of a Form of a Compound of Structure (I)

[0125] It has been found that the compound of structure (I) exhibits effects consistent with inhibition of AhR. Accordingly, provided herein is a method of modulating (e.g., inhibiting) AhR in a cell (e.g., a cell expressing AhR), comprising contacting a cell with a form of a compound of structure (I) (e.g., an effective amount of a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I)), e.g., in the form of a pharmaceutical composition thereof. In some embodiments, the method is conducted in vitro. In other embodiments, the method is conducted in vivo. In some embodiments, therefore, the cell is in a subject (e.g., a subject having a disease, disorder or condition described herein).

[0126] Also provided herein is a method of modulating (e.g., inhibiting) AhR in a subject in need thereof (e.g., a subject having a disease, disorder or condition described herein), comprising administering to the subject a therapeutically effective amount of a form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), e.g., in the form of a pharmaceutical composition thereof.

[0127] In some embodiments, disclosed herein is a method of treating a disease or condition mediated by AhR signaling in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a form of the compound of structure (I). In some embodiments, disclosed herein is a method of treating a disease or condition associated with aberrant AhR signaling in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a form of the compound of structure (I). In some embodiments, disclosed herein is a method of inhibiting AhRAttorney Docket No. 01374-0001-00PCT comprising administering to a subject in need thereof a form of the compound of structure (I). In some embodiments, disclosed herein is a method of reducing the activity of AhR comprising administering to a subject in need thereof a form of the compound of structure (I). In some embodiments, such pharmaceutical compositions may further comprise one or more additional therapies.

[0128] In some embodiments, disclosed herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a form of the compound of structure (I) or pharmaceutical composition thereof. In some embodiments, disclosed herein is a method of inhibiting cancer cell proliferation mediated by AhR signaling in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a form of the compound of structure (I) or pharmaceutical composition thereof. In some embodiments, the cancer is a hematological caner. In some embodiments, the cancer is a solid tumor cancer. In some embodiments, disclosed herein is a method of inhibiting tumor cell invasion or metastasis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a form of the compound of structure (I) or pharmaceutical composition thereof. In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a form of the compound of structure (I) or a pharmaceutical composition thereof wherein the cancer is a hematologic cancer. In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a form of the compound of structure (I) or a pharmaceutical composition thereof wherein the cancer is a solid tumor. In some embodiments, the cancer is chosen from breast cancers, respiratory tract cancers, brain cancers, cancers of reproductive organs, digestive tract cancers, urinary tract cancers, eye cancers, liver cancers, skin cancers, head and neck cancers, thyroid cancers, parathyroid cancers, and metastases of any of the foregoing.

[0129] In some embodiments, disclosed herein is a method of treating cancer comprising administering to a subject in need thereof a form of the compound of structure (I) and one or more additional therapies. In some embodiments, the cancer is chosen from non-small cell lung cancer (NSCLC); small cell lung cancer; head and neck squamous cell carcinoma; renal cell carcinoma; gastric adenocarcinoma; nasopharyngeal neoplasms; urothelial carcinoma; colorectal cancer; pleural mesothelioma; triple-negative breastAttorney Docket No. 01374-0001-00PCT cancer (TNBC); esophageal neoplasms; multiple myeloma; gastric and gastroesophageal junction cancer; melanoma; Hodgkin lymphoma; hepatocellular carcinoma; lung cancer; head and neck cancer; non-Hodgkin lymphoma; metastatic clear cell renal carcinoma; squamous cell lung carcinoma; mesothelioma; gastric cancer; gastroesophageal junction cancer; metastatic melanoma; metastatic non-cutaneous melanoma; urothelial cancer; diffuse large B-cell lymphoma; renal cell cancer; ovarian cancer, fallopian tube cancer; peritoneal neoplasms; extensive stage small cell lung cancer; bladder cancer; transitional cell carcinoma; prostatic neoplasms; recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck (SCCHN); recurrent squamous cell lung cancer; advanced solid malignancies; SCCHN; hypo pharyngeal squamous cell carcinoma; laryngeal squamous cell carcinoma; unresectable or metastatic melanoma; biliary tract neoplasms; esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostatic cancer, solid organ cancer; stomach cancer; colon cancer; and liver cancer. In some embodiments, the cancers are chosen from breast cancers, pancreatic cancers, prostate cancers, and colon cancers. In some embodiments, the cancers are chosen from lymphomas, sarcomas, and leukemias. In some embodiments, the disease, condition, or cancer treated by a form of the compound of structure (I) is breast cancer, pancreatic cancer, prostate cancer, or colon cancer. In some embodiments, the disease, condition, or cancer treated by a form of the compound of structure (I) is lymphoma, sarcoma, melanoma, glioblastoma, or leukemia.

[0130] In some embodiments, the cancer is chosen from acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); adrenocortical carcinoma; adrenocortical carcinoma, childhood; Acquired immunodeficiency syndrome (AIDS)-related cancer (e.g., Kaposi Sarcoma, AIDS-related lymphoma, primary central nervous system (CNS) lymphoma); anal cancer; appendix cancer; astrocytoma, childhood; atypical teratoid / rhabdoid tumor, childhood, CNS; basal cell carcinoma of the skin; bile duct cancer; bladder cancer; bladder cancer, childhood; bone cancer (including Ewing sarcoma, osteosarcoma and malignant fibrous histiocytoma); brain tumors / cancer; breast cancer; Burkitt lymphoma; carcinoid tumor (gastrointestinal); carcinoid tumor, childhood; cardiac (heart) tumors, childhood; embryonal tumors, childhood; germ cell tumor, childhood; primary CNS lymphoma; cervical cancer; childhood cervical cancer; cholangiocarcinoma; chordoma, childhood; chronic lymphocytic leukemia (CLL); chronic myelogenous leukemia (CML); chronic myeloproliferative neoplasms; colorectal cancer; childhoodAttorney Docket No. 01374-0001-00PCT colorectal cancer; craniopharyngioma, childhood; cutaneous T-cell lymphoma (e.g., mycosis fungoides and Sézary syndrome); ductal carcinoma in situ (DCIS); embryonal tumors, central nervous system, childhood; endometrial cancer (uterine cancer); ependymoma, childhood; esophageal cancer; childhood esophageal cancer; esthesioneuroblastoma; Ewing sarcoma; extracranial germ cell tumor, childhood; extragonadal germ cell tumor; eye (ocular) cancer; childhood intraocular melanoma; intraocular melanoma; retinoblastoma; fallopian tube cancer; fibrous histiocytoma of bone, malignant, and osteosarcoma; gallbladder cancer; gastric (stomach) cancer; childhood gastric (stomach) cancer; gastrointestinal carcinoid tumor; gastrointestinal stromal tumors (GIST); childhood gastrointestinal stromal tumors; germ cell tumors; childhood CNS germ cell tumors (e.g., childhood extracranial germ cell tumors, extragonadal germ cell tumors, ovarian germ cell tumors, testicular cancer); gestational trophoblastic disease; hairy cell leukemia; head and neck cancer; heart tumors, childhood; hepatocellular (liver) cancer; histiocytosis, Langerhans cell; Hodgkin lymphoma; hypopharyngeal cancer; intraocular melanoma; childhood intraocular melanoma; islet cell tumors, pancreatic neuroendocrine tumors; Kaposi sarcoma; kidney (renal cell) cancer; Langerhans cell histiocytosis; laryngeal cancer; leukemia; lip and oral cavity cancer; liver cancer; lung cancer (non-small cell and small cell); childhood lung cancer; lymphoma; male breast cancer; malignant fibrous histiocytoma of bone and osteosarcoma; melanoma; childhood melanoma; melanoma, intraocular (eye); childhood intraocular melanoma; Merkel cell carcinoma; mesothelioma, malignant; childhood mesothelioma; metastatic cancer; metastatic squamous neck cancer with occult primary; midline tract carcinoma with NUT gene changes; mouth cancer; multiple endocrine neoplasia syndromes; multiple myeloma / plasma cell neoplasms; mycosis fungoides; myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms; myelogenous leukemia, chronic (CML); myeloid leukemia, acute (AML); myeloproliferative neoplasms, chronic; nasal cavity and paranasal sinus cancer; nasopharyngeal cancer; neuroblastoma; non-Hodgkin lymphoma; non-small cell lung cancer; oral cancer, lip and oral cavity cancer and oropharyngeal cancer; osteosarcoma and malignant fibrous histiocytoma of bone; ovarian cancer; childhood ovarian cancer; pancreatic cancer; childhood pancreatic cancer; pancreatic neuroendocrine tumors; papillomatosis (childhood laryngeal); paraganglioma; childhood paraganglioma; paranasal sinus and nasal cavity cancer; parathyroid cancer; penile cancer; pharyngeal cancer; pheochromocytoma; childhood pheochromocytoma; pituitary tumor;Attorney Docket No. 01374-0001-00PCT plasma cell neoplasm / multiple myeloma; pleuropulmonary blastoma; pregnancy and breast cancer; primary peritoneal cancer; prostate cancer; rectal cancer; recurrent cancer; renal cell (kidney) cancer; retinoblastoma; rhabdomyosarcoma, childhood; salivary gland cancer; sarcoma (e.g., childhood rhabdomyosarcoma, childhood vascular tumors, Ewing sarcoma, Kaposi sarcoma, osteosarcoma (bone cancer), soft tissue sarcoma, uterine sarcoma); Sézary syndrome; skin cancer; childhood skin cancer; small cell lung cancer; small intestine cancer; soft tissue sarcoma; squamous cell carcinoma of the skin; squamous neck cancer with occult primary, metastatic; T-cell lymphoma, cutaneous (e.g., mycosis fungoides and Sèzary syndrome); testicular cancer; childhood testicular cancer; throat cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer); thymoma and thymic carcinoma; thyroid cancer; transitional cell cancer of the renal pelvis and ureter; ureter and renal pelvis, transitional cell cancer; urethral cancer; uterine cancer, endometrial; uterine sarcoma; vaginal cancer; childhood vaginal cancer; vascular tumors; vulvar cancer; and Wilms tumor and other childhood kidney tumors.

[0131] In some embodiments, the cancer is metastatic.

[0132] In some embodiments, disclosed herein is a method of treating ocular disorders comprising administering to a subject in need thereof a form of the compound of structure (I) and optionally one or more additional therapies.

[0133] A form of the compound of structure (I), optionally in addition to one or more additional therapies, can be used in therapeutic treatments.

[0134] In some embodiments, the form of the compound of structure (I) can be administered as a monotherapy. In some embodiments, the form of the compound of structure (I) can be administered in combination with at least one additional therapy. In some embodiments, the at least one additional therapy is chosen from immune checkpoint inhibitors (ICIs).

[0135] A form of a compound of structure (I), such as an unsolvated hydrochloride salt of a compound of structure (I), can also be administered in combination with one or more other therapies (e.g., radiation therapy, a chemotherapy, such as a chemotherapeutic agent; an immunotherapy, such as an immunotherapeutic agent) to treat a disease, disorder or condition described herein (e.g., cancer, an ocular disorder). In some embodiments, the method of treating a disease, condition, or cancer in a subject in need thereof comprising administering to the subject a therapeutic amount of the form of the compound of structure (I) further comprises administering to the subject at least one additional therapy. WhenAttorney Docket No. 01374-0001-00PCT administered “in combination,” the form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), can be administered before, after or concurrently with the other therapy(ies) (e.g., radiation therapy, an additional therapeutic agent(s)). When co-administered simultaneously (e.g., concurrently), the form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), and another therapeutic agent can be in separate formulations or the same formulation. Alternatively, the form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), and another therapeutic agent can be administered sequentially, either at approximately the same time or at different times, as separate compositions. When the form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), and the other therapy (e.g., therapeutic agent) are administered as separate formulations or compositions, the form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), and the other therapy can be administered by the same route of administration or by different routes of administration. A skilled clinician can determine appropriate timing for administration of each therapy being used in combination (e.g., timing sufficient to allow an overlap of the pharmaceutical effects of the therapies).

[0136] In some embodiments, a method described herein further comprises administering to the subject (e.g., a therapeutically effective amount of) an additional therapy(ies) (e.g., radiation therapy; an additional therapeutic agent, such as a chemotherapeutic agent, an immunotherapeutic agent, an antibody, such as a monoclonal antibody; a vaccine), e.g., in combination with the form of a compound of structure (I) such as an unsolvated hydrochloride salt of a compound of structure (I). In some embodiments, the form of a compound of structure (I), such as an unsolvated hydrochloride salt of a compound of structure (I), is administered before the additional therapy(ies). In some embodiments, the form of a compound of structure (I), such as an unsolvated hydrochloride salt of a compound of structure (I), is administered after the additional therapy(ies). In some embodiments, the form of a compound of structure (I), such as an unsolvated hydrochloride salt of a compound of structure (I), is administered concurrently with the additional therapy(ies).

[0137] In some embodiments, e.g., for the treatment of cancer, a method further comprises administering to the subject hormone therapy (e.g., a therapeutically effective amount of hormone therapy), e.g., anti-estrogen therapy, androgen deprivation therapyAttorney Docket No. 01374-0001-00PCT (ADT), such as flutamide, nilutamide, bicalutamide, leuprolide or goserelin, a luteinizing hormone-releasing hormone (LHRH) agonist, an aromatase inhibitor (AI), such as anastrozole, exemestane or letrozole, an estrogen receptor modulator, such as tamoxifen, raloxifene or toremifene.

[0138] In some embodiments, e.g., for the treatment of cancer, a method further comprises administering to the subject an immunotherapy (e.g., a therapeutically effective amount of an immunotherapy). Immunotherapy agents include antibodies that inhibit proteins expressed by cancer cells, vaccines and immune cell (e.g., T-cell) infusions. Antibody agents useful for promoting anti-tumor responses include anti-CTLA-4 antibodies (e.g., ipilimumab, tremelimumab), anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab, cemiplimab), anti-PD-L1 antibodies (e.g., atezolizumab, avelumab, durvalumab), anti-PD-L2 antibodies, anti-TIM-3 antibodies, anti-LAG-3 antibodies (e.g., relatlimab), anti-TIGIT antibodies, anti-VISTA antibodies, anti-OX40 antibodies, and anti-GITR antibodies. In some embodiments, the immunotherapy is an immune checkpoint inhibitor (e.g., a therapeutically effective amount of an immune checkpoint inhibitor), e.g., for treating a solid tumor cancer. In some embodiments, the method of treating a disease, condition, or cancer in a subject in need thereof comprising administering to the subject a therapeutic amount of the form of the compound of structure (I) further comprises administering to the subject at least one checkpoint inhibitor. Examples of immune checkpoint inhibitors include inhibitors of CTLA-4 (e.g., ipilimumab, tremelimumab), PD-1 (e.g., nivolumab, pembrolizumab), PD-L1 (e.g., avelumab), PD-L2, TIM-3, LAG-3 (e.g., relatlimab), TIGIT, VISTA, OX40 and GITR. In some embodiments, the immune checkpoint inhibitor (e.g., for treating a solid tumor cancer) is an inhibitor of CTLA-4, PD-1, PD-L1 or LAG-3. In some embodiments, the at least one additional therapy is chosen from anti-LAG-3 (lymphocyte activation gene-3) compounds; anti-TIM-3 (T-cell immunoglobulin and mucin-domaincontaining-3) compounds; anti-TIGIT (T-cell immunoglobulin and ITIM domain) compounds; anti- VISTA (V-domain Ig suppressor of T-cell activation) compounds; or a combination thereof. In some embodiments, the method of treating a disease, condition, or cancer in a subject in need thereof comprising administering to the subject a therapeutic amount of the form of the compound of structure (I) further comprises administering to the subject at least one checkpoint inhibitor selected from a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-Attorney Docket No. 01374-0001-00PCT L1), lymphocyte activation gene-3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), T-cell immunoglobulin and ITIM domain (TIGIT), and V-domain Ig suppressor of T-cell activation (VISTA) inhibitor.

[0139] In some embodiments, e.g., for the treatment of cancer, a method further comprises administering to the subject a chemotherapy (e.g., a therapeutically effective amount of a chemotherapy), e.g., comprising one or more chemotherapeutic agents. Examples of chemotherapeutic agents include, for example, antimetabolites (e.g., anti- folates, nucleotide analogs, in particular, purine and pyrimidine derivatives); alkylating agents (e.g., cyclophosphamide, mechlorethamine, chlorambucil, melphalan, dacarbazine, temozolomide, thiotepa); anthracyclines (e.g., daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin); taxanes (e.g., paclitaxel, docetaxel, abraxane, taxotere); epothilones; histone deacetylase inhibitors (e.g., vorinostat, romidepsin); topoisomerase inhibitors (e.g., irinotecan, topotecan, etoposide, teniposide, tafluposide); kinase inhibitors (e.g., bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, vismodegib); nucleotide analogs (e.g., azacitidine, azathioprine, capecitabine, cytarabine, doxifluridine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, tioguanine); peptide antibiotics (e.g., bleomycin, actinomycin); platinum-based agents (e.g., carboplatin, cisplatin, oxaliplatin); retinoids (e.g., tretinoin, alitretinoin, bexarotene); and vinca alkaloids (e.g., vinblastine, vincristine, vindesine, vinorelbine), as well as their pharmaceutically acceptable salts. Further examples of chemotherapeutic agents include alkylating agents, such as thiotepa and cyclophosphamide (CYTOXANTM); alkyl sulfonates, such as busulfan, improsulfan and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, such as altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; acetogenins, such as bullatacin and bullatacinone; camptothecins, including the synthetic analogue topotecan; bryostatin; callystatin; CC-1065, including its adozelesin, carzelesin and bizelesin analogues; cryptophycins, such as cryptophycin 1 and cryptophycin 8; dolastatin; duocarmycin, including the synthetic analogues, KW-2189 and CBI-TMI; eleutherobin; pancratistatin; sarcodictyins; spongistatin; nitrogen mustards, such as chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine,Attorney Docket No. 01374-0001-00PCT nimustine, and ranimustine; antibiotics, such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma 1 and calicheamicin theta I, see, e.g., Angew Chem. Intl. Ed. Engl. 33:183-186 (1994); dynemicin, such as dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino- doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, nitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; anti-metabolites, such as methotrexate and 5-fluorouracil (5- FU); folic acid analogues, such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, and 5-FU; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; anti- adrenals, such as aminoglutethimide, mitotane, and trilostane; folic acid replenishers, such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; epothilones; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes, such as T-2 toxin, verracurin A, roridin A and anguidine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as paclitaxel (e.g., TAXOLTM, Bristol-Myers Squibb Oncology, Princeton, N.J.; nab-paclitaxel, such as the nanoparticle albumin-bound form of paclitaxel sold as ABRAXANE®) and doxetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6- thioguanine; mercaptopurine; methotrexate; folinic acid; platinum analogs such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16);Attorney Docket No. 01374-0001-00PCT ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitors, such as irinotecan and RFS 2000; difluoromethylomithine (DFMO); retinoic acid; and capecitabine; as well as their pharmaceutically acceptable salts.

[0140] Specific examples of chemotherapeutic agents include aclarubicin, actinomycin, alitretinon, altretamine, aminopterin, aminolevulinic acid, amrubicin, amsacrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecan, bexarotene, bendamustine, bleomycin, bortezomib, busulfan, camptothecin, capecitabine, carboplatin, carboquone, carmofur, carmustine, celecoxib, chlorambucil, chlormethine, cisplatin, cladribine, clofarabine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, demecolcine, docetaxel, doxorubicin, efaproxiral, elesclomol, elsamitrucin, enocitabine, epirubicin, estramustine, etoglucid, etoposide, floxuridine, fludarabine, fluorouracil (5FU), fotemustine, gemcitabine, gliadel implants, hydroxycarbamide, hydroxyurea, idarubicin, ifosfamide, irinotecan, irofulven, ixabepilone, larotaxel, leucovorin, liposomal doxorubicin, liposomal daunorubicin, lonidamine, lomustine, lucanthone, mannosulfan, masoprocol, melphalan, mercaptopurine, mesna, methotrexate, methyl aminolevulinate, mitobronitol, mitoguazone, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, oblimersen, omacetaxine, ortataxel, oxaliplatin, paclitaxel, pegaspargase, pemetrexed, pentostatin, pirarubicin, pixantrone, plicamycin, porfimer sodium, prednimustine, procarbazine, raltitrexed, ranimustine, rubitecan, sapacitabine, semustine, sitimagene ceradenovec, strataplatin, streptozocin, talaporfin, tegafur-uracil, temoporfin, temozolomide, teniposide, tesetaxel, testolactone, tetranitrate, thiotepa, tiazofurine, tioguanine, tipifarnib, topotecan, trabectedin, triaziquone, triethylenemelamine, triplatin, tretinoin, treosulfan, trofosfamide, uramustine, valrubicin, verteporfin, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat and zorubicin, or a pharmaceutically acceptable salt of the foregoing.

[0141] In some embodiments of the method described herein comprising at least one additional therapy, the disease, condition, or cancer being treated is resistant to the at least one additional therapy when administered in the absence of the form of the compound of structure (I).

[0142] Numerous other therapies can also be administered during treatment (e.g., cancer treatment, treatment of an autoimmune disease) to mitigate the effects of theAttorney Docket No. 01374-0001-00PCT disease and / or side effects of the treatment, including therapies to manage pain (e.g., narcotics, acupuncture), gastric discomfort (e.g., antacids), dizziness (e.g., anti-vertigo medications), nausea (e.g., anti-nausea medications), infection (e.g., medications to increase red / white blood cell counts) and the like, all of which are readily appreciated by the person skilled in the art.

[0143] A form of a compound of structure (I), such as an unsolvated hydrochloride salt of a compound of structure (I), or other therapeutic agent described herein can be administered via a variety of routes of administration, including, for example, oral, dietary, topical, transdermal, rectal, parenteral (e.g., intra-arterial, intravenous, intramuscular, subcutaneous injection, intradermal injection), intravenous infusion and inhalation (e.g., intrabronchial, intranasal or oral inhalation, intranasal drops) routes of administration, depending on the compound and the particular disease to be treated. Administration can be local or systemic as indicated. In some embodiments, administration (e.g., of a form of a compound of structure (I), such as an unsolvated hydrochloride salt of a compound of structure (I)) is oral. In some embodiments, administration (e.g., of a form of a compound of structure (I), such as an unsolvated hydrochloride salt of a compound of structure (I)) is intravenous. The preferred mode of administration can vary depending on the particular form of the compound or agent.

[0144] With regard to the methods disclosed herein, the mode (or modes) of administration, dose (or doses), and pharmaceutical form (or forms) can be determined according to criteria generally considered during the establishment of a treatment of a patient, such as, by way of non-limiting examples, the potency of the form of the compound of structure (I), the at least one additional therapy (if present), the age of the patient, the body weight of the patient, the severity of the patient’s condition (or conditions), the patient’s tolerance to the treatment, and secondary effects observed in treatment. Determination of doses effective to provide therapeutic benefit for specific modes and frequency of administration is within the capabilities of those skilled in the art.

[0145] A form of a compound of structure (I), such as an unsolvated salt of a compound of structure (I), or other therapeutic agent can be administered in a dosage ranging from about 0.001 mg / kg to about 100 mg / kg of body weight or, alternatively, in a dosage ranging from about 1 mg / dose to about 5,000 mg / dose, every 4 to 120 hours, or according to the requirements of the particular agent. For example, suitable dosages can be from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 100 mg / kg, fromAttorney Docket No. 01374-0001-00PCT about 0.01 mg / kg to about 10 mg / kg, from about 0.01 mg / kg to about 1 mg / kg body weight per treatment. Suitable dosages can be from about 1 mg / dose to about 5,000 mg / dose, from about 10 mg / dose to about 2,500 mg / dose or from about 100 mg / dose to about 1,000 mg / dose.

[0146] Effective amounts and dosages can be estimated initially from in vitro assays. For example, an initial dosage for use in animals can be formulated to achieve a circulating blood or serum concentration of active compound that is at or above an IC50 of the particular compound as measured in an in vitro assay. Calculating dosages to achieve such circulating blood or serum concentrations taking into account the bioavailability of the particular compound is well within the capabilities of skilled artisans. For guidance, the reader is referred to Fingl & Woodbury, “General Principles,” in Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latest edition, Pergamagon Press, and the references cited therein, which methods are incorporated herein by reference in their entirety. Initial dosages can also be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of compounds to treat or prevent the various diseases described in this disclosure are well-known in the art.

[0147] In some embodiments, the administered dose ranges from 0.0001 or 0.001 or 0.01 mg / kg / day to 100 mg / kg / day, but can be higher or lower, depending upon, among other factors, the activity of the compound, its bioavailability, the mode of administration and various factors discussed above. Doses and intervals can be adjusted individually to provide plasma levels of the compound(s) which are sufficient to maintain therapeutic or prophylactic effect. For example, the form of the compound of structure (I) can be administered once per week, several times per week (e.g., every other day), once per day or multiple times per day (e.g., twice per day, three times per day, four times per day), depending upon, among other things, the mode of administration, the specific indication being treated and the judgment of the prescribing physician. In cases of local administration or selective uptake, such as local topical administration, the effective local concentration of active compound(s) may not be related to plasma concentration. Skilled artisans will be able to optimize effective local dosages without undue experimentation.

[0148] In some embodiments, a form of the compound of structure (I) is administered in an amount ranging from 5 µg to 2,000 mg. In some embodiments, a form of the compound of structure (I) is administered in an amount ranging from 5 µg to 1,000 mg. InAttorney Docket No. 01374-0001-00PCT some embodiments, a form of the compound of structure (I) is administered in an amount ranging from 5 µg to 500 mg. In some embodiments, a form of the compound of structure (I) is administered in an amount ranging from 5 µg to 250 mg. In some embodiments, a form of the compound of structure (I) is administered in an amount ranging from 5 µg to 100 mg. In some embodiments, a form of the compound of structure (I) is administered in an amount ranging from 5 µg to 50 mg.

[0149] In some embodiments, a form of compound of structure (I) is administered in an amount ranging from 1 mg to 5,000 mg. In some embodiments, a form of the compound of structure (I) is administered in an amount ranging from 1 mg to 3,000 mg. In some embodiments, a form of the compound of structure (I) is administered in an amount ranging from 1 mg to 2,000 mg. In some embodiments, a form of the compound of structure (I) is administered in an amount ranging from 1 mg to 1,000 mg. In some embodiments, a form of the compound of structure (I) is administered in an amount ranging from 1 mg to 500 mg. In some embodiments, a form of the compound of structure (I) is administered in an amount ranging from 1 mg to 250 mg. In some embodiments, a form of the compound of structure (I) is administered in an amount ranging from 1 mg to 100 mg. In some embodiments, a form of the compound of structure (I) is administered in an amount ranging from 1 mg to 50 mg.

[0150] In some embodiments, a form of the compound of structure (I) is administered in an amount of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1,000 mg, 1,100 mg, 1,200 mg, 1,300 mg, 1,400 mg, 1,500 mg, 1,600 mg, 1,700 mg, 1,800 mg, 1,900 mg, 2,000 mg, 2,100 mg, 2,200 mg, 2,300 mg, 2,400 mg, 2,500 mg, 2,600 mg, 2,700 mg, 2,800 mg, 2,900 mg, 3,000 mg, 3,100 mg, 3,200 mg, 3,300 mg, 3,400 mg, 3,500 mg, 3,600 mg, 3,700 mg, 3,800 mg, 3,900 mg, 4,000 mg, 4,100 mg, 4,200 mg, 4,300 mg, 4,400 mg, 4,500 mg, 4,600 mg, 4,700 mg, 4,800 mg, 4,900 mg, or 5,000 mg. EXEMPLIFICATION Materials and Methods

[0151] XRPD: XRPD of screening samples was performed with a Panalytical X’Pert3Powder XRPD on a Si zero-background holder. The 2θ position was calibrated against aAttorney Docket No. 01374-0001-00PCT Panalytical Si reference standard disc. Unless otherwise noted, the parameters used are listed in Table 1. Table 1: Parameters for XRPD measurements

[0152] TGA / DSC: TGA data was collected using a TA Discovery 550 TGA from TA Instrument. DSC was performed using a TA Q2500 DSC from TA Instrument. DSC was calibrated with Indium reference standard and the TGA was calibrated using nickel reference standard. Detailed parameters used are listed in Table 2. Table 2: Parameters for TGA and DSC Measurements

[0153] Polarized Light Microscopy (PLM): Polarized light microscopic picture was captured on Nikon DS-Fi2 upright microscope at room temperature.

[0154] HPLC: Agilent 1100 HPLC was utilized to analyze solubility, with details of the method listed in Table 3. Thermo Vanquish Core HPLC with CAD (charged aerosol detector) was utilized to analyze the chloride content of HCl salt Type 3, with details of this method listed in Table 4.Attorney Docket No. 01374-0001-00PCT Table 3: HPLC Method Details for Solubility ExperimentsTable 4: HPLC Method Details for Chloride Content MeasurementsAttorney Docket No. 01374-0001-00PCT

[0155] Crystal16: A Crystal16 from Technobis Crystallization Systems was utilized to evaluate solubility and metastable zone width (MSZW). Parameters are displayed in Table 4A. Table 4A: Parameters for Crystal16

[0156] Dynamic Vapor Sorption (DVS): DVS was measured using SMS (Surface Measurement Systems) DVS Intrinsic Plus Instrument (CPNJ-E82). The relative humidity at 25 ºC was calibrated against deliquescence point of LiCl, Mg(NO3)2and KCl. The parameters for DVS are listed in Table 4B. Table 4B: DVS Analysis Parameters

[0157] PSD: The parameters for PSD analysis are listed in Table 4C. Table 4C: Parameters for PSD AnalysisAttorney Docket No. 01374-0001-00PCTExample 1: Salt and Crystal Form Screen

[0158] A salt screening was performed using 100 different experimental conditions with seven different counterions in five different solvents, starting from Free Base Type 1 (a crystalline hydrate) of the compound of structure (I). Sixteen unique salt forms were observed from the screening, in addition to four polymorph crystal hits of the free base (including Free Base Type 1). A summary of the results is shown in Table 5. The XRPD results are shown in FIGs. 1-4. Table 5: Summary of Results from Salt and Crystal Form Screen Crystal DSC Form Form Preparation Weight Loss Endotherm. Identified by Conditions by TGA Identifier (Onset, ºC) TGA Free Base Prepared as 2.0% up to described in 121.8 Hydrate Type 1 141.2 ℃ Example 17Free Base 3.5% up to Solvate or Addition with 135.9 Type 2 THF / H 67.3 ℃ Hydrate 2O 203.7 Anti-solvent 32.5 Free Base Addition with 0.7% up to 144.6 Solvate or Type 3 215.4 ℃ Hydrate THF / H2O 212 ℃ Free Base HCl Salt Type 3 4.3% up to 29.2 Hydrate Type 4 RT Slurry in H2O 133.4 ℃ Anti-Solvent HCl Salt 6.0% up 107.6 Type 1 Addition with 131.7 ℃ 212.1 Solvate THF / IPA Heat Cool 29.6 HCl Salt Temperature 1.7% up to 119.9 Hydrate Type 2 Cycling with 134.8 ℃ 212. 3 Acetone Reactive Crystallization in HCl Salt 0.07% up to Type 3 EtOH, THF, or 153.6 ℃ 220.8 Anhydrate IPA with conc. HCl Phosphate Heat Cool 6.7% up to 77.7 Solvate Salt Type 1 Temperature 95.2 ℃ 212.0Attorney Docket No. 01374-0001-00PCT Crystal DSC Form Preparation Weight Loss Form Conditions by TGA Endotherm. Identified by Identifier (Onset, ºC) TGA Cycling with ACN Phosphate Reactive2.6% up 323.3 Solvate or Salt Type 2 143.5 ℃ 127.0 Hydrate EtOH and H2O Anti-Solvent L-Tartrate 7.2% up to 32.3 Salt Type 1 Addition with 161.1 ℃ 96.3 Solvate THF / IPA Nicotinate Anti-Solvent 5.4% up to 96.1 Addition with 160.0 Solvate Salt Type 1 143.5 ℃ THF / EtOAc 176.5 Anti-Solvent 28.9 Benzoate 1.8% up to Solvate or Addition with 98.6 Salt Type 1 THF / EtOAc 87.1 ℃ 121.3 hydrate 44.7 Maleate Anti-Solvent 4.9% up to 90.1 Addition with Solvate Salt Type 1 104.2 ℃ 116.3 THF / H2O 153.6 Maleate Slow Cooling 5.7% up to 30.4 Solvate Salt Type 2 with EtOH 145.9 ℃ 158.8 Maleate Slow Cooling 2.1% up to 58.3 Salt Type 3 with MeOH 122.4 ℃ 169.6 Solvate Heat Cool Maleate Temperature 5.2% up to 140.3 Solvate Salt Type 4 Cycling with 151.1 ℃ 161.7 Acetone Heat Cool 83.4 Maleate Temperature 2.6% up to 110.1 Solvate or Salt Type 5 Cycling with 71.5 ℃ hydrate 140.8 ACN Anti-Solvent 46.1 Maleate 5.2% up to Salt Type 6 Addition with 128.2 ℃ 106.8 Solvate 138.6Maleate Addition with 8.4% up to 65.8 Solvate Salt Type 7 128.2 ℃ 133.4 THF / EtOAc35.8 Maleate 1.0% up to 77.5 Salt Type 8 Type 1 Vacuum 121.1 ℃ 116.2 Solvate Dried 141.3Attorney Docket No. 01374-0001-00PCT Example 2: Characterization of Free Base Type 1

[0159] A representative XRPD result of the crystalline material is displayed in FIG. 1. TGA exhibited a total of 2.0% weight loss up to 141.2 °C before decomposition, and the DSC thermogram showed a melting endotherm with an onset of 212.8 °C. KF analysis showed that the sample contained 1.27% (w / w) water. Based on these data, Free Base Type 1 was concluded to be a hydrate. The approximate solubility of Free Base Type 1 was determined, and the findings are summarized in Table 6. These solubility measurements were used to guide the design of the salt screening. Table 6: Approximate Solubility of Free Base Type 1 in Selected Solvents Solvent Solubility Solubility (mg / mL) Solvent (mg / mL) H2O S<2.7 Acetone 6.3<S<19.0 MeOH 3.0<S<10.0 EtOAc 2.3<S<7.7 EtOH 2.6<S<8.7 ACN 3.0<S<10.0 IPA S<2.4 THF 22.0<S<44.0 TFE S>48.0 DMSO 21.0<S<42.0 Example 3: Characterization of Free Base Type 2

[0160] Free Base Type 2 was obtained from reverse anti-solvent addition in acetone: H2O (1:5). Free base Type 2 can also be obtained from anti-solvent addition in THF: H2O (1:3). A representative XRPD result of the crystalline material is displayed in FIG. 1. TGA exhibited a total of 3.5% weight loss up to 67.3 °C, and the DSC thermogram showed three endotherms with onset temperatures of 30.8 °C, 135.9 °C and 203.7 °C. Example 4: Characterization of Free Base Type 3

[0161] Free Base Type 3 was obtained from anti-solvent addition experiments in THF: H2O (1:3). A representative XRPD result of the crystalline material is displayed in FIG. 1. TGA exhibited a total of 0.7% weight loss up to 215.4 °C. The DSC thermogram showed two endotherms with onsets at 32.5 °C and 144.6 °C, followed by a recrystallization exotherm with an onset at 154.9 °C. The melting endotherm with an onset of 212.0 °C is due to the melting of the Free Base Type 1 that forms during the exothermic re- crystallization event. Example 5: Characterization of Free Base Type 4

[0162] Free Base Type 4 was obtained from a room temperature overnight slurry of HCl Salt Type 3 in H2O. It was confirmed via CAD that no HCl was present in the sampleAttorney Docket No. 01374-0001-00PCT of Free Base Type 4. A representative XRPD result of the crystalline material is displayed in FIG. 1. TGA exhibited a total of 4.3% weight loss up to 133.4 °C. The DSC thermogram showed a broad endotherm with an onset at 29.2 °C, which is consistent with the solvent loss shown in the TGA. Based on these data, it was concluded that Free Base Type 4 is a hydrate. Example 6: Characterization of HCl Salt Type 1

[0163] HCl Salt Type 1 was obtained from an anti-solvent addition experiment with THF:IPA (1:5) and a 0.1 N HCl THF solution in a 1:2 compound of structure (I):HCl ratio. A representative XRPD result of the crystalline material is displayed in FIG. 2. TGA exhibited a total of 6.0% weight loss up to 131.7 °C. The DSC thermogram showed an endotherm with an onset at 49.8 °C corresponding to the solvent loss observed in the TGA, and a melting endotherm with an onset of 212.0 °C. Based on these data, it can be concluded that HCl salt Type 1 is likely a solvate.

[0164] HCl salt Type 1 was scaled up to 100-mg scale by the method of anti-solvent addition. The scale-up procedure involved dissolution of 99.2 mg of the compound of structure (I) in 4.5 mL of 0.1 N THF solution (1:2 API: HCl) to form a saturated solution. The solution was stirred at room temperature (RT) at 300 rpm while adding dropwise 22.75 mL of H2O. After stirring for 30 minutes, the sample was then moved to 5 °C for 24 hours to induce precipitation. Once 24 hours had passed, the sample was set to slow evaporation to induce precipitation. The XRPD of the scaled-up batch matched that of the original batch. Example 7: Characterization of HCl Salt Type 2

[0165] HCl Salt Type 2 was obtained from a heat-cool temperature cycling experiment with acetone and 0.1 N HCl in a 1:2 compound of structure (I):HCl ratio. A representative XRPD of the resulting crystalline material is displayed in FIG. 2. TGA exhibited a total of 1.7% weight loss up to 134.8 °C, and the DSC thermogram showed three endotherms with onsets at 29.6 °C, 119.9 °C and of 212.0 °C. Based on these data, it was concluded that HCl Salt Type 2 is likely a hydrate. Attempts to reproduce this salt form were unsuccessful. Example 8: Characterization of HCl Salt Type 3

[0166] HCl Salt Type 3 was obtained from reactive crystallization in THF, EtOH, and IPA with concentrated HCl. TGA exhibited a total of 0.07% weight loss up to 156.2 °C, and the DSC thermogram showed a melting endotherm with an onset of 220.8 °C, both ofAttorney Docket No. 01374-0001-00PCT which plots are shown in FIG. 5. The DSC and TGA overlay showed reproducibility of HCl Salt Type 3 in THF, IPA, and EtOH. The thermal data indicated that HCl Salt Type 3 is an anhydrate.

[0167] HCl Salt Type 3 was scaled up to a 300-mg scale. The scale-up procedure involved slurring 300 mg of the compound of structure (I) in 3 mL of EtOH with 150 µL of concentrated HCl. The 150 µL of concentrated HCl was added in increments of 50 µL while stirring. After stirring for 2 hours, the sample was air dried. The XRPD, TGA, and DSC for the scaled-up batch matched that of the smaller scale sample obtained during screening.

[0168] For XRPD analysis, 10 mg of a representative batch of crystalline HCl Salt Type 3 material was prepared and transferred to a Si zero-background XRPD holder. The surface of the sample was then gently smoothed out. The XRPD diffraction data were collected on Panalytical Aeris Powder X-ray Diffractometer, and the 2θ position was calibrated against a Panalytical Si reference standard disc. The scanning range was from 3 to 40 degrees 2θ. The parameters used are shown in Table 7. The resulting pattern is displayed in FIG. 6, with the details of the peak data provided in Table 8.

[0169] Single crystals of the salt were grown, and the structure solution confirmed the stoichiometry of 1:1 compound of structure (I):HCl. A block-like single crystal with high diffraction quality was immersed in Paratone-N (an oil based cryoprotectant). The crystal was mounted on a mylar loop in a random orientation and immersed in a stream of liquid nitrogen at 213K. The X-ray intensity data were measured on a Bruker D8 VENTURE (IμS microfocus X-ray source, Cu Kα, λ =1.54178Å, PHOTON III CMOS detector) diffractometer. The frames were integrated with the Bruker SAINT software package. The integration of the data using a monoclinic unit cell yielded a total of 3988 reflections to a maximum θ angle of 67.679° (0.83 Å resolution), of which 3988 were independent (completeness = 99.9%) and were greater than 2σ(F2). The final cell constants of a = 7.340(18) Å, b = 17.07(4) Å, c = 17.42(4) Å, α = γ = 90°, β = 92.49(9)°, cell volume = 2180(9) Å3, are based upon the refinement of the XYZ-centroids of 2987 reflections above 20 σ(I) with 7.594° < θ < 67.374°. Data were corrected for absorption effects using the Multi-Scan method (SADABS). The absorption coefficient μ of this material is 2.055 mm-1 at this wavelength (1.54178 Å). The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.5367 and 0.7531. The agreement factor for the averaging was 7.50% based on intensity. The structure was solved with theAttorney Docket No. 01374-0001-00PCT ShelXT1 structure solution program using Intrinsic Phasing and refined with ShelXL1 (Version 2014 / 7) refinement package using full-matrix least-squares on F2using the space group P21 / n, with Z = 4 for the formula unit, C22H19FN5O2Cl). All non-hydrogen atoms were refined anisotropically. The positions of the hydrogen atoms connected to carbon atoms were calculated geometrically and refined using the riding model. The final anisotropic full-matrix least-squares refinement on F2with 298 variables converged at R1 = 7.52%, for the observed data and wR2= 21.04% for all data. The goodness-of-fit was 1.111. The largest peak in the final difference electron density synthesis was 0.374 e- / Å3and the largest hole was -0.406 e- / Å3. Based on the final model, the calculated density is 1.456 g / cm3and F (000), 984 e-.

[0170] The packing for this molecule does not contain any standard hydrogen bonding interactions. The chloride ions function as bridging atoms to form a pseudo-dimer unit. The rest of the intermolecular forces observed in this packing arrangement are low-energy Van der Waals interactions.

[0171] HPLC analysis with a CAD detector indicated that the stoichiometry of chloride to compound of structure (I) was 0.8:1. HCl Salt Type 3 showed a water absorption of 0.3% at 25 ℃ / 80% RH by DVS when analyzed by a 40-95-0-95% RH method, indicating that the sample is minimally hygroscopic in nature. The DVS plot is shown in FIG. 7. The sample showed no form conversion post-DVS by XRPD. Table 7: Parameters of XRPD Data Collection for HCl Salt Type 3Attorney Docket No. 01374-0001-00PCT Table 8: Detailed Peak Data for XRPD of HCl Salt Type 3Example 9: pH Dependent Solubility of HCl Salt Type 3 and Free Base Type 1 at Room Temperature

[0172] Solubility studies were conducted in duplicate on HCl Salt Type 3 at pH 2.0, 3.9, 5.9, and 7.9 at room temperature. Similar experiments were conducted on Free Base Type 1, at pH 2 (0.01N HCl), 4, 6, 8, and 10. The vials containing the slurries were kept at a room temperature (20-25 °C) and samples were drawn, filtered, and analyzed by HPLC, drawn at 24 hours and 48 hours.Attorney Docket No. 01374-0001-00PCT

[0173] A summary of the pH solubility experiments is given in Table 9. After 24 hours and 48 hours, HCl salt Type 3 converted to Free Base Type 4 in each of the pH 2.0, 2.9, 5.9, and 7.9 slurries. Table 9: pH solubility of HCl salt Type 3 and Free Base Type 1Example 10: Kinetic Solubility of HCl Salt Type 3 and Free Base Type 1 in Biorelevant Media at Room Temperature

[0174] The kinetic solubility of HCl salt Type 3 and Free Base Type 1 was assessed in the biorelevant media SGF, FeSSIF, and FaSSIF at room temperature. Samples were slurried at 300 RPM at room temperature and the supernatant was isolated for HPLC analysis at the 24-hour and 48-hour time points. A summary of the kinetic solubility experiments for HCl salt Type 3 and Free Base Type 1 is provided in Table 10. The HCl salt Type 3 showed no observable form change in SGF at the 24-hour and 48-hour timeAttorney Docket No. 01374-0001-00PCT points. However, HCl salt Type 3 converted to Free Base Type 4 in FaSSIF and FeSSIF at the 24-hour and 48-hour time points. Observations of form type were done by XRPD.

[0175] HCl salt Type 3 was added at approximately 7.5 mg / ml to each buffer. For SGF, an additional 57.9 mg of HCl salt Type 3 was added to maintain a slurry at room temperature. At the 48-hour time point, few solids remained in the HCl salt Type 3 SGF slurry.Example 11: Temperature-Dependent Solubility of HCl Salt Type 3 and Free Base Type 1 in Ethanol

[0176] A solubility study was conducted to determine the temperature ranges where seeding can be performed. Crystalline samples were used to determine the clear and cloud point for API dissolution and crystallization as well as the solubility for HCl Salt Type 3, respectively, in ethanol. Briefly, 1 mL of EtOH was added to an HPLC vial containing pre-weighted HCl salt Type 3. The sample was heated form 10 °C to 70 °C over 8 hours and then the samples were cooled to 10 °C over 8 hours and held at 10 °C. The same procedure was repeated for Free Base Type 1. The temperature at which the sample dissolved to produce clear solution during heating was the clear point, while during the cooling, the temperature at which API precipitated was called the cloud point. The solubility, the clear point, and cloud point data of Free Base Type 1 and HCl Salt Type 3 is presented in Table 11 and Table 12.Attorney Docket No. 01374-0001-00PCT Table11: Clear point and cloud point data for Free Base Type 1 in EtOHTable 12: Clear point and cloud point data for HCl Salt Type 3 in EtOHExample 12: Kinetics of HCl Salt Type 3 Crystallization as a Function of Temperature and Seeding

[0177] After discovery of HCl Salt Type 3 in the salt screening in THF and successful formation of HCl Salt Type 3 in EtOH by reactive crystallization, EtOH was chosen as the crystallization solvent for future experiments because it is a class 3 solvent according to the U.S. FDA and provides a wider temperature range for crystallization compared to THF.

[0178] It was previously shown that salt crystallization and full conversion to HCl Salt Type 3 takes time at room temperature (20-25°C). Three experiments, the details of whichAttorney Docket No. 01374-0001-00PCT are outlined in Table 13, were set up to probe the effect of temperature and seeding on the kinetics of the salt formation.

[0179] At room temperature the free base peak at 2θ = 9.2° was visible by XRPD even after 3 hours of stirring. The XRPD analysis of the sample crystallized at elevated temperature, 42-45 °C, did not show Free Base Type 1 peaks at even at the 15 min or 20 min time point after the HCl was added. No difference was observed between the XRPD patterns of the samples that were seeded and those that were not at 15 and 30 min time points. Table 13: Kinetics of HCl Salt Type 3 Crystallization ExperimentsExample 13: Design of Experiments (DOE) to Optimize HCl Salt Type 3 Crystallization

[0180] The crystallization development started with two-level, full 3-factorial DOE (23) executed at 300 mg scale, varying the temperature at which the HCl was added, the time the sample was equilibrated before isolation, and the equivalents of excess HCl relative to the API free base. Since many previous crystallization experiments were performed at room temperature (20-25 °C), and there was no knowledge about the stability of 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3- yl)pyrido[3,4-d]pyrimidin-4(3H)-one at elevated temperatures, temperature levels of 40 °C and 60 °C were chosen for the DOE to collect stability information. Previous chlorideAttorney Docket No. 01374-0001-00PCT content analysis using HPLC with CAD detector showed chloride levels lower than the theoretical amount for a mono-HCl salt. To probe the HCl excess needed to obtain 1:1 API:Cl ratio, the level of excess HCl in the DOE was set to 0.2 and 0.5 mole equivalent. The reaction kinetics were probed by varying the reaction time in the DOE from 20 to 60 min. A single experiment was performed for each set of experimental conditions, and one experiment was conducted at the center point, for a total number of nine experiments. All experiments included HCl addition in a single aliquot and no seeding. The results from the DOE were analyzed in terms of chloride content, LC Area%, form and particle morphology. All experiments have been set at 100mg / mL concentration of API.

[0181] The DOE and experimental results are shown in Table 14. No correlation was observed between the temperature to which the reaction mixture was heated and the purity of the resulting solids. The LC area % of the product in the experiments varied between 98.61 and 99.01%. The crystalline form was consistently HCl Salt Type 3, as confirmed by XRPD. The Cl:API ratio varied from 0.66 to 0.87. There seems to be a slight correlation between the temperature at the which the reaction is conducted, and Cl:API ratio. All 40 °C experiments showed Cl:API ratio <0.8, while for the 60 °C experiments the ratio was greater than 0.8.

[0182] Polarized microscopy images indicated that the largest crystals with block-like morphology were obtained from samples where the reaction was conducted at 60 °C (DOE Experiments 6, 7, and 8), while the samples heated to 40 °C where 0.5 mole equivalent excess HCl was used (DOE Experiments 3 and 4) exhibited mixtures of needle- like and plate-like crystals. Table 14: HCl Salt Type 3 Crystallization Procedure DOE Design and ResultsAttorney Docket No. 01374-0001-00PCTExample 14: HCl Salt Type 3 Crystallization Scale-up and Additional Experiments

[0183] HCl Salt Type 3 Crystallization Scale-Up Experiment 1

[0184] Starting with free base, a 1 g crystallization was performed. The crystallization parameters used in this 1 g batch are outlined below. 1. 1.0007 g of free base 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one was added to 10 mL of EtOH. 2. The slurry was heated at 60 ⁰C and held. 3. 566 μL of 6M aqueous HCl was added (0.5 mol equivalent excess HCl) at a rate of 18.88 μL / min over 30 minutes. 4. 1% w / w seeds of HCl Salt Type 3 were added at the clear point. 5. The suspension was cooled to 40 ⁰C over 1 hour, then to 25 ⁰C over 10 hours and held at 25 ⁰C. 6. Solids were isolated by vacuum filtration and washing with 2 mL of EtOH: H2O (1:1). 7. Solids were dried at RT.

[0185] The XRPD showed the same crystalline pattern as other batches of HCl Salt Type 3. The PLM showed large plate-like birefringent particles approximately 50 μm in size after being cooled to 25 °C. The TGA showed a weight loss of 0.16% up to 147.9 ⁰C and the DSC showed a melting endotherm with an onset at 231.9 °C, both of which plots are shown in FIG. 11. The particle size distribution (PSD) analysis showed a D90 of 44.9 μm (Table 15). The product of Scale-up Experiment 1 showed a purity of 99.15% (Table 16) and was also analyzed by CAD to have a 0.80 Chloride:API ratio.Attorney Docket No. 01374-0001-00PCTTable 16 Purity of Scale-up Experiment 1

[0186] HCl Salt Type 3 Crystallization Scale-Up Experiment 2

[0187] Starting with free base, a 1 g crystallization was performed. The crystallization parameters used in this 1 g batch are outlined below. 1. 1.0299 g of 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one was added to 10 mL of EtOH. 2. The slurry was heated at 60 ⁰C and held. 3. 566 μL of 6M aqueous HCl was added (0.5 mol equivalent excess HCl) at a rate of 18.88 μL / min over 30 minutes. 4. 1% w / w seeds of HCl Salt Type 3 were added at the clear point. 5. The suspension was held at 60 ⁰C for 1 hour, then cooled to 20 ⁰C over 4 hours and held at 20 ⁰C overnight. 6. Solids were isolated by vacuum filtration and washing with 2 mL of EtOH: H2O (1:1). 7. Solids were dried at RT.

[0188] The XRPD showed the same crystalline pattern as previous batches of HCl Salt Type 3. The PLM showed large plate-like birefringent particles approximately 100 μm in size at the 1.5-hour time point at 60 °C (FIG. 9A). PLM was also taken at the 4-hour time point after being cooled to 20 °C and showed large plate-like birefringent particles approximately 100 μm in size (FIG. 9B).Attorney Docket No. 01374-0001-00PCT

[0189] The mother liquor concentration was measured by HPLC after the 4-hours cool down to 20 °C and determined to be 10.85 mg / mL. The TGA of the dried solid showed a weight loss of 0.03% up to 153.3 ⁰C and the DSC showed a melting endotherm with an onset at 239.3 °C. The PSD analysis showed a D90 of 46.0 μm (Table 17, FIG. 8). The product of Scale-up Experiment 2 showed a purity of 99.06% (Table 18) and was also analyzed by CAD to have a Chloride:API ratio of 0.8.Table 18 Purity of Scale-up Experiment 2

[0190] Additional HCl Salt Type 3 Crystallization Experiment 1

[0191] 300 mg of free base was used in the crystallization experiment outlined below. 1. 301.5 mg of 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one was added to 3 mL of EtOH. 2. The slurry was heated at 40 ⁰C and held. 3. 170 μL of 6M aqueous HCl was added (0.5 mol equivalent excess HCl) in one portion. 4. 1% w / w seeds of HCl Salt Type 3 were added at the clear point. 5. The suspension was held at 40 ⁰C for 20 minutes. 6. Solids were isolated by vacuum filtration and washing with 1 mL of EtOH: H2O (1:1). 7. Solids were dried at RT.Attorney Docket No. 01374-0001-00PCT

[0192] The XRPD showed the same crystalline pattern as other batches of HCl Salt Type 3. The PLM showed large plate-like birefringent particles approximately 50 μm in size. The PSD analysis showed a D90 of 41.2 μm (Table 19). The product of Additional Crystallization Experiment 1 showed a purity of 98.94% (Table 20) and was also analyzed by CAD to have a 0.83 Chloride:API ratio.Table 20 Purity of Additional Crystallization Experiment 1

[0193] Additional HCl Salt Type 3 Crystallization Experiment 2

[0194] Starting with free base, a 300 mg crystallization was performed. The crystallization parameters used in this 300 mg batch are outlined below. 1. 298.4 mg of 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one was added to 3 mL of EtOH. 2. The slurry was heated at 60 ⁰C. 3. 170 μL of 6M aqueous HCl was added (0.5 excess HCl) in one portion. 4. 1% w / w seeds of HCl Salt Type 3 were added at the clear point. 5. Suspension held at 60 ⁰C for 20 minutes.Attorney Docket No. 01374-0001-00PCT 6. Solids were isolated by vacuum filtration and washing with 1 mL of EtOH: H2O (1:1). 7. Solids were dried at RT.

[0195] The XRPD showed the same crystalline pattern as previous batches of HCl Salt Type 3. The PLM showed large plate-like birefringent particles approximately 50 μm in size. The PSD analysis showed a D90 of 41.2 μm (Table 21). The product of Additional Crystallization Experiment 2 showed a purity of 99.17% (Table 22) and was also analyzed by CAD to have a 0.83 Chloride: API ratio.Table 22 Purity of Additional Crystallization Experiment 2Example 15: Stability of HCl Salt Type 3 Crystals at Ambient and Accelerated Storage Conditions

[0196] Samples of HCl Type 3 were held at 20 ℃, 25 ℃ / 60% RH, and 40 ℃ / 75% RH to determine the stability of the samples at different ambient and accelerated storage conditions for up to 4 weeks in closed and open vials. Samples were analyzed via XRPD at the 1-, 2-, 3-, and 4-week time points to determine if any form conversion had occurred. After 4 weeks, no form change was observed via XRPD for any of the storage conditions.

[0197] HCl Salt Type 3 was also slurried for 24 hours in EtOH at 40 ℃ and 50 ℃ then analyzed via XRPD and HPLC to test for purity and any form conversion. HCl Salt Type 3 slurried in EtOH at 40 ℃ and 50 ℃ showed a purity of 98.69% and 98.61% comparedAttorney Docket No. 01374-0001-00PCT to the standard, respectively. XRPD showed no form conversion for the 40 ℃ and 50 ℃ samples. Example 16. 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one inhibits tumor growth in a high AhR expressing Hepa 1-6 murine in vivo syngeneic tumor model

[0198] To gain mechanistic insight into the anti-tumor effects of 3-(2-hydroxy-2- methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one, a syngeneic tumor model was evaluated. Commercially available RNASeq data was used to evaluate AhR gene expression across a set of 32 syngeneic mouse models. In this context, Hepa1-6, a murine hepatocellular carcinoma tumor line was identified to have the highest AhR expression. Mice were implanted with Hepa1-6 cells, randomized once tumors reached an average volume of 100mm3and dosed with different concentrations of 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one daily for 36 days while anti-PD-1 was used as a positive control. 3-(2-Hydroxy-2-methylpropyl)-8-(pyridin-3-yl)- 6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one treatment resulted in significantly reduced tumor growth in a dose-dependent manner, with the 3 mg / kg dose group exhibiting tumor regression in 6 mice, 4 of which were complete responses. Reduced tumor volume in groups treated with 3-(2-hydroxy-2-methylpropyl)- 8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one on the final day prior to termination highlighted that 3-(2-hydroxy-2-methylpropyl)-8- (pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one significantly reduced tumor volume at a dose to 0.1 mg / kg over the study.

[0199] The results, which are reported in Table 23 and FIGs. 10A and 10B, show that 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3- yl)pyrido[3,4-d]pyrimidin-4(3H)-one demonstrates anti-tumor efficacy in Hepa1-6 model. In Table 23, TGI refers to tumor growth inhibition. Table 23Attorney Docket No. 01374-0001-00PCTExample 17. Synthesis of 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0200] 3-(2-Hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3- yl)pyrido[3,4-d]pyrimidin-4(3H)-one was prepared in accordance with procedures described in International Publication No. WO 2021 / 102288 using a telescoped cross- coupling of the appropriate heteroaryl dichloride with both boronic acid coupling partners in the final step, as depicted in Scheme 1.Scheme 1

[0201] To a N2-flushed 12 L round-bottomed flask equipped with mechanical stirring, a temperature probe, a reflux condenser, and an N2 inlet was charged the heteroaryl dichloride, 3-pyridylboronic acid, Na2CO3, dioxane, and water. Reaction mixture was sparged via sub-surface N2 flow with agitation for 30 minutes. Charged (dppf)PdCl2 • CH2Cl2 to reactor. Reaction mixture was sparged via sub-surface N2 flow with agitation for additional 10 minutes. Reaction mixture was heated to 60°C and aged for 18 hours. HPLC analysis of the reaction mixture indicated full conversion of the heteroaryl dichloride. [6-(trifluoromethyl)-3-pyridyl]boronic acid was charged to reactor. Reaction mixture was heated to 80°C and aged for 2 hours. HPLC analysis of the reaction mixture indicated full conversion of heteroaryl chloride. Reaction mixture was cooled to ambientAttorney Docket No. 01374-0001-00PCT temperature. Reaction mixture was diluted with water (10 volumes) and EtOAc (10 volumes). Layers were separated. Aqueous layer was extracted with EtOAc (5 volumes x 2). Combined organic layers washed with water (5 volumes x 2). 1M HCl (10 volumes) was charged to the organic layers. Layers were separated. Organic layer was extracted with 1M HCl (10 volumes x 2). Combined aqueous (acidic) layers basified by the addition of 6M NaOH solution. Aqueous layer was extracted with EtOAc (10 volumes x 3). Combined organics were filtered over a pad of silica, silica pad was washed with additional EtOAc (10 volumes). Combined organics were washed with 1% N-Ac-L- Cysteine solution (5 volumes x 3) and water (10 volumes). Activated carbon (10 wt%) and Na2SO4 was charged to the organic layer, and the organic layer was filtered over a pad of Celite, and concentrated to a light orange solid. MeOH (5 volumes) / water (5 volumes) were charged to the crude solid, and the suspension was heated to reflux, allowed to cool to ambient temperature and filtered to provide a light-yellow solid. This crystallization was repeated, the resulting solids were dried in a vacuum oven 50°C to provide 3-(2- hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4- d]pyrimidin-4(3H)-one as an off-white solid.

Claims

CLAIMS:

1. An unsolvated hydrochloride salt of a compound of structure (I):

2. A crystalline form of the salt of claim 1.

3. The crystalline form of claim 2, comprising HC1 salt Type 3.

4. The crystalline form of claim 2, consisting essentially of HC1 salt Type 3.

5. The salt of claim 1 or crystalline form of claim 2, 3, or 4, wherein the salt or crystalline form is substantially pure.

6. The crystalline form of any one of claims 2-5, characterized by an x-ray powder diffraction pattern comprising at least three peaks at 2-theta angles selected from the group consisting of 10.1+0.2°, 11.6+0.2°, 14.5+0.2°, 16.0+0.2°, 16.6+0.2°, 19.8+0.2°, and 20.3+0.2°.

7. The crystalline form of claim 6, characterized by an x-ray powder diffraction pattern comprising at least four peaks at 2-theta angles selected from the group consisting of 10.1+0.2°, 11.6+0.2°, 14.5+0.2°, 16.0+0.2°, 16.6+0.2°, 19.8+0.2°, and 20.3+0.2°.

8. The crystalline form of claim 7, characterized by an x-ray powder diffraction pattern comprising at least five peaks at 2-theta angles selected from the group consisting of 10.1+0.2°, 11.6+0.2°, 14.5+0.2°, 16.0+0.2°, 16.6+0.2°, 19.8+0.2°, and 20.3+0.2°.

9. The crystalline form of claim 8, characterized by an x-ray powder diffraction pattern comprising at least six peaks at 2-theta angles selected from the group consisting of 10.1+0.2°, 11.6+0.2°, 14.5+0.2°, 16.0+0.2°, 16.6+0.2°, 19.8+0.2°, and 20.3+0.2°.

10. The crystalline form of any one of claims 2-5, characterized by an x-ray powder diffraction pattern comprising peaks at the 2-theta angles 10.1+0.2°, 11.6+0.2°, and 14.5+0.2°.

11. The crystalline form of claim 10, further comprising a peak at the following 2-theta angle: 16.0+0.2°.

12. A crystalline form of an unsolvated hydrochloride salt of a compound of structurehaving an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 6.

13. The crystalline form of any one of claims 2-12, wherein the x-ray powder diffraction pattern is as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.

14. The crystalline form of any one of claims 2-13, characterized by a differential scanning calorimetry thermogram comprising an endothermic peak at 247 °C.

15. The crystalline form of any one of claims 2-14, characterized by a differential scanning calorimetry thermogram substantially in accordance with that depicted in FIG. 11.

16. The crystalline form of any one of claims 2-15, characterized by a melting temperature of 232 °C.

17. The crystalline form of claim 14, 15, or 16, wherein the differential scanning calorimetry thermogram is as measured by differential scanning calorimetry over a range of 30 °C to 300 °C using a scanning rate of 10 °C / minute.

18. The crystalline form of any one of claims 2-17, characterized by a thermogravimetric analysis thermal curve with a 0.16% weight loss over the range of from about 30 °C to about 148 °C.

19. The crystalline form of any one of claims 2-18, characterized by a thermogravimetric analysis thermal curve substantially in accordance with that shown in FIG. 11.

20. The crystalline form of claim 18 or 19, wherein the thermogravimetric analysis thermal curve is as measured using a heating rate of 10 °C / minute.

21. The salt or crystalline form of any one of claims 1-20, wherein molar ratio of hydrochloric acid to compound of structure (I) in the salt or crystalline form is about 0.8 to 1.

22. The salt or crystalline form of any one of claims 1-21, in the form of particles having a D90 of from about 40 pm to about 50 pm.

23. The salt or crystalline form of any one of claims 1-22, in the form of particles having a D50 of from about 10 pm to about 20 pm.

24. The salt or crystalline form of any one of claims 1-23, in the form of particles having a D10 of from about 5 pm to about 10 pm.

25. A pharmaceutical composition comprising a salt or crystalline form of any one of claims 1-24 and at least one pharmaceutically acceptable excipient.

26. A pharmaceutical combination comprising a salt or crystalline form of any one of claims 1-24 or a pharmaceutical composition of claim 25 and an additional therapeutic agent.

27. A method of treating a disease or condition mediated by aryl hydrocarbon receptor (AhR) signaling in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a salt or crystalline form of any one of claims 1 to 24 or pharmaceutical composition of claim 25.

28. A method of treating a disease or condition associated with aberrant AhR signaling in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a salt or crystalline form of any one of claims 1 to 24 or pharmaceutical composition of claim 25.

29. A method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a salt or crystalline form of any one of claims 1 to 24, pharmaceutical composition of claim 25, or pharmaceutical combination of claim 26.

30. The method of any one of claims 27-29, wherein the disease, condition, or cancer is a hematologic cancer.

31. The method of any one of claims 27-29, wherein the disease, condition, or cancer is a solid tumor.

32. The method of any one of claims 27-29, wherein the disease, condition, or cancer is chosen from a non-small cell lung cancer (NSCLC); small cell lung cancer; head and neck squamous cell carcinoma; renal cell carcinoma; gastric adenocarcinoma;nasopharyngeal neoplasms; urothelial carcinoma; colorectal cancer; pleural mesothelioma; triple-negative breast cancer (TNBC); esophageal neoplasm; multiple myeloma; gastric and gastroesophageal junction cancer; melanoma; Hodgkin lymphoma; hepatocellular carcinoma; lung cancer; head and neck cancer; non-Hodgkin lymphoma; metastatic clear cell renal carcinoma; squamous cell lung carcinoma; mesothelioma; gastric cancer; gastroesophageal junction cancer; metastatic melanoma; metastatic non-cutaneous melanoma; urothelial cancer; diffuse large B-cell lymphoma; renal cell cancer; ovarian cancer, fallopian tube cancer; peritoneal neoplasm; extensive stage small cell lung cancer; bladder cancer; transitional cell carcinoma; prostatic neoplasm; recurrent or metastatic PD- LI positive or negative squamous cell carcinoma of the head and neck (SCCHN); recurrent squamous cell lung cancer; advanced solid malignancy; SCCHN; hypopharyngeal squamous cell carcinoma; laryngeal squamous cell carcinoma; unresectable or metastatic melanoma; biliary tract neoplasm; esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostatic cancer, solid organ cancer; stomach cancer; colon cancer; or liver cancer.

33. The method of any one of claims 27 to 29, wherein the disease, condition, or cancer is chosen from a breast cancer, respiratory tract cancer, brain cancer, cancer of reproductive organs, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, or a metastasis of any of the foregoing.

34. The method of any one of claims 27 to 29, wherein the disease, condition, or cancer is chosen from a breast cancer, pancreatic cancer, prostate cancer, or colon cancer.

35. The method of any one of claims 27 to 29, wherein the disease, condition, or cancer is chosen from a lymphoma, sarcoma, melanoma, glioblastoma, or leukemia.

36. The method of any one of claims 27 to 35, further comprising administering to the subject at least one additional therapy.

37. The method of claim 36, wherein the at least one additional therapy comprises a checkpoint inhibitor.

38. The method of claim 36 or 37, wherein the disease, condition, or cancer is resistant to the at least one additional therapy when administered in the absence of the salt, crystalline form, or pharmaceutical composition.

39. The method of claim 37 or 38, wherein the checkpoint inhibitor is chosen from a cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), lymphocyte activation gene-3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), T-cell immunoglobulin and ITIM domain (TIGIT), or V-domain Ig suppressor of T-cell activation (VISTA) inhibitor.

40. A method of inhibiting cancer cell proliferation mediated by AhR signaling in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a salt or crystalline form of any one of claims 1 to 24 or pharmaceutical composition of claim 25.

41. A method of inhibiting tumor cell invasion or metastasis mediated by AhR signaling in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a salt or crystalline form of any one of claims 1 to 24 or pharmaceutical composition of claim 25.

42. A method of making the salt or crystalline form of any one of claims 1-24, comprising: a) providing a compound of structure (I):in a polar organic solvent; and b) adding HC1 to the polar organic solvent under conditions sufficient to induce reactive precipitation of the salt or crystalline form from the polar organic solvent, thereby making the salt or crystalline form.

43. The method of claim 42, wherein the polar organic solvent is an alcohol.

44. The method of claim 42 or 43, wherein the polar organic solvent is ethanol, isopropyl alcohol, or tetrahydrofuran.

45. The method of claim 44, wherein the polar organic solvent is ethanol.

46. The method of any one of claims 42-45, further comprising heating the polar organic solvent to or above a clear point.

47. The method of any one of claims 42-46, further comprising seeding the polar organic solvent at or above a clear point with seeds of the salt or crystalline form.

48. The method of any one of claims 42-47, further comprising cooling the polar organic solvent to or below a cloud point.

49. The method of claim 48, wherein cooling is at a rate of less than or about 10 °C / hour.

50. The method of claim 48 or 49, wherein cooling is to a temperature of less than or about 25 °C.

51. The method of any one of claims 42-50, further comprising collecting the salt or crystalline form.

52. The method of any one of claims 42-51, further comprising formulating the salt or crystalline form into a pharmaceutical composition.

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