WO2025144911A1 - Solid forms of 6-[4-[[3-(difluoromethoxy)-2-pyridinyl]oxy]-2-methylphenyl]-1,5-dimethyl-2,4(1h, 3h)-pyrimidinedione, a - Google Patents

Abstract

Solid crystalline forms of D1 agonist as-(-)-1,5-dimethyl-6-(2-methyl-4- (3-difluoromethoxy-pyridin-2-yloxy)-phenyl]-1H-pyrimidine-2, 4-dione, as well as methods of making and using the same.

Description

SOLID FORMS OF 6-[4-[[3-(DIFLUOROMETHOXY)-2-PYRIDINYL]OXY]-2- METHYLPHENYL]-1,5-DIMETHYL-2,4(1 H, 3H)-PYRIMIDINEDIONE, A

1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/615,091, filed December 27, 2023, the disclosure of which is incorporated by reference herein in its entirety.

2. FIELD

[0002] The present disclosure provides solid forms of a D1 agonist and methods of its therapeutic use.

3. BACKGROUND

[0003] Dopamine acts upon neurons through two families of dopamine receptors, D1-like receptors (DlRs) and D2-like receptors (D2Rs). The D1-like receptor family consists of D1 and D5 receptors which are expressed in many regions of the brain. Dopamine D1 receptors are implicated in numerous neuropharmacological and neurobiological functions. Moreover, D1 receptors have been implicated in a variety of psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ophthalmic, endocrine, and/or other disorders described herein including schizophrenia (e.g., cognitive and negative symptoms in schizophrenia), cognitive impairment associated with D2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer's dementia, Parkinson's disease (PD), Huntington's chorea, depression, anxiety, treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, post-partum depression, serotonin syndrome, substance abuse and drug dependence, Tourette's syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dyslipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, resistant edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular hypotonia, sleep disorders, pain, and other disorders in a mammal. See e.g., Goulet and Madras, Journal of Pharmacology and Experimental Therapy 292(2): 714-24 (2000) and Surmeier et al., Prog. Brain Res. 183: 149-67 (2010).

[0004] For the production of a drug substance intended for use in humans, procedures need to be in place that can control the levels of impurities and ensure that API products are produced, which consistently meet their predetermined specifications. Thus, a need exists for a process to prepare drug compounds suitable for human use, particularly on a commercial scale, that is, inter alia, safe, scalable, efficient, economically viable, and/or having other desirable properties. Among other entities, provided herein are solid forms and pharmaceutical compositions comprising such solid forms to address these needs and provide exemplary advantages.

4. SUMMARY

[0005] In one aspect, the present disclosure provides solid forms of Compound (I):

or a pharmaceutically acceptable salt thereof.

[0006] In one embodiment, the solid form of Compound (I) is a free base of Compound (I).

[0007] In one embodiment, the solid form of Compound (I) is a crystalline solid.

[0008] In one embodiment, a single crystal of Compound (I) is characterized by the following triclinic cell parameters: a = 8.057 A, b = 10.488 A, c = 12.421 A, a = 106.60°, P = 95.75°, y = 110.35°, V = 919.5 A³.

[0009] In one embodiment, the solid form of Compound (I) is anhydrous.

[0010] In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern, when measured using Cu Ka radiation, comprising at least three peaks, each at a 29 angle selected from the group consisting of approximately 8.7, 14.9, 17.5, 21.5, 23.2, and 26.3° 29 ± 0.2° 29. In one embodiment, the XRPD pattern further comprises at least one peak at a 29 angle selected from the group consisting of approximately 19.4, 20.7, 22.6, 24.8, 25.1, and 29.1° 29 ± 0.2° 29. In one embodiment, the XRPD pattern further comprises at least two peaks, each at a 29 angle selected from the group consisting of approximately 19.4, 20.7, 22.6, 24.8, 25.1, and 29.1° 29 ± 0.2° 29. In one embodiment, the XRPD pattern further comprises at least three peaks, each at a 29 angle selected from the group consisting of approximately 19.4, 20.7, 22.6, 24.8, 25.1, and 29.1° 29 ± 0.2° 29.

[0011] In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern, when measured using Cu Ka radiation, comprising peaks at approximately 17.5, 23.2, and 26.3° 29. In one embodiment, the XRPD pattern further comprises peaks at approximately 8.7, 14.9, and 21.5° 29 ± 0.2° 29. In one embodiment, the XRPD pattern further comprises peaks at approximately 20.7 and 22.6° 29 ± 0.2° 29.

[0012] In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern essentially as shown in FIG. 1. In one embodiment, the solid form of Compound (I) exhibits a thermal event with an onset temperature of about 210 °C as characterized by DSC. In one embodiment, the solid form of Compound (I) exhibits a weight loss of about 0.8% upon heating from about 25 °C to about 200 °C.

[0013] In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern, when measured using Cu Ka radiation, comprising at least three peaks, each at a 29 angle selected from the group consisting of approximately 7.7, 14.6, 17.2, 18.0, 19.0, 23.0, 25.6, and 26.6° 29 ± 0.2° 29. In one embodiment, the XRPD pattern further comprises at least one peak at a 29 angle selected from the group consisting of approximately 12.0, 13.9, 14.1, 15.3, 19.2, 23.0, 23.6, and 24.1° 29 ± 0.2° 29. In one embodiment, the XRPD pattern further comprises at least two peaks, each at a 29 angle selected from the group consisting of approximately 12.0, 13.9, 14.1, 15.3, 19.2, 23.0, 23.6, and 24.1° 29 ± 0.2° 29. In one embodiment, the XRPD pattern further comprises at least three peaks, each at a 29 angle selected from the group consisting of approximately 12.0, 13.9, 14.1, 15.3, 19.2, 23.0, 23.6, and 24.1° 29 ± 0.2° 29. In one embodiment, the XRPD pattern further comprises peaks at approximately 14.6, 18.0, and 23.0° 29 ± 0.2° 29. In one embodiment, the XRPD pattern further comprises peaks at approximately 7.7, 19.0, and 25.6° 29 ± 0.2° 29. In one embodiment, the XRPD pattern further comprises peaks at approximately 17.2 and 26.6° 29. In one embodiment, the XRPD pattern further comprises a peak at a 29 angle selected from the group consisting of approximately 13.9, 14.1 and 24.1° 29 ± 0.2° 29.

[0014] In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern essentially as shown in FIG. 4.

[0015] In one embodiment, a composition comprising the solid form of Compound (I) has chemical purity of the composition is at least about 97%. In one embodiment, a composition comprising the solid form of Compound (I) has a chiral purity of the composition is at least about 99%. In one embodiment, a composition comprising the solid form of Compound (I) comprises not more than about 1% by weight of any single impurity. [0016] In another aspect, the present disclosure provides a pharmaceutical composition comprising a solid form of Compound (I) and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition is a solid intended for reconstitution prior to use. In certain embodiments, the pharmaceutical composition is an oral dosage form. In certain embodiments, the pharmaceutical composition is an oral tablet.

[0017] In another aspect, the present disclosure provides a method of treating a disorder, disease, or condition for which a D1 agonist is indicated in a subject comprising administering a therapeutically effective amount of a solid form of Compound (I) or a pharmaceutical composition comprising the same to the subject. In certain embodiments, about 1 mg to about 3 mg of the solid form of Compound (I) is administered to the subject. In certain embodiments, the solid form of Compound (I) is administered to the subject once per day.

[0018] In another aspect, the present disclosure provides a method of treating a symptom of dementia in a subject comprising administering a therapeutically effective amount of a solid form of Compound (I) or a pharmaceutical composition comprising the same to the subject. In certain embodiments, the symptom is dementia-related apathy. In certain embodiments, about 1 mg to about 3 mg of the solid form of Compound (I) is administered to the subject. In certain embodiments, the solid form of Compound (I) is administered to the subject once per day.

[0019] In another aspect, the present disclosure provides a method of treating schizophrenia, cognitive impairment, mild cognitive impairment (MCI), age-related cognitive decline, dementia, or Parkinson's disease in a subject comprising administering a therapeutically effective amount of a solid form of Compound (I) or a pharmaceutical composition comprising the same to the subject. In certain embodiments, about 1 mg to about 3 mg of the solid form of Compound (I) is administered to the subject. In certain embodiments, the solid form of Compound (I) is administered to the subject once per day. [0020] In another aspect, the present disclosure provides a method of preparing a solid form of Compound (I).

[0021] In one embodiment, a method of preparing a solid form of Compound (I) comprises:

(a) combining Compound (I) with a mixture of tetrahydrofuran and heptane; and

(b) cooling the mixture to yield the solid form of Compound (I). In certain embodiments, Compound (I) is combined with a mixture of tetrahydrofuran and heptane at a temperature of at least 50 °C and is cooled to about 20 °C to yield the solid form of Compound (I).

[0022] In one embodiment, a method of preparing a solid form of Compound (I) comprises:

(a) dissolving Compound (I) in tetrahydrofuran to form a solution;

(b) exchanging the tetrahydrofuran for ethanol to form a solvent-exchanged solution; and

(c) adding water to the solvent-exchanged solution to yield the solid form of Compound (I).

In certain embodiments, the solvent-exchanged solution is cooled.

[0023] In one embodiment, a method of preparing a solid form of Compound (I) comprises:

(a) dissolving Compound (I) in acetone to form a solution; and

(b) adding water to the solution to yield the solid form of Compound (I).

In certain embodiments, the solution is cooled.

[0024] In one embodiment, a method of preparing a solid form of Compound (I) comprises:

(a) combining Compound (I) with 2-methyl THF; and

(b) evaporating the 2-methyl THF to yield the solid form of Compound (I).

5. DRAWINGS

[0025] FIG. 1 is a representative X-ray powder diffraction (XRPD) pattern of Form 1 of Compound (I).

[0026] FIG. 2 is a representative thermogravimetric analysis (TGA) thermogram of Form 1 of Compound (I).

[0027] FIG. 3 is a representative differential scanning calorimetry (DSC) thermogram of Form 1 of Compound (I).

[0028] FIG. 4 is a representative X-ray powder diffraction (XRPD) pattern of Form 2 of Compound (I). 6. DETAILED DESCRIPTION

[0029] Provided herein are solid forms of Compound (I):

which has a chemical name of aN-(-)-l,5-dimethyl-6-[2-methyl-4-(3-difluoromethoxy- pyri din-2 -yloxy)-phenyl]-lH-pyrimidine-2, 4-dione. As shown above, Compound (I) displays atropisomerism and has (-) rotation and stereochemistry defined as based on Bringmann, G. et al., Agnew Chem. Int. Ed., 2005, 44, 5384, which is incorporated herein by reference with respect to its description of various stereochemistries. In certain embodiments, the solid form is a crystalline form of Compound (I). In certain embodiments, the solid form is a crystalline form of the free base of Compound (I). Compound (I) has been previously disclosed, e.g., in WO 2014/207601 Al by Pfizer Inc., which is incorporated by reference herein in its entirety, particularly with respect to its disclosure of Compound (I), methods of synthesizing crude Compound (I), pharmaceutical compositions comprising the same, and use of Compound (I) in therapeutic treatment, including use in combination with other therapeutic agents. The solid forms of Compound (I) as disclosed herein may be any solid form disclosed in Section 5.1. Such solid forms may be prepared as described in Section 5.2. Compositions and pharmaceutical compositions as described in Section 5.3 may comprise a solid form of Compound (I) as described in any embodiment in Section 5.1. The solid forms of Compound (I) and pharmaceutical compositions comprising the same may be used to treat a disease, disorder, or condition, such as a neurological condition, in subject as described in Section 5.4 and in Section 5.5.

Definitions

[0030] Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. [0031] The singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0032] All publications, patents and patent applications cited herein, whether supra or infra, are incorporated by reference in their entirety.

[0033] In some embodiments, chemical structures are disclosed with a corresponding chemical name. In case of conflict, the chemical structure controls the meaning, rather than the name.

[0034] As used herein, and unless otherwise specified, the term “about” when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. In certain embodiments, the term “about” contemplates a dose, amount, or weight percent within 10%, such as within 5% of the specified dose, amount, or weight percent.

[0035] Solid forms may exhibit distinct physical characterization data that are unique to a particular solid form, such as the crystal forms described herein. These characterization data may be obtained by various techniques known to those skilled in the art. The data obtained by analyzing a sample of a solid via these techniques may be used to identify a particular solid form, because different solid forms, such as different crystal forms, will provide different diffraction patterns when analyzed by XRPD, the particular methods of which are described in greater detail in Section 6 (Examples), and in many cases will also provide different results when analyzed by DSC or TGA One skilled in the art appreciates that these analyses are subject to experimental error, and that, when comparing, for example, two XRPD patterns, the patterns can be assigned to the same solid form even if one or more, and in some cases all, of the peaks in the pattern vary within the experimental error. Thus, as an example, values of degrees 29 derived from XRPD, even when presented as exact numbers, should therefore be understood as encompassing those deviations from the presented values that would be considered to be within experimental error. In some embodiments, the value of XRPD peak position may vary by up to ± 0.5 degrees 29 while still describing the particular XRPD peak, due to, for example, experimental error. In some embodiments, the value of XRPD peak position may vary by up to ± 0.2 degrees 29 while still describing the particular XRPD peak due to, for example, experimental error. In some embodiments, the value of XRPD peak position may vary by up to ± 0.1 degrees 29 due to, for example, experimental error. In some embodiment, the value of XRPD peak position may vary by up to ± 0.05 degrees 29 due to, for example, experimental error.

[0036] Unless otherwise indicated in the examples were used to characterize the various solid forms disclosed herein.

[0037] The disclosure can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments.

6.1 Solid Forms of Compound (I)

[0038] A solid form of Compound (I) refers to a composition of Compound (I) comprising crystalline Compound (I), amorphous Compound (I), or a mixture thereof. As used herein and unless otherwise specified, the term “crystal form” and related terms refer to a solid form that is crystalline. The crystal forms described herein, therefore, may have varying degrees of crystallinity or lattice order. Crystal forms include, but are not limited to, non-solvates, non-hydrates, solvates, hydrates, and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, and other molecular complexes of salts thereof. Methods of determining the degree of crystallinity are known to those of ordinary skill in the art, such as those described in Suryanarayanan, R., X-Ray Powder Diffractometry, Physical Characterization of Pharmaceutical Solids, H.G. Brittain, Editor, Marcel Dekker, Murray Hill, N.J., 1995, pp. 187 - 199, which is incorporated herein by reference in its entirety.

[0039] “Crystalline,” as used herein, refers to a 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 homogenous 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. In particular, crystalline forms of a solid can be distinguished from non-crystalline forms by the presence of sharp, distinct peaks in the XRPD patterns of crystalline forms.

[0040] In certain embodiments, a solid form composition (e.g., crystal form composition) of Compound (I) (e.g., Form 1 or Form 2) may be substantially physically pure (e.g., contain no detectable amount of other solid form types, e.g., amorphous solid) and/or substantially chemically pure (e.g., contain no detectable amount of compounds other than Compound (I)). Physical purity may be established and determined by observing no detectable significant differences in an XRPD and/or DSC pattern between the single crystalline form and a crystalline composition of Compound (I). In certain embodiments, a solid form composition (e.g., crystal form composition) of Compound (I) (e.g., Form 1 or Form 2) may contain less than about 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more amorphous forms and/or other solid forms and/or crystal forms on a weight basis. In certain embodiments, a solid form composition (e.g., crystal form composition) of Compound (I) (e.g., Form 1 or Form 2) may be about 99.9%, 99.5%, 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% by weight physically pure. A substantially physically pure composition of a solid form of Compound (I) can include impurities, such as, but not limited to, synthetic reactants or by-products generated during the chemical synthesis, and as such, be not substantially chemically pure. However, in certain embodiments, a substantially physically pure composition of a solid form of Compound (I) can also be substantially chemically pure, having independently (e.g., physical purity and chemical purity may be different) a physical purity and chemical purity of about 99.9%, 99.5%, 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% by weight. In yet further embodiments, a solid form composition (e.g., crystal form composition) of Compound (I) e.g., Form 1 or Form 2) may be about 99.9%, 99.5%, 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% by weight chemical pure but not substantially physically pure and comprise another solid form, e.g, other crystalline form or amorphous solid, as an impurity (e.g, not a racemic mixture).

[0041] Chemical purity may, in certain embodiments, may collectively refer to achiral purity and chiral purity. In certain embodiments, a solid form composition (e.g., crystal form composition) of Compound (I) (e.g., Form 1 or Form 2) may be substantially chirally pure (e.g., contain no detectable amount of the atropisomer of Compound (I)) and/or substantially achirally pure (e.g., contain no detectable amount of compounds other than Compound (I) or its atropisomer). In some embodiments, a solid form composition (e.g., crystal form composition) of Compound (I) (e.g., Form 1 or Form 2) may have at least about 85% by weight of Compound (I) relative to its atropisomer. In some embodiments, a solid form composition (e.g., crystal form composition) of Compound (I) (e.g., Form 1 or Form 2) may have at least about 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% by weight of Compound (I) relative to its atropisomer. In other embodiments, a solid form composition (e.g., crystal form composition) of Compound (I) (e.g., Form 1 or Form 2) comprises an atropisomeric excess of at least about 95%, at least about 98%, or at least about 99% by weight of Compound (I).

[0042] Solid forms of Compound (I) provided herein (e.g., Form 1 and/or Form 2) may be used as active pharmaceutical ingredients in the preparation of a pharmaceutical composition or medicament for treating a disease, disorder, or condition in animals, e.g., a human, such as described in Section 5.4. Thus, disclosed herein, e.g, in Section 5.3 are pharmaceutical compositions and dosage forms that incorporate solid forms of Compound (I). [0043] Solid forms may exhibit distinct physical characterization data that are unique to a particular solid form, such as the crystal forms described herein. These characterization data may be obtained by various techniques known to those skilled in the art. The data provided by these techniques may be used to identify a particular solid form. For example, an XRPD pattern, DSC thermogram or TGA thermal curve that “matches” or, interchangeably, is “substantially in accordance” with one or more figures herein showing an XRPD pattern or DSC thermogram or TGA thermal curve, respectively, is one that would be considered by one skilled in the art to represent the same single crystalline form of the compound as the sample of the compound that provided the pattern or thermogram or thermal curve of one or more figures provided herein. Thus, an XRPD pattern or DSC thermogram or TGA thermal curve that matches or is substantially in accordance may be identical to that of one of the figures or, more likely, may be somewhat different from one or more of the figures. 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 or DSC thermogram or TGA thermal curve of the sample and the corresponding XRPD pattern or DSC thermogram or TGA thermal curve disclosed herein. [0044] In certain embodiments, the solid form of Compound (I) is a free base of Compound (I). In certain embodiments, the solid form of Compound (I) is a crystalline form. In certain embodiments, the solid form of Compound (I) is anhydrous. In certain embodiments, a single crystal of the solid form of Compound (I) is characterized by triclinic cell parameters as follows: a = 8.057 A, b = 10.488 A, c = 12.421 A, a = 106.60°, p = 95.75°, 7 = 110.35°, V = 919.5 A³.

[0045]

6.1.1 Form 1 of Compound (I)

[0046] In one embodiment, provided herein is solid Form 1 of Compound (I).

[0047] In one embodiment, Form 1 of Compound (I) may be characterized by an XRPD pattern essentially as shown in FIG. 1.

[0048] In one embodiment, provided herein is a solid form (e.g., Form 1) of Compound (I) comprising a free base of Compound (I), characterized an XRPD pattern, collected when measured using Cu Ka radiation, comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks, each of which is located at a 29 angle selected from the group consisting of approximately (e.g, ± 0.2 °29) 8.7, 14.9, 17.5, 19.4, 20.7, 21.5, 22.6, 23.2, 24.8, 25.1, 26.3, and 29.1° 29. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least five (5) of the peaks. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least seven (7) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least nine (9) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising all (e.g, 12) of the identified peaks.

[0049] In one embodiment, the solid form (e.g., Form 1) of Compound (I) is characterized by an XRPD pattern, when measured using Cu Ka radiation, comprising at least three peaks (e.g., 3, 4, 5, or 6 peaks), each at a 29 angle selected from the group consisting of approximately (e.g., ± 0.2 °29) 8.7, 14.9, 17.5, 21.5, 23.2, and 26.3° 29. In one embodiment, the XRPD pattern further comprises at least one peak (e.g., 1, 2, 3, 4, 5, or 6 peaks) at a 29 angle selected from the group consisting of approximately (e.g., ± 0.2 °29) 19.4, 20.7, 22.6, 24.8, 25.1, and 29.1° 29. In one embodiment, the XRPD pattern further comprises at least two peaks (e.g., 2, 3, 4, 5, 6, or 7 peaks), each at a 29 angle selected from the group consisting of approximately e.g., ± 0.2 °29) 19.4, 20.7, 22.6, 24.8, 25.1, and 29.1° 29. In one embodiment, the XRPD pattern further comprises at least three peaks (e.g., 3, 4, 5, 6, or 7 peaks), each at a 29 angle selected from the group consisting of approximately (e.g., ± 0.2 °29) 19.4, 20.7, 22.6, 24.8, 25.1, and 29.1° 29. In one embodiment, the XRPD pattern further comprises at least four peaks (e.g., 4, 5, 6, or 7 peaks), each at a 29 angle selected from the group consisting of approximately e.g., ± 0.2 °29) 19.4, 20.7, 22.6, 24.8, 25.1, and 29.1° 29.

[0050] In one embodiment, the solid form is characterized by an XRPD pattern, when measured using Cu Ka radiation, comprising peaks at approximately (e.g., ± 0.2 °29) 17.5, 23.2, and 26.3° 29. In one embodiment, the XRPD pattern further comprises comprising at least one peak (e.g., 1, 2, or 3 peaks) at a 29 angle selected from the group consisting of approximately (e.g., ± 0.2 °29) 8.7, 14.9, and 21.5° 29. In one embodiment, the XRPD pattern further comprises comprising a peak at approximately (e.g., ± 0.2 °29) 20.7 and/or 22.6° 29.

[0051] In one embodiment, a single crystal of the solid form is characterized by triclinic cell parameters as follows: a = 8.057 A, b = 10.488 A, c = 12.421 A, a = 106.60°, p = 95.75°, 7 = 110.35°, V = 919.5 A³.

[0052] In one embodiment, the solid form undergoes a weight loss of about 0.8% upon heating from about 25 °C to about 200 °C when analyzed by TGA. In one embodiment, the solid form is characterized by TGA by heating a sample of the solid form from 0 °C to 200 °C at a rate of 10 °C/min. In one embodiment, the solid form is characterized by a TGA thermogram essentially as shown in FIG. 2.

[0053] In one embodiment, the solid form undergoes a thermal event at about 210 °C when characterized by DSC. In one embodiment, the solid form has a melting point of about 210 °C. In one embodiment, the solid form is characterized by DSC by heating a sample of the solid form from -30 °C to 265 °C at a rate of 10 °C/min. In one embodiment, the solid form is characterized by a DSC thermogram essentially as shown in FIG. 3.

[0054] In one embodiment, provided herein is a solid form comprising a free base of Compound (I), characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 1

[0055] In one embodiment, the XRPD pattern is measured by XRPD using Cu Ka radiation having a wavelength of 1.5406 A.

[0056] In one embodiment, the solid form is characterized by an XRPD pattern according to any of the above embodiments, wherein the identified peak location has an error of (e.g., may vary by) ± 0.1 °29. In certain embodiments, the solid form is characterized by an XRPD pattern according to any of the above embodiments, wherein the identified peak location has an error of (e.g., may vary by) ± 0.05 °29. [0057] In some embodiments, provided herein is a solid form comprising a free base of Compound (I), which is a crystalline anhydrate (Form 1) of free base of Compound (I). In some embodiments, the solid form is substantially free non-crystalline forms (e.g., amorphous) of Compound (I). In some embodiments, the solid form is substantially free of Form 2 of Compound (I). In some embodiments, the solid form is substantially free of other solid forms (e.g., another crystalline form) of Compound (I). In some embodiments, the solid form is substantially free of salts of Compound (I). In some embodiments, the solid form is provided as substantially pure. In some embodiments, the solid form is substantially chemically pure (e.g., at least about 98% pure, at least about 99% pure, at least about 99.5% pure, or at least about 99.7% pure. In some embodiments, the solid form is substantially physically pure.

[0058] In one embodiment, Form 1 of Compound (I) is stable at 25°C/60% RH (relative humidity). In one embodiment, Form 1 of Compound (I) is stable at 40°C/75% RH.

[0059] In one embodiment, Form 1 of Compound (I) is essentially non-hygroscopic. For example, in one embodiment, Form 1 of Compound (I) undergoes a weight gain of not more than about 0.25% weight gain at 25 °C/90% RH.

[0060] All of the combinations of the above embodiments are encompassed by this application.

6.1.2 Form 2 of Compound (I)

[0061] In one embodiment, provided herein is Form 2 of Compound (I).

[0062] In one embodiment, Form 2 of Compound (I) may be characterized by an XRPD pattern essentially as shown in FIG. 4.

[0063] In one embodiment, provided herein is a solid form (e.g., Form 1) of Compound (I) comprising a free base of Compound (I), characterized an XRPD pattern, collected when measured using Cu Ka radiation, comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks, each of which is located at a 29 angle selected from the group consisting of approximately (e.g., ± 0.2 °29) 7.7, 12.0, 13.9, 14.1, 14.6, 15.3, 17.2, 18.0, 19.0, 19.2, 23.0, 23.6, 25.6, 24.1, and 26.6° 29. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least five (5) of the peaks. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least seven (7) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least nine (9) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least eleven (11) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least eleven (13) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising all (e.g., 15) of the identified peaks.

[0064] In one embodiment, the solid form (e.g., Form 1) of Compound (I) is characterized by an XRPD pattern, when measured using Cu Ka radiation, comprising at least three peaks (e.g., 3, 4, 5, 6, or 7 peaks), each at 29 angle selected from the group consisting of approximately (e.g., ± 0.2 °29) 7.7, 14.6, 17.2, 18.0, 19.0, 25.6, and 26.6° 29. In one embodiment, the XRPD pattern further comprises at least one peak (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 peaks) at a 29 angle selected from the group consisting of approximately (e.g., ± 0.2 °29) 12.0, 13.9, 14.1, 15.3, 19.2, 23.0, 23.6, and 24.1° 29. In one embodiment, the XRPD pattern further comprises at least two peaks (e.g., 2, 3, 4, 5, 6, 7, or 8 peaks), each at a 29 angle selected from the group consisting of approximately (e.g., ± 0.2 °29) 12.0, 13.9, 14.1, 15.3, 19.2, 23.0, 23.6, and 24.1° 29. In one embodiment, the XRPD pattern further comprises at least three peaks (e.g., 3, 4, 5, 6, 7, or 8 peaks), each at a 29 angle selected from the group consisting of approximately (e.g., ± 0.2 °29) 12.0, 13.9, 14.1, 15.3, 19.2, 23.0, 23.6, and 24.1° 29. In one embodiment, the XRPD pattern further comprises at least four peaks (e.g., 4, 5, 6, 7, or 8 peaks), each at a 29 angle selected from the group consisting of approximately (e.g., ± 0.2 °29) 12.0, 13.9, 14.1, 15.3, 19.2, 23.0, 23.6, and 24.1° 29.

[0065] In one embodiment, the solid form is characterized by an XRPD pattern, when measured using Cu Ka radiation, comprising peaks at approximately (e.g., ± 0.2 °29) 14.6, 18.0, and 23.0° 29. In one embodiment, the XRPD pattern further comprises comprising peaks at approximately (e.g., ± 0.2 °29) 7.7, 19.0, and 25.6° 29. In one embodiment, the XRPD pattern further comprises comprising at least one peak (e.g., 1 or 2 peaks) at a 29 angle selected from the group consisting of approximately (e.g., ± 0.2 °29) 17.2 and 26.6° 29. [0066] In one embodiment, provided herein is a solid form comprising a free base of Compound (I), characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 4

[0067] In one embodiment, the XRPD pattern is measured by XRPD using Cu Ka radiation having a wavelength of 1.5406 A.

[0068] In one embodiment, the solid form is characterized by an XRPD pattern according to any of the above embodiments, wherein the identified peak location has an error of (e.g., may vary by) ± 0.1 °29. In certain embodiments, the solid form is characterized by an XRPD pattern according to any of the above embodiments, wherein the identified peak location has an error of (e.g., may vary by) ± 0.05 °29.

[0069] In some embodiments, provided herein is a solid form comprising a free base of Compound (I), which is a crystalline anhydrate (Form 2) of free base of Compound (I). In some embodiments, the solid form is substantially free non-crystalline forms (e.g., amorphous) of Compound (I). In some embodiments, the solid form is a mixture of Form 1 of Compound (I), as described herein, and Form 2 of Compound (I). In some embodiments, the solid form is substantially free of Form 1 of Compound (I). In some embodiments, the solid form is substantially free of other solid forms (e.g., another crystalline form) of Compound (I). In some embodiments, the solid form is substantially free of salts of Compound (I). In some embodiments, the solid form is provided as substantially pure. In some embodiments, the solid form is substantially chemically pure. In some embodiments, the solid form is substantially physically pure.

[0070] In one embodiment, Form 2 of Compound (I) is metastable.

[0071] All of the combinations of the above embodiments are encompassed by this application.

6.2 Methods of Preparing Solid Forms of Compound (I)

[0072] In one aspect, the present disclosure provides methods for preparing a crystalline form of Compound (I):

6.2.1 Form 1 of Compound (I)

[0073] In one embodiment, provided herein is a method for preparing crystalline Form 1 of Compound (I).

[0074] In one embodiment, a method for preparing Form 1 of Compound (I) comprises: (a) combining Compound (I) with a mixture of tetrahydrofuran and heptane; and

(b) cooling the mixture to yield the crystalline form of Compound (I). In one embodiment, Compound (I) is combined with a mixture of tetrahydrofuran and heptane at a temperature of at least 50 °C and is cooled to about 20 °C to yield the crystalline form of Compound (I).

6.2.2 Form 2 of Compound (I)

[0075] In one embodiment, provided herein is a method for preparing crystalline Form 2 of Compound (I).

[0076] In one embodiment, a method for preparing Form 2 of Compound (I) comprises:

(a) combining Compound (I) with 2-m ethyl THF; and

(b) evaporating the 2-methyl THF to yield the crystalline form of Compound (I).

6.3 Compositions and Pharmaceutical Compositions

[0077] In one embodiment, crystallizing Compound (I), which may be in any form (e.g., crude Compound (I) or amorphous Compound (I)), by a method disclosed herein to generate Form 1 of Compound (I) generates a composition of Form 1 of Compound (I) that is substantially achirally pure. Said otherwise, a composition prepared by methods disclosed herein may consist of Compound (I) or its atropisomer. In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 3% by weight of one or more compounds other than Compound (I) (or its atropisomer). In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 2% by weight of one or more compounds other than Compound (I) (or its atropisomer). In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 1% by weight of one or more compounds other than Compound (I) (or its atropisomer). In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 0.5% by weight of one or more compounds other than Compound (I) (or its atropisomer). In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 1% by weight of any single impurity. Said differently, in certain embodiments, a composition of Form 1 of Compound (I) may be at least about 97%, at least about 98% pure, at least about 99% pure or at least about 99.5% achirally pure. In certain embodiments, the one or more compounds other than Compound (I) (or its atropisomer) that may be present as an impurity comprise an intermediate or a reagent used in the synthesis of Compound (I), such as disclosed in the Examples, or a side product generated in the synthesis of Compound (I) (other than its atropisomer). One of skill in the art would recognize the various side products that could be generated in the synthesis of Compound (I) as disclosed in the Examples.

[0078] In one embodiment, crystallizing Compound (I), which may be in any form (e.g., crude Compound (I) or amorphous Compound (I)), by a method disclosed herein to generate Form 1 of Compound (I) generates a composition of Form 1 of Compound (I) that is substantially chirally pure. Said otherwise, a composition prepared by methods disclosed herein may consist of Compound (I). In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 2% by weight of one or more compounds other than Compound (I) (or its atropisomer). In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 1% by weight of one or more compounds other than Compound (I) (or its atropisomer). In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 0.5% by weight of one or more compounds other than Compound (I) (or its atropisomer). Said differently, in certain embodiments, a composition of Form 1 of Compound (I) may be at least about 98% chirally pure, at least about 99% chirally pure or at least about 99.5% chirally pure. In certain embodiments, a composition of Form 1 of Compound (I) may at least about 98% chemically pure and at least about 99% chirally pure. Said differently, a composition of Form 1 of Compound (I) may comprise about 98% to about 100%, such as 98%, 99%, or 99% of a combined amount of Compound (I) and its atropisomer, wherein at least about 98%, at least about 99%, or at least about 99.5% of that total amount is Compound (I).

[0079] In one embodiment, crystallizing Compound (I), e.g., crude Compound (I), by a method disclosed herein to generate Form 1 of Compound (I) generates a composition of Form 1 of Compound (I) that is substantially crystalline (e.g., comprising not more than 2% by weight of amorphous material). In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 1% by weight of amorphous material. In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 0.05% by weight of amorphous material (e.g., amorphous Compound (I)). Said differently, in certain embodiments, a composition of Form 1 of Compound (I) may be at least about 98% crystalline, at least about 99% crystalline, at least about 99.5% crystalline, or 100% crystalline (e.g., no detectable amorphous content).

[0080] In one embodiment, crystallizing Compound (I), e.g., crude Compound (I), by a method disclosed herein to generate Form 1 of Compound (I) generates a composition of Form 1 of Compound (I) that is substantially physically pure. In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 2% by weight of another solid form of Compound (I), such as Form 2 or amorphous Compound (I). In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 1% by weight of another solid form of Compound (I), such as Form 2 or amorphous Compound (I). In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 0.05% by weight of another solid form of Compound (I), such as Form 2 or amorphous Compound (I). Said differently, in certain embodiments, a composition of Form 1 of Compound (I) may be at least about 98% by weight of Form 1 of Compound (I), at least about 99% by weight of Form 1 of Compound (I), or at least about 99.5% by weight of Form 1 of Compound (I).

[0081] In one embodiment, crystallizing Compound (I), e.g., crude Compound (I), by a method disclosed herein generates a composition comprising Form 1 of Compound (I), and further comprises Form 2, as an impurity (e.g., 0.1%, 0.25%, 0.5%, 0.75%, or 1% of Form 2). In certain embodiments, such a composition may further exhibit one or more of a) an achiral purity of at least about 98% and b) a chiral purity of at least about 99%. In one embodiment, the present disclosure provides a composition comprising Form 1 of Compound (I) and not more than about 5% by weight (e.g., 0%, not more than 1%, not more than 2%, not more than 3%, not more than 4%, or not more than 5%), of Form 2 of Compound (I) which may, in some embodiments, further exhibit one or more of a) an achiral purity of at least about 98% and b) a chiral purity of at least about 99%. In one embodiment, the present disclosure provides a composition comprising Form 1 of Compound (I) and not more than about 1% by weight of Form 2 of Compound (I) which may, in some embodiments, further exhibit one or more of a) an achiral purity of at least about 98% and b) a chiral purity of at least about 99%. [0082] The present disclosure also provides compositions, such as pharmaceutical compositions, formulated from a solid form of Compound (I) (e.g., Form 1 or Form 2). In one embodiment, a pharmaceutical composition comprises a composition comprising a solid form of Compound (I) (e.g., Form 1 or Form 2) as described according to any embodiment herein (e.g., having a certain chiral, achiral, chemical, or physical purity) and one or more pharmaceutically acceptable excipients. In one embodiment, a solid form of Compound (I) (e.g., Form 1 or Form 2) is mixed with one or more liquid excipients to generate a pharmaceutical composition comprising Compound (I).

[0083] Suitable pharmaceutically acceptable excipients include any conventional pharmaceutical excipient, such as, but not limited to, carriers such as inert diluents or fillers, water, and various organic solvents (such as hydrates and solvates). In any embodiment, a pharmaceutical composition comprising a solid form of Compound (I) (e.g., Form 1 or Form 2) may comprise contain additional ingredients such as flavorings, binders, excipients, and the like. For pharmaceutical compositions intended for oral administration, tablets containing various excipients, such as citric acid, may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin, and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Compositions of a similar type may also be employed in soft and hard filled gelatin capsules, which may employ, for example, lactose or milk sugar and high molecular weight polyethylene glycols. In other embodiments, a pharmaceutical composition intended for oral administration may be an aqueous suspensions or elixir, for example, wherein a solid form of Compound (I) (e.g., Form 1 or Form 2) may be combined with various sweetening or flavoring agents, coloring matters or dyes, emulsifying agents, and/r suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0084] A solid form of Compound (I) (e.g., Form 1 or Form 2) may formulated for administered to a subject, e.g., in a pharmaceutical composition as disclosed herein by any route that enables delivery of the compounds to the site of action. Non-limiting examples of routes that may be employed include methods include oral routes, intranasal routes, inhaled routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal routes. As used herein, “subject” refers to any animal, such as a mammal. In certain embodiments, the subject is a human subject.

[0085] In certain embodiments, a pharmaceutical composition comprising a solid form of Compound (I) (e.g., Form 1 or Form 2) is formulated for oral administration. In one embodiment the solid form of Compound (I) is Form 1 of Compound (I). Solid formulations for oral administration may be formulated to be immediate and/or modified release.

Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

[0086] In one embodiment, oral administration involves swallowing the pharmaceutical composition such that the Compound (I) enters the gastrointestinal tract. In one embodiment, oral administration involves buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth. [0087] In one embodiment, the solid form of Compound (I) is Form 1 of Compound (I) is administered in the form of a solid oral dosage form, such as a tablet or capsule.

Pharmaceutical compositions suitable for oral administration include solid, semi-solid and liquid forms such as tablets, soft or hard capsules containing multi- or nano-particulates, liquids, or powders, lozenges (including liquid-filled), chews, gels, fast dispersing dosage forms, films, ovules, sprays, and buccal/mucoadhesive patches. A solid or semi-solid pharmaceutical composition may comprise a solid form of Compound (I) (e.g., Form 1 or Form 2).

[0088] In one embodiment, the pharmaceutical composition is a tablet. In certain embodiments, the tablet may comprise about 1% by weight to 80% by weight of a solid form of Compound (I) (e.g., Form 1 or Form 2), such as about 5% by weight to 60% by weight. A tablet may, in any embodiment, further comprise one or more disintegrants, such as, but not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and/or sodium alginate. In certain embodiments, a tablet comprising a solid form of Compound (I) (e.g., Form 1 or Form 2) may comprise about 1% by weight to about 25% by weight, for example, about 5% by weight to about 20% by weight of one or more disintegrants. A tableted pharmaceutical composition may, in any embodiment, further comprise one or more binders, e.g., to impart cohesive qualities. Non-limiting examples of suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. A tablet may, in any embodiment, further comprise one or more diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate, and/or one or more lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. In certain embodiments, a tableted pharmaceutical composition may comprise about 0.25% by weight to 10% by weight, for example, about 0.5% by weight to 3% by weight of one or more lubricants. A tablet may, in any embodiment, further comprise one or more antioxidants, colorants, flavoring agents, preservatives, and/or taste-masking agents. A tablet may, in any embodiment, further comprise one or more surface active agents, such as sodium lauryl sulfate and polysorbate 80, and/or one or more glidants, such as silicon dioxide and/or talc. In certain embodiments, a tableted pharmaceutical composition may comprise about 0.2% by weight to 5 % by weight of one or more surface active agents and/or about 0.2% by weight to about 1 by weight of one or more glidants.

[0089] In one non-limiting example, a tableted pharmaceutical composition comprising a solid form of Compound (I) (e.g., Form 1 or Form 2) may comprise up to about 80% by weight of the solid form of Compound (I) (e.g., Form 1 or Form 2), about 10% by weight to about 90% by weight binder, up to about 85% by weight diluent, about 2% by weight to about 10% by weight disintegrant, and about 0.25% by weight to about 10% by weight lubricant.

[0090] Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropyl methyl cellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. As would be understood by one of skill in the art, a liquid form may not comprise the solid form of Compound (I) but may be prepared from a solid form of Compound (I) (e.g., Form 1 or Form 2).

[0091] A pharmaceutical composition comprising and/or prepared from a solid form of Compound (I) (e.g., Form 1 or Form 2) may be prepared by any method readily apparent to one skilled in the art. Such compositions and methods for their preparation may be found, for example, in "Remington: The Science and Practice of Pharmacy", 23rd Edition (Academic Press, 2020).

[0092] For example, a tablet blend comprising the aforementioned components may be compressed directly or by roller to form tablets. A tablet blend may alternatively be wet-, dry-, or melt-granulated, melt-congealed, or extruded before tableting. A final formulation may comprise one or more layers and may be coated or uncoated or, in certain embodiments, encapsulated.

[0093] In certain embodiments, a solid form of Compound (I) (e.g., Form 1 or Form 2) may be manufactured into a form suitable for parenteral injection, such as a sterile solution, suspension, or emulsion, or for topical administration, such as an ointment or cream, for rectal administration, such as a suppository. Exemplary pharmaceutical compositions suitable for parenteral injection include, but are not limited to, solutions or suspensions prepared by combining a solid form of Compound (I) (e.g, Form 1 or Form 2) with a sterile aqueous solution, e.g., an aqueous propylene glycol solution or a dextrose solution. In certain embodiments, such dosage forms may further comprise a buffering agent. As would be understood by one of skill in the art, a liquid form may not comprise the solid form of Compound (I) but may be formulated from a solid form of Compound (I) (e.g., Form 1 or Form 2).

[0094] Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (for example to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

[0095] A solid form of Compound (I) may also be formulated for administration topically, (intra)dermally, or transdermally to the skin or mucosa. Typical topical, intradermal, and transdermal formulations include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated.

[0096] Further contemplated is a kit comprising one or more pharmaceutical compositions comprising or formulated from a solid form of Compound (I) as disclosed herein (e.g., Form 1 or 2) and a pharmaceutically acceptable excipient. Such a kit may further comprise means for separately retaining said pharmaceutical compositions in discreet dosage amounts, such as a container, divided bottle, or divided foil packet. One example of such a kit is a blister pack, such as is commonly employed for the packaging of tablets, capsules, and the like. Such a kit may be suitable for administering different dosage forms, such as, oral, and parenteral, for administering the pharmaceutical composition at a prescribed dosage interval. Such a kit may further comprise directions for administration and may be provided.

6.4 Methods of Use

[0097] In another aspect, the present disclosure provides a method for modulating (e.g., agonizing or partially agonizing) D1 receptor activity of a subject (e.g., a human), comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of solid form of Compound (I) (e.g., Form 1 or Form 2), or formulated from a solid form of Compound (I) (e.g., Form 1 or Form 2). In certain embodiments, the method for modulating (e.g., agonizing or partially agonizing) D1 receptor activity of a subject comprises administering to the subject a pharmaceutical composition comprising Form 1 of Compound (I). The pharmaceutical composition comprising Form 1 of Compound (I) may have characteristics according to any embodiment disclosed herein, such as a certain chemical, physical, achiral, or chiral purity such as described in Section 5.3.

[0098] As used herein, the term "therapeutically effective amount" refers to an amount of a solid form of Compound (I) that, upon administering to a subject, will treat the disease, disorder, or condition. As used herein, the term "treating", unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, and/or preventing the disorder, disease, or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined herein. The term "treating" also includes adjuvant and neo-adjuvant treatment of a subject. In one embodiment, “treating” refers to at least partially (e.g., partially or fully) reduce the severity one or more of the symptoms of the disease, condition, or disorder being treated. For example, in the treatment of a D1 -mediated disorder (e.g., schizophrenia), a therapeutically effective amount of a solid form of Compound (I) may refer to an amount which at least partially relieves (or, e.g., eliminates) one or more symptoms associated with the D1 -mediated disorder, such a cognitive or negative symptom experience in schizophrenia, e.g., cognitive impairment associated with schizophrenia.

[0099] In another aspect, the present disclosure provides a method for treating a Dl- mediated (or D1 -associated) disorder, disease, or condition, comprising administering to a subject (e.g., a human) a therapeutically effective amount of a solid form of Compound (I) (e.g., Form 1 or Form 2) to modulate (e.g., agonize or partially agonize) D1 in the subject. In one aspect, the present disclosure provides a method for treating a disease or disorder that benefits from administration of a selective dopamine D1/D5 partial agonist. Examples of Dl- mediated (or D1 -associated) disorders that may be treated include, without limitation, neurological disorders (such as Tourette's syndrome, tardive dyskinesia, Parkinson's Disease (including, e.g., cognitive impairment associated with Parkinson’s Disease), cognitive disorders (such as amnesia, age-related cognitive decline, dementia (e.g., senile dementia, dementia-related apathy, Alzheimer's-associated dementia, HIV-associated dementia, Huntington's-associated dementia, Lewy body dementia, vascular dementia, frontotemporal dementia, drug-related dementia (e.g., dementia associated with pharmacotherapy therapy such as D2 antagonist therapy)), delirium, and cognitive impairment (e.g., cognitive impairment associated with Alzheimer’s Disease or cognitive impairment associated with Parkinson’s Disease), and mild cognitive impairment); Huntington's chorea/disease, and restless leg syndrome (RLS)), psychiatric disorders (such as cognitive impairment (e.g., cognitive impairment associated with schizophrenia or cognitive impairment associated with pharmacotherapy therapy (e.g., D2 antagonist therapy)), anxiety (including acute stress disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, and obsessive-compulsive disorder), factitious disorder (including acute hallucinatory mania), impulse control disorders/impulsivity (including compulsive gambling and intermittent explosive disorder), mood disorders (including bipolar I disorder, bipolar II disorder, mania, mixed affective state, depression (e.g., age-related depression, major depression, chronic depression, seasonal depression, psychotic depression, postpartum depression, and treatment resistant depression (TRD)), psychomotor disorders; psychotic disorders (including schizophrenia (including, for example, cognitive and negative symptoms in schizophrenia), schizoaffective disorder, schizophreniform, and delusional disorder), substance abuse and drug dependence (including narcotic dependence, alcoholism, amphetamine dependence, cocaine addiction, nicotine dependence, and drug withdrawal syndrome), drug abuse relapse, eating disorders (including anorexia, bulimia, binge eating disorder, overeating, hyperphagia, and pagophagia), autism spectrum disorder (e.g., autism), chronic apathy, anhedonia, chronic fatigue, seasonal affective disorder, and pediatric psychiatric disorders (including attention deficit disorder, attention deficit hyperactive disorder (ADHD), conduct disorder, and autism)], endocrine disorders (such as hyperprolactinemia), or other disorders including drowsiness, excessive daytime sleepiness, cachexia, inattention, sexual dysfunction (e.g., erectile dysfunction, post-SSRI sexual dysfunction), pain, migraine, systemic lupus erythematosus (SLE), hyperglycemia, atherosclerosis, dyslipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, hyponatremia, resistant edema, narcolepsy, cardiovascular disease (e.g, hypertension), congestive heart failure, postoperative ocular hypotonia, sleep disorders, and serotonin syndrome.

[00100] As such, in one embodiment, the present disclosure provides a method for treating a neurological disorder, disease, or condition in a subject (e.g., a human) comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a solid form of Compound (I) (e.g., Form 1 or Form 2) or formulated from a therapeutically effective amount of a solid form of Compound (I) (e.g., Form 1 or Form 2) to the subject, wherein the neurological disorder, disease, or condition is Tourette's syndrome, tardive dyskinesia, Parkinson's Disease, a cognitive disorder (including amnesia, dementia (mild to moderate dementia, dementia-induced apathy, senile dementia, HIV-associated dementia, Alzheimer's associated dementia, Huntington's-associated dementia, Lewy body dementia, vascular dementia, drug-related dementia (e.g., cognitive impairment associated with D2 antagonist therapy)), delirium, and mild cognitive impairment)), RLS, and Huntington's chorea/disease), a psychiatric disorder (such as anxiety (including acute stress disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive-compulsive disorder), factitious disorder (including acute hallucinatory mania), impulse control disorders/impulsivity (including compulsive gambling and intermittent explosive disorder), a mood disorder (including bipolar I disorder, bipolar II disorder, mania, mixed affective state, major depression, chronic depression, seasonal depression, psychotic depression, and postpartum depression), a psychomotor disorder, a psychotic disorder (including schizophrenia, schizoaffective disorder, schizophreniform, and delusional disorder), drug dependence (including narcotic dependence, alcoholism, amphetamine dependence, cocaine addiction, nicotine dependence, and drug withdrawal syndrome), an eating disorder (including anorexia, bulimia, binge eating disorder, hyperphagia, and pagophagia), and a pediatric psychiatric disorder (including attention deficit disorder, attention deficit/hyperactive disorder, conduct disorder, and autism)), or an endocrine disorder (such as hyperprolactinemia).

[00101] In another embodiment, the present disclosure provides a method for treating a disorder, disease, or condition in a subject (e.g., a human) comprising a therapeutically effective amount of a solid form of Compound (I) (e.g., Form 1 or Form 2) or formulated from a therapeutically effective amount of a solid form of Compound (I) (e.g., Form 1 or Form 2) to the subject, wherein the disorder, disease, or condition is schizophrenia (e.g., cognitive and negative symptoms in schizophrenia), cognitive impairment (e.g., cognitive impairment associated with schizophrenia, cognitive impairment associated with Alzheimer’s Disease, cognitive impairment associated with Parkinson’s Disease, or cognitive impairment associated with pharmacotherapy therapy (e.g., D2 antagonist therapy), or mild cognitive impairment), ADHD, impulsivity, compulsive gambling, an eating disorder (e.g., anorexia, bulimia, binge eating disorder, overeating, hyperphagia, or pagophagia), autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, dementia (e.g., senile dementia, HIV-associated dementia, Alzheimer's dementia, Lewy body dementia, vascular dementia, or frontotemporal dementia), restless leg syndrome (RLS), Parkinson's disease, Huntington's chorea, anxiety, depression (e.g., age-related depression), major depressive disorder (MOD), treatment resistant depression (TRD), bipolar disorder, apathy (including chronic and/or clinically significant apathy), anhedonia, chronic fatigue, post- traumatic stress disorder, seasonal affective disorder, social anxiety disorder, postpartum depression, serotonin syndrome, substance abuse and drug dependence, drug abuse relapse, Tourette's syndrome, tardive dyskinesia, drowsiness, excessive daytime sleepiness, cachexia, inattention, sexual dysfunction (e.g., erectile dysfunction or post-SSRI sexual dysfunction), migraine, systemic lupus erythematosus (SLE), hyperglycemia, atherosclerosis, dyslipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, hyponatremia, resistant edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular hypotonia, sleep disorders, pain, or any combination of the foregoing.

[00102] In another embodiment, the present disclosure provides a method for treating schizophrenia (e.g., cognitive and negative symptoms in schizophrenia or cognitive impairment associated with schizophrenia) or psychosis in subject, e.g., a human, comprising administering to subject a pharmaceutical composition comprising a therapeutically effective amount of a solid form of Compound (I) (e.g., Form 1 or Form 2) or formulated from a therapeutically effective amount of a solid form of Compound (I) (e.g., Form 1 or Form 2). In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of Form 1 of Compound (I), which may have characteristics according to any embodiment disclosed herein, such as a certain chemical, physical, achiral, or chiral purity such as described in Section 5.3.

[00103] In another embodiment, the present disclosure provides a method for treating schizophrenia (e.g., cognitive and negative symptoms in schizophrenia or cognitive impairment associated with schizophrenia) in a subject, e.g., a human, comprising administering to the subject a therapeutically effective amount of a solid form of Compound (I) (e.g., Form 1 or Form 2). In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of Form 1 of Compound (I), which may have characteristics according to any embodiment disclosed herein, such as a certain chemical, physical, achiral, or chiral purity such as described in Section 5.3.

[00104] In another embodiment, the present disclosure provides a method for treating cognitive impairment (e.g., cognitive impairment associated with schizophrenia, cognitive impairment associated with AD, or cognitive impairment associated with Parkinson’s Disease) in a subject, e.g., a human, comprising administering to the subject a therapeutically effective amount of a compound of a solid form of Compound (I) (e.g., Form 1 or Form 2). In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of Form 1 of Compound (I), which may have characteristics according to any embodiment disclosed herein, such as a certain chemical, physical, achiral, or chiral purity such as described in Section 5.3.

[00105] In another embodiment, the present disclosure provides a method for treating Alzheimer’s Disease (e.g., treating cognitive impairment associated with Alzheimer’s Disease), Parkinson’s Disease (e.g., treating cognitive impairment associated with Parkinson’s Disease), RLS, depression, or MOD in a subject, e.g., a human, comprising administering to the subject a therapeutically effective amount of a solid form of Compound (I) (e.g., Form 1 or Form 2).

[00106] In another embodiment, the present disclosure provides a method for treating dementia (e.g., treating apathy associated with dementia) in a subject, e.g., a human, comprising administering to the subject a pharmaceutical composition comprising or formulated from a therapeutically effective amount of a solid form of Compound (I) (e.g., Form 1 or Form 2). In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of Form 1 of Compound (I), which may have characteristics according to any embodiment disclosed herein, such as a certain chemical, physical, achiral, or chiral purity such as described in Section 5.3.

[00107] A solid form of Compound (I) (e.g., Form 1 or Form 2) may be administered to a subject, e.g., in a pharmaceutical composition as disclosed herein by any route that enables delivery of Compound (I) to the site of action. Non-limiting examples of routes that may be employed include oral routes, intranasal routes, inhaled routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal routes.

[00108] In one embodiment, a pharmaceutical composition comprising Compound (I) is administered to a subject via oral administration. In one embodiment, Compound (I) is solid Form 1 of Compound (I). In one embodiment, the pharmaceutical composition comprising solid Form 1 of Compound (I) is administered orally in the form of a solid oral dosage form, such as a tablet or capsule.

[00109] The frequency of administration and dosing of a pharmaceutical composition comprising or formulated from a solid form of Compound (I) (e.g., a Form 1 or Form 2) to a subject to treat a disease, disorder, or condition thereof may be adjusted to provide a desired therapeutic effect. For example, in one embodiment, a single bolus or unit dosage form may be administered, several divided doses or dosage forms may be administered over time, or a dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. In certain embodiments, a pharmaceutical composition intended for parenteral administration may be provided in a dosage unit form, e.g., for ease and uniformity of administration and administered dose.

[00110] The amount of a solid form of Compound (I) (e.g., Form 1 or Form 2) that is administered may be a therapeutically effective amount which may, in any embodiment, vary with the type and severity of the disease, disorder, or condition to be treated (e.g., symptoms to be alleviated) and may comprise administering a single dose or multiple doses of a pharmaceutical composition comprising or formulated from a solid form of Compound (I) (e.g., Form 1 or Form 2). It is to be further understood that for any particular subject, a specific dosage regimen may be adjusted over time according to the subject’s need and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition comprising or formulated from a solid form of Compound (I), and that dosing amounts and regimens described herein are exemplary only and are not intended to limit the scope of a method of using a solid form of Compound (I) or a pharmaceutical composition comprising or formulated from the same to treat a disease, disorder, or condition in a subject. For example, dosing may be adjusted based on observed pharmacokinetic or pharmacodynamic profiles, such as toxicity, blood plasma levels, or the like. As such, methods disclosed herein of treating a disease, condition, or disorder in a subject by administering a pharmaceutical composition comprising or formulated from a solid form of Compound (I) encompasses intra-patient dose-escalation, which may be determined by a skilled artisan (e.g., the subject’s clinician).

[00111] In certain embodiments, a therapeutically effective amount of a solid form of Compound (I) (e.g., Form 1 or Form 2) may be about 0.0001 to about 50 mg per kg of body weight of the subject per day (“mg/kg/day”), for example about 0.01 mg/kg/day to about 10 mg/kg/day. Such amounts may be administered to a subject in a single dose or two or more divided doses throughout the day. For example, in a 70 kg human subject, about 0.007 mg/day to about 3500 mg/day, for example about 0.7 mg/day to about 700 mg/day may be administered.

[00112] In certain embodiments, a dose of about 0.25 mg to about 10 mg of Compound (I) is administered to a subject in the form of a pharmaceutical composition comprising or formulated from a solid form of Compound (I) (e.g., Form 1 or Form 2) (e.g., in an oral tablet form), to treat a disease, disorder, or condition, such as dementia-related apathy, in the subject. In some embodiments, the dose is about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg of Compound (I) administered in the form of a pharmaceutical composition comprising or formulation from a solid of Compound (I) (e.g., Form 1 or Form 2). In some embodiments, the method of treatment involves a dosing titration period of about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, or about 28 days. In some embodiments the method of treatment does not require a dose titration period.

6.5 Combination Therapies

[00113] In some embodiments, a pharmaceutical composition comprising or formulated from a solid form of Compound (I) as disclosed herein (e.g., Form 1 or 2) may be used as part of a combination therapy to treat a disease, disorder, or condition in a subject. As used herein, the term "combination therapy" refers to the administration of Compound (I) together with an at least one additional therapeutic agent (e.g., an anti-schizophrenia agent). The additional therapeutic agent(s) may be administered to the subject together or separately, both physically (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions) or in time (e.g., at least 30 minutes, 1 hour, 2 hours, 12 hours, or 24 hours apart).

[00114] As such, it is contemplated that a pharmaceutical composition comprising or formulated from a solid form of Compound (I) and a pharmaceutically acceptable excipient may further comprise one or more additional therapeutic agents as described according to any embodiment herein. Accordingly, the present disclosure provides a pharmaceutical composition comprising or formulated from a solid form of Compound (I) as disclosed herein (e.g., Form 1 or 2), a second pharmaceutically active agent, and or more pharmaceutically acceptable excipients.

[00115] In certain embodiments, pharmaceutical composition comprising or formulated from a solid form of Compound (I) as disclosed herein (e.g., Form 1 or 2) may be administered to a subject in combination with one or more agents selected from the group consisting of:

• an acetylcholinesterase inhibitor, such as donepezil hydrochloride (e.g., ARICEPT, MEMAC); • an adenosine A2A receptor antagonist, such as Preladenant (SCH 420814) or SCH 412348;

• an amyloid-P (or fragments thereof), such as Api-15 conjugated to pan HLA DR- binding epitope (PADRE) and ACC-001 (Elan/Wyeth);

• an antibody to amyloid- P (or fragments thereof), such as bapineuzumab (also known as AAB-001) and AAB-002 (Wyeth/Elan);

• an amyloid-lowering or -inhibiting agent (including those that reduce amyloid production, accumulation and fibrillization), such as colostrinin and bisnorcymserine (also known as BNC);

• an alpha-adrenergic receptor agonist, such as clonidine (e.g, CATAPRES);

• a beta-adrenergic receptor blocking agent (beta blockers), such as carteolol;

• an anticholinergic, such as amitriptyline (e.g., ELAVIL, ENDEP);

• an anticonvulsant, such as carbamazepine (e.g, TEGRETOL, CARBATROL);

• an antipsychotic, such as lurasidone (also known as SM- 13496; Dainippon Sumitomo);

• a calcium channel blocker, such as nilvadipine (e.g., ESCOR, NIVAD1L);

• a catechol O-methyltransferase (COMT) inhibitor, such as tolcapone (TASMAR);

• a central nervous system stimulant, such as caffeine;

• a corticosteroid, such as prednisone (e.g., STERAPRED, DELTASONE);

• a dopamine receptor agonists such as apomorphine (e.g., APOKYN);

• a dopamine receptor antagonist, such as tetrabenazine (e.g., NITOMAN, XENAZINE);

• a dopamine D2 antagonist, such as Quetiapinel;

• a dopamine reuptake inhibitor, such as nomifensine maleate (e.g., MERITAL);

• a gamma-aminobutyric acid (GABA) receptor agonist, such as baclofen (e.g., LIORESAL, KEMSTRO);

• a histamine 3 (H3) antagonist, such as ciproxifan;

• an immunomodulator, such as glatiramer acetate (also known as copolymer-1; e.g., COPAXONE);

• an immunosuppressant, such as methotrexate (e.g., TREXALL, RHEUMATREX);

• an interferon, including interferon beta- la (e.g., AVON EX, REBIF) and interferon beta-1 b (e.g., BETASERON, BETAFERON); • levodopa (or its methyl or ethyl ester), alone or in combination with a DOPA decarboxylase inhibitor (e.g., carbidopa (e.g., SINEMET, CARBILEV, PARCOP A));

• an N-methyl-D-aspartate (NMD A) receptor antagonist, such as memantine (e.g., NAMENDA, AXURA, EBIXA);

• a monoamine oxidase (MAO) inhibitor, such as selegiline (e.g., EMS AM);

• a muscarinic receptor (particularly Ml subtype) agonist, such as bethanechol chloride (e.g., DUVOID, URECHOLINE);

• a neuroprotective drug, such as 2,3,4,9-tetrahydro-l H-carbazol-3-one oxime;

• a nicotinic receptor agonist, such as epibatidine;

• a norepinephrine (noradrenaline) reuptake inhibitor, such as atomoxetine (e.g. , STRATTERA);

• a phosphodiesterase (PDE) inhibitor, e.g., PDE9 inhibitors such as BAY 73-6691 (e.g., Bayer AG);

• a PDE 10 (e.g., PDE1 OA) inhibitor, such as papaverine;

• another PDE inhibitor, such as (a) a PDE1 inhibitor (e.g., vinpocetine), (b) a PDE2 inhibitors (e.g., erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA)), (c) a PDE4 inhibitor (e.g., rolipram), and (d) a PDE5 inhibitor (e.g., sildenafil (e.g., VIAGRA, REVATIO));

• a quinoline, such as quinine (including its hydrochloride, dihydrochloride, sulfate, 5 bi sulfate and gluconate salts);

• a P -secretase inhibitor, such as WY-25105;

• a y -secretase inhibitor, such as LY-411575 (Lilly);

• a serotonin (5-hydroxytryptamine) 1A (5-HT1A) receptor antagonist, such as spiperone;

• a serotonin (5-hydroxytryptamine) 4 (5-HT4) receptor agonist, such as PRX-03140 (e.g., Epix);

• a serotonin (5-hydroxytryptamine) 6 (5-HT6) receptor antagonist, such as mianserin (e.g., TORVOL, BOLVIDON, NORVAL);

• a serotonin (5-HT) reuptake inhibitor, such as alaproclate, citalopram (e.g., CELEXA, CIPRAMIL); and

• a trophic factor, such as nerve growth factor (NGF), basic fibroblast growth factor (bFGF; e.g., ERSOFERMIN), neurotrophin-3 (NT-3), cardiotrophin-1, brain-derived neurotrophic factor (BDNF), neublastin, meteorin, and glial-derived neurotrophic factor (GDNF), and agents that stimulate production of trophic factors, such as propentofylline; and the like.

[00116] Accordingly, in another embodiment, the present disclosure provides a method of treating a D1 -mediated disorder, disease, or condition (e.g., a neurological and psychiatric disorder associated with D1), the method comprising administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of a solid form of Compound (I) (e.g., Form 1 or Form 2) and one or more additional active agents, as described herein.

[00117] As used herein, the term "additional active agent" refers to any therapeutic agent, other than Compound (I) that is known or expected to be therapeutically effective on the treatment of the disease, disorder, or condition to be treated.

[00118] In one embodiment the additional active agent is an atypical antipsychotic, an anti-Parkinson's disease agent, or an anti-Alzheimer's agent. Accordingly, in another embodiment, the present disclosure provides a method of treating a D1 -mediated disorder, disease, or condition (e.g., a neurological and psychiatric disorder, disease, or condition associated with D1), the method comprising administering to a subject a pharmaceutical composition comprising or formulated from a therapeutically effective amount of a solid form of Compound (I) (e.g., Form 1 or Form 2) and an atypical antipsychotic, an antiParkinson's disease agent, or an anti-Alzheimer's agent. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of Form 1 of Compound (I), which may have characteristics according to any embodiment disclosed herein, such as a certain chemical, physical, achiral, or chiral purity such as described in Section 5.3.

[00119] In one embodiment, the additional active agent comprises one or more additional anti-schizophrenia agents as described herein. Accordingly, in another embodiment, the present disclosure provides a method of treating schizophrenia, the method comprising administering to a subject a pharmaceutical composition comprising or formulated from a therapeutically effective amount of a solid form of Compound (I), such as Form 1 or Form 2, and one or more additional anti-schizophrenia agents as described herein. In one embodiment, the anti-schizophrenia agent is ziprasidone, risperidone, olanzapine, quetiapine, aripiprazole, asenapine, blonanserin, or iloperidone. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of Form 1 of Compound (I), which may have characteristics according to any embodiment disclosed herein, such as a certain chemical, physical, achiral, or chiral purity such as described in Section 5.3. In one embodiment, the total amount of Compound (I) and the antischizophrenia agent therapeutically effective for treating schizophrenia.

[00120] In another embodiment, the present disclosure provides a method of treating Parkinson’s Disease, the method comprising administering to a subject a pharmaceutical composition comprising or formulated form a therapeutically effective amount of Compound (I) (e.g., a solid form of Compound (I), such as Form 1 or Form 2) one or more additional anti-Parkinson's disease agents, such as L-DOPA. In one embodiment, the total amount of Compound (I) and the anti-schizophrenia agent therapeutically effective for treating Parkinson's disease. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of Form 1 of Compound (I), which may have characteristics according to any embodiment disclosed herein, such as a certain chemical, physical, achiral, or chiral purity such as described in Section 5.3.

7. EXAMPLES

Example 1: Synthesis of Crude Compound (I)

[00121] Step 1. Synthesis of 6-amino-l,5-dimethylpyrimidine-2,4(lH,3H)-dione, hydrochloride salt (Cl).

[00122] A solution of sodium methoxide in methanol (4.4 M, 27 mL, 119 mmol) was added to a solution of ethyl 2-cyanopropanoate (95%, 13.2 mL, 99.6 mmol) and 1-methylurea (98%, 8.26 g, 109 mmol) in methanol (75 mL), and the reaction mixture was heated at reflux for 18 hours, then cooled to room temperature. After removal of solvent in vacuo, the residue was repeatedly evaporated under reduced pressure with acetonitrile (3 x 50 mL), then partitioned between acetonitrile (100 mL) and water (100 mL). Aqueous 6 M hydrochloric acid was slowly added until the pH had reached approximately 2; the resulting mixture was stirred for 1 hour. The precipitate was collected via filtration and washed with tert-butyl methyl ether, affording the product as a white solid. Yield: 15.2 g, 79.3 mmol, 80%. LCMS m/z 156.1 [M+H]⁺. 'HNMR (400 MHz, DMSO-de) o 10.38 (br s, 1H), 6.39 (s, 2H), 3.22 (s, 3H), 1.67 (s, 3H).

[00123] Step 2. Synthesis of 6-bromo-l,5-dimethylpyrimidine-2,4(lH,3H)-dione (C2).

C1 C2

[00124] A 1 : 1 mixture of acetonitrile and water (120 mL) was added to a mixture of Cl (9.50 g, 49.6 mmol), sodium nitrite (5.24 g, 76 mmol), and copper(II) bromide (22.4 g, 100 mmol), and the reaction mixture was allowed to stir at room temperature for 66 hours.

Addition of aqueous sulfuric acid (1 N, 200 mL) and ethyl acetate (100 mL) provided a precipitate, which was collected via filtration and washed with water and ethyl acetate to afford the product as a light yellow solid (7.70 g). The organic layer of the filtrate was concentrated to a smaller volume, during which additional precipitate formed; this was isolated via filtration and washed with 1 : 1 ethyl acetate: heptane to provide additional product (0.4 g). Total yield: 8.1 g, 37 mmol, 75%. GCMS m/z 218, 220 [M⁺], 'H NMR (400 MHz, DMSO-de) 5 11.58 (br s, 1H), 3.45 (s, 3H), 1.93 (s, 3H).

[00125] Step 3. Synthesis of 2-chloro-3-(difluoromethoxy)pyridine (C36)

C36

[00126] This reaction was carried out 3 times. A mixture of potassium carbonate (282 g, 2.04 mol) and AA-dimethylformamide (750 mL) was heated to 100 °C and slowly treated, in a dropwise manner over 1 hour, with a solution of 2-chl oropyri din-3 -ol (66.7 g, 515 mmol) and sodium chloro(difluoro)acetate (200 g, 1.31 mol) in A, A-di methyl form am ide (750 mL). After completion of the addition, the reaction mixture was stirred at 100 °C for 1 hour, then cooled to 25 °C and partitioned between water (10 L) and tert-butyl methyl ether (5 L). The aqueous layer was extracted with ethyl acetate (4 x 2.5 L), and the combined organic layers were washed with saturated aqueous sodium chloride solution (6 x 2.5 L), dried over sodium sulfate, filtered, and concentrated in vacuo. The combined crude products from the three reactions were purified via distillation at reduced pressure (30-40 °C, 1-5 mm Hg) to provide the product as a colorless oil. Yield: 192 g, 1.07 mol, 69%. LCMS m/z 180.0 [M+H]⁺. 'H NMR (400 MHz, CDCh) 5 8.26-8.30 (m, 1H), 7.60 (br d, J=8.2 Hz, 1H), 7.28 (br dd, J=8.0, 4.8 Hz, 1H), 6.60 (t, JHF=72.5 HZ, 1H).

[00127] Step 4. Synthesis of 3-[(benzyloxy)methyl}-6-bromo-l,5-dimethylpyrimidine-

2,4(lH,3H)dione (C37)

[00128] l,8-Diazabicyclo[5.4.0]undec-7-ene (6.00 mL, 40.2 mmol) was added to a suspension of C2 (Step 2) (8.00 g, 36.5 mmol) and benzyl chloromethyl ether (95%, 5.86 mL, 40.2 mmol) in acetonitrile (100 mL). After 90 hours at room temperature, the reaction mixture was concentrated in vacuo, diluted with water, and extracted several times with ethyl acetate. The combined organic layers were washed sequentially with water and with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 10% to 25% ethyl acetate in heptane) afforded the product as a white solid. Yield: 10.1 g, 29.8 mmol, 82%. 'HNMR (400 MHz, CDCb) 5 7.24-7.39 (m, 5H), 5.52 (s, 2H), 4.71 (s, 2H), 3.63 (s, 3H), 2.11 (s, 3H).

[00129] Step 5. Synthesis of 3-[(benzyloxy)methyl]-6-[4-(methoxymethoxy)-2- methylphenyl]-l,5-dimethylpyrimidine-2,4(lH,3H)-dione (C38)

[00130] To a mixture of C37 (10.5 g, 31.0 mmol), [4-(methoxymethoxy)-2- methylphenyl]boronic acid (7.58 g, 38.7 mmol) and potassium carbonate (13 g, 94 mmol) in

1.4-dioxane (170 mL) was added [1,T- bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (1.3 g, 1.6 mmol). The reaction mixture was stirred at 80 °C for 18 hours and filtered; the filtrate was concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 30% ethyl acetate in petroleum ether) provided the product as a yellow oil. Yield: 10.5 g, 25.6 mmol, 83%. 'HNMR (400 MHz, CDC13) 5 7.25-7.46 (m, 5H), 6.93-7.02 (m, 3H), 5.60 (AB quartet, JAB=9.4 HZ, AVAB=9.7 HZ, 2H), 5.22 (s, 2H), 4.79 (s, 2H), 3.52 (s, 3H), 3.00 (s, 3H), 2.12 (br s, 3H), 1.63 (s, 3H).

[00131] Step 6. Synthesis of 3-[(benzyloxy)methyl]-6-(4-hydroxy-2-methylphenyl)-

1.5-dimethylpyrimidine-2,4(lH,3H)-dione (C39)

[00132] To a solution of C38 (9.0 g, 22 mmol) in tetrahydrofuran (70 ml) was added aqueous hydrochloric acid (8 M, 70 ml), and the reaction mixture was stirred at room temperature for 1 hour. After extraction with ethyl acetate (5 x 100 ml), the combined organic layers were concentrated in vacuo. silica gel chromatography (Gradient: 0% to 50% ethyl acetate in petroleum ether) afforded the product as a white solid. Yield: 6.3 g, 17 mmol, 77%. LCMS m/z 389.0 [M+Na⁺], 'H NMR (400 MHz, CDCh) 5 7.43 (br d, J=7 Hz, 2H), 7.25-7.37 (m, 3H), 6.91 (d, J=7.9 Hz, 1H), 6.78-6.84 (m, 2H), 5.61 (AB quartet, JAB=9.4 Hz, Av AB =9.2 Hz, 2H), 5.47 (s, 1H), 4.79 (s, 2H), 3.01 (s, 3H), 2.09 (s, 3H), 1.64 (s, 3H).

[00133] Step 7. Synthesis of 3-[(benzyloxy)methyl]-6-(4-{[3- (difluoromethoxy)pyridin-2-yl]oxy}-2-methylphenyl)-l,5-dimethylpyrimidine- 2,4(lH,3H)-dione (C40).

[00134] A suspension of C39 (10 g, 27 mmol), C36 (5.88 g, 32.7 mmol), and cesium carbonate (99%, 13.5 g, 41.0 mmol) in dimethyl sulfoxide (200 mL) was heated to 80 °C for 18 hours. Compound C36 (2.9 g, 16 mmol) was added, and the reaction mixture was heated at 90 °C for 3 hours, then at 80 °C for 66 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water (5 x 300 mL), washed with saturated aqueous sodium chloride solution (200 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 25% to 50% ethyl acetate in heptane) provided the product as a viscous, light yellow oil. Yield: 10.8 g, 21.2 mmol, 78%. LCMS m/z 510.2 [M+H]⁺. 'H NMR (400 MHz, CDCh) 5 8.05 (dd, J=4.9, 1.7 Hz, 1H), 7.61-7.65 (m, 1H), 7.40-7.44 (m, 2H), 7.30- 7.36 (m, 2H), 7.24-7.29 (m, 1H), 7.11-7.16 (m, 2H), 7.10 (dd, J=7.9, 4.9 Hz, 1H), 7.08 (br d, J=8 Hz, 1H), 6.70 (t, JHF=73.5 Hz, 1H), 5.61 (AB quartet, JAB=9.5 HZ, AVAB=9.2 HZ, 2H), 4.79 (br s, 2H), 3.04 (s, 3H), 2.16 (br s, 3H), 1.66 (s, 3H).

[00135] Step 8. Synthesis of (-)-6-(4-{[3-(difluoromethoxy)pyridin-2-yl]oxy}-2- methylphenyl)-l,5-dimethylpyrimidine-2,4(lH,3H)-dione (Compound (I)).

[00136] A mixture of C40 (10.8 g, 21.2 mmol) and trifluoroacetic acid (110 mL) was heated at 80 °C for 1 hour. The reaction mixture was concentrated in vacuo, treated with dichloromethane, and concentrated again, then treated with tetrahydrofuran, concentrated under reduced pressure, and dried under high vacuum. The residue was diluted with tetrahydrofuran (50 mL), cooled in an ice bath, and treated with concentrated ammonium hydroxide (50 mL). The flask was removed from the ice bath and the reaction mixture was stirred at room temperature for 45 minutes; after removal of solvents in vacuo, purification via silica gel chromatography (Gradient: 25% to 100% ethyl acetate in heptane) provided a racemic mixture of Compound (I) and its atropenantiomer. This was combined with material obtained from a similar reaction carried out on C40 (15.3 g, 30.0 mmol), and separated via supercritical fluid chromatography (Column: Phenomenex Lux Cellulose-2, 5 pm; Eluent: 3:2 carbon dioxide/ methanol). The first-eluting atropenantiomer, which exhibited a negative (-) rotation, was assigned as atropenantiomer Compound (I). Yield: 4.8 g, 12 mmol, 23%.

Example 2: Preparation of Form 1 of Compound (I)

[00137] Process A: Crude Compound (I), e.g., as prepared in Example 1, was purified via recrystallization from tetrahydrofuran and heptane to generate Form 1 of Compound (I).

[00138] Process B: Crude Compound (I), e.g., as prepared in Example 1, was collected by filtration, and washed with water. Compound (I) was dissolved in tetrahydrofuran (THF) (approximately 30 volumes) and speck-free filtered into a clean reaction vessel. THF was exchanged with ethanol (EtOH). The API was crystallized by addition of water followed by cooling. The slurry was filtered and the product dried under vacuum to generate Form 1 of Compound (I).

[00139] Process C: Crude Compound (I), e.g., as prepared in Example 1, was collected by filtration and washed with water. Compound (I) was dissolved in acetone (approximately 18- 22 volumes) and speck-free filtered into a clean reaction vessel. Compound (I) was crystallized by addition of water followed by cooling. The slurry was filtered and the product cake was washed with water and dried under vacuum to generate Form 1 of Compound (I).

Example 3: Physical Characterization of Form 1 of Compound (I)

[00140] Solid Forms were characterized by XRPD analysis using Cu Ka radiation, DSC, and TGA as follows: [00141] X-Ray Powder Diffraction (XRPD) patterns were collected on a Bruker D8 Advance using Cu Ka radiation comprising Kai radiation having a wavelength of 1.5406 A, a Ka2 radiation having a wavelength of 1.54439 A, and a Kai :Ka2 ratio of about 0.5.

Differential Scanning Calorimetry (DSC) was carried out on a TA Instruments Discovery DSC at a heating rate of 10 °C/min. Thermogravimetric analysis (TGA) was carried out on a TA Instruments Discovery TGA at a heating rate of 10 °C/min to a final temperature of about 270°C.

[00142] Characterization of Form 1 of Compound (I): The XRPD pattern, shown in FIG. 1, indicates that Form 1 is crystalline. The DSC thermogram, shown in FIG. 3, shows a sharp endotherm with peak maximum at about 210 °C. TGA, shown in FIG. 2, indicates a -0.8% weight loss between 110 and 200 °C.

[00143] Characterization of Form 2: The XRPD pattern indicates Form 2 is crystalline and is shown in FIG. 4.

Example 4: Impurity Assay of Prepared Form 1 of Compound (I)

[00144] Organic impurities of Form 1 of Compound (I) were assayed by reversed-phase HPLC with conditions as described below:

Column: Waters Aquity HSS T3, 2.1 x 150 mm 1.8 pm

Detector: UV at 210 nm

Column Temp: 45 °C

Flow Rate: 0.4 mL/min

Injector Volume: 2 pL

Mobile Phase A: 0.1% v/v methane sulfonic acid in water

Mobile Phase B: Acetonitrile

Program:

[00145] Quantification of impurities is achieved by area percent.

[00146] Chiral impurities of Form 1 of Compound (I) were assayed by isocratic supercritical fluid chromatography (SFC) with conditions as described below:

Instrument: Waters UPCC with PDA detector Column: Daicel Chiralpak OD-3, 4.6 * 150 mm, 3.0 pm

Detector: UV at 210 nm

Column Temp: 30 °C

Flow Rate: 2.0 mL/min

Injector Volume: 2 pL

Mobile Phase A: CO2

Mobile Phase B: Ethanol

Program: 80% A/20% B for 6 minutes

ABPR 2000 psi

[00147] Residual solvents of Form 1 of Compound (I) were assayed by headspace capillary gas chromatography with conditions as described below:

Column: DB-624 (25 m x 0.2 mm, ID 1.12 pm)

Carrier Gas: N2

FID Temp: 260 °C

Makeup Flow: 30 mL/min

H2 Flow Rate: 40 mL/min

Air Flow: 400 mL/min

Flow Rate: 1.2 mL/min

Column Temp: 45 °C for 0.2 min, ramp at 2 °C/min to 50 °C, then ramp to 250

°C at a rate of 25 °C/min and hold for 3.3 min

Injector Temp: 240 °C

Split Ratio: 30: 1

[00148] Water content was determined by coulometric Karl Fischer titration using USP<921>.

[00149] Table 1 below reports the results of the above-noted assays:

Table 1: Impurities in Form 1 of Compound (I)

Example 5: Solubility Assays

[00150] Aqueous solubility experiments revealed that Form 1 of Compound has an aqueous solubility of about 4.7 pg/mL at 25 °C in water. More specifically, Form 1 of Compound has an aqueous solubility of about 5.0 pg/mL at 25°C at pH 6.1, of about 4.6 pg/mL at 25°C at pH 2.2, and about 4.5 pg/mL at 25°C at pH 1.2.

[00151] For solubility in organic solvents, 95% ethanol (EtOH) and 70% isopropyl alcohol (IP A) were prepared by adding the appropriate quantity of 100% organic solvent to a graduated cylinder and QS with purified water. 100% isopropanol was used as-is. 0.5 mL of the solvent of interest was added to a centrifuge tube and portions of API were added sequentially with the mass recorded. The tubes were hand-shaken and mixed with a vortex for ca. 15 seconds between additions. The presence of visible parti culates/turbidity was used as a measure of when the solubility limit was reached. Form 1 of Compound has a solubility of about 1.07 mg/mL at 25°C in ethyl alcohol, about 0.34 mg/mL at 25°C in isopropyl alcohol, about 56 mg/mL at 25°C in tetrahydrofuran, and about 20 mg/mL at 25°C in acetone.

Example 6: Stability Assay

[00152] Stability of Form 1 of Compound (I) was assessed by storing for 6 months at 40°C/75% RH to simulate accelerated conditions and for 12-48 months at 25°C/60% RH to simulate long-term storage conditions. Table 2 reports the results of the stability assays. In Table 2, “A” indicates stability as indicated by appearance, assay, related substances by HPLC, and water content. “B” indicates stability of polymorphic form (e.g., Form 1).

Table 2: Stability of Form 1 of Compound (I)

[00153] A photostability study was also completed under IHC conditions. No significant change has been observed in the drug substance over the stability programs which indicates that Form 1 of Compound (I) is highly stable. Example 7: Summary of Polymorph Screening

[00154] A polymorph screen was conducted on Compound (I). Room temperatures slurries (14 solvents including 4 aqueous binary mixtures) were utilized for 2 weeks along with and also a 1-day slurry at 40 °C with ethanol. The results of this screen demonstrated that Form 1 was consistently produced. Form 2 was produced from rapid evaporation of Compound (I) from 2-methyl THF. Attempts to scale-up Form 2 consistently resulted in formation of Form 1. Likewise, competitive slurrying at room temperature led to the formation of Form 1.

[00155] A quench cool experiment conducted on a DSC was not successful in creating amorphous material - no glass transition temperature was detected as Compound (I) readily crystallized during the cooling step. No amorphous material was identified during this screen.

[00156] Form 1 was deemed the most thermodynamically stable form at ambient conditions.

[00157] Throughout this application, various publications, patents, patent applications and other documents have been referenced. The disclosures of these publications, patents, patent applications and other documents in their entireties are hereby incorporated by reference in this application for all purposes, including in order to more fully describe the state of the art to which this the subject matter disclosed herein pertains. Although the disclosed subject matter has been described with reference to the examples provided above, it should be understood that various modifications could be made without departing from the spirit of the disclosed subject matter. Many variations will become apparent to those skilled in the art upon review of this specification.

Claims

CLAIMS What is claimed is:

1. A solid form comprising Compound (I) or a pharmaceutically acceptable salt thereof:

2. The solid form of claim 1, comprising a free base of Compound (I).

3. The solid form of claim 2, which is characterized by an XRPD pattern, when measured using Cu Ka radiation, comprising at least three peaks, each at a 29 angle selected from the group consisting of approximately 8.7, 14.9, 17.5, 21.5, 23.2, and 26.3° 29 ±

0.2° 29.

4. The solid form of claim 3, which is characterized by an XRPD pattern, when measured using Cu Ka radiation, further comprising at least one peak at a 29 angle selected from the group consisting of approximately 19.4, 20.7, 22.6, 24.8, 25.1, and 29.1° 29 ± 0.2° 29.

5. The solid form of claim 3, which is characterized by an XRPD pattern, when measured using Cu Ka radiation, further comprising at least two peaks, each at a 29 angle selected from the group consisting of approximately 19.4, 20.7, 22.6, 24.8, 25.1, and 29.1° 29 ± 0.2° 29.

6. The solid form of claim 3, which is characterized by an XRPD pattern, when measured using Cu Ka radiation, further comprising at least three peaks, each at a 29 angle selected from the group consisting of approximately 19.4, 29.7, 22.6, 24.8, 25.1, and 29.1° 29 ± 9.2° 29.

7. The solid form of claim 2, which is characterized by an XRPD pattern comprising peaks at approximately 17.5, 23.2, and 26.3° 29.

8. The solid form of claim 7, wherein the XRPD pattern further comprises peaks at approximately 8.7, 14.9, and 21.5° 29 ± 0.2° 29.

9. The solid form of claim 8, wherein the XRPD pattern further comprises peaks at approximately 29.7 and 22.6° 29 ± 9.2° 29.

19. The solid form of claim 2, which is characterized by an XRPD pattern essentially as shown in FIG. 1.

11. The solid form of any one of claims 3 to 19, which exhibits a thermal event with an onset temperature of about 219 °C as characterized by DSC.

12. The solid form of any one of claims 3 to 11, which exhibits a weight loss of about 9.8% upon heating from about 25 °C to about 299 °C.

13. The solid form of any claim 1 or 2, wherein a single crystal Compound (I) is characterized by the following triclinic cell parameters: a = 8.957 A, b = 19.488 A, c = 12.421 A, a = 196.69°, 0 = 95.75°, y = 119.35°, V = 919.5 A³.

14. The solid form of claim 1, which is characterized by an XRPD pattern, when measured using Cu Ka radiation, comprising at least three peaks, each at a 29 angle selected from the group consisting of approximately 7.7, 14.6, 17.2, 18.9, 19.9, 23.9, 25.6, and 26.6° 29 ± 9.2° 29.

15. The solid form of claim 14, which is characterized by an XRPD pattern, when measured using Cu Ka radiation, further comprising at least one peak at a 29 angle selected from the group consisting of approximately 12.9, 13.9, 14.1, 15.3, 19.2, 23.9, 23.6, and 24.1° 29 ± 9.2° 29.

16. The solid form of claim 14, which is characterized by an XRPD pattern, when measured using Cu Ka radiation, further comprising at least two peaks, each at a 29 angle selected from the group consisting of approximately 12.9, 13.9, 14.1, 15.3, 19.2, 23.9, 23.6, and 24.1° 29 ± 9.2° 29.

17. The solid form of claim 14, which is characterized by an XRPD pattern, when measured using Cu Ka radiation, further comprising at least three peaks, each at a 29 angle selected from the group consisting of approximately 12.0, 13.9, 14.1, 15.3, 19.2, 23.0, 23.6, and 24.1° 29 ± 0.2° 29.

18. The solid form of claim 1, which is characterized by an XRPD pattern comprising peaks at approximately 14.6, 18.0, and 23.0° 29 ± 0.2° 29.

19. The solid form of claim 18, wherein the XRPD pattern further comprises peaks at approximately 7.7, 19.0, and 25.6° 29 ± 0.2° 29.

20. The solid form of claim 19, wherein the XRPD pattern further comprises peaks at approximately 17.2 and 26.6° 29.

21. The solid form of claim 20, wherein the XRPD pattern further comprises a peak at a 29 angle selected from the group consisting of approximately 13.9, 14.1 and 24.1° 29 ± 0.2° 29.

22. The solid form of claim 1, which is characterized by an XRPD pattern essentially as shown in FIG. 4.

23. The solid form of any one of claims 1 to 13, wherein the solid form is anhydrous.

24. A composition comprising the solid form of any one of claims 1 to 23, wherein the chemical purity of the composition is at least about 97%.

25. A composition comprising the solid form of any one of claims 1 to 23, wherein the chiral purity of the composition is at least about 99%.

26. The composition of claim 24 or claim 25, wherein composition comprises not more than about 1% by weight of any single impurity.

27. A pharmaceutical composition comprising the solid form of any one of claims 1 to 26 or the composition of any one of claims 24 to 26, and a pharmaceutically acceptable excipient.

28. The pharmaceutical composition of claim 27, which is a solid intended for reconstitution prior to use.

29. The pharmaceutical composition of claim 27, which is an oral dosage form.

30. The pharmaceutical composition of claim 29, which is an oral tablet.

31. A method of treating a disorder, disease, or condition for which a D 1 agonist is indicated in a subject comprising administering a therapeutically effective amount of the solid form of any one of claims 1 to 23, or the pharmaceutical composition of any one of claims 27, 29, and 30 to the subject.

32. A method of treating a symptom of dementia in a subject comprising administering a therapeutically effective amount of the solid form of any one of claims 1 to 23, or the pharmaceutical composition of any one of claims 27, 29, and 30 to the subject.

33. The method of claim 32, wherein the symptom is dementia-related apathy.

34. The method of claim 32 or 33, wherein about 1 mg to about 3 mg of the solid form is administered to the subject.

35. The method of any one of claims 32 to 34, wherein the solid form of Compound (I) is administered to the subject once per day.

36. A method of treating schizophrenia, cognitive impairment, mild cognitive impairment (MCI), age-related cognitive decline, dementia, or Parkinson's disease in a subject comprising administering a therapeutically effective amount of the solid form of any one of claims 1 to 23, or the pharmaceutical composition of any one of claims 27, 29, and 30 to the subject.

37. A method of preparing the solid form of any one of claims 3 to 12:

comprising

(a) combining Compound (I) with a mixture of tetrahydrofuran and heptane; and

(b) cooling the mixture to yield the crystalline form of Compound (I).

38. The method of claim 37, wherein Compound (I) is combined with a mixture of tetrahydrofuran and heptane at a temperature of at least 50 °C and is cooled to about 20 °C to yield the solid form of Compound (I).

39. A method of preparing the solid form of any one of claims 3 to 12:

comprising

(a) dissolving Compound (I) in tetrahydrofuran to form a solution;

(b) exchanging the tetrahydrofuran for ethanol to form a solvent-exchanged solution; and

(c) adding water to the solvent-exchanged solution to yield the solid form of Compound (I).

40. The method of claim 39, wherein the solvent-exchanged solution is cooled.

41. A method of preparing the solid form of any one of claims 3 to 12:

comprising

(a) dissolving Compound (I) in acetone to form a solution; and

(b) adding water to the solution to yield the solid form of Compound (I).

42. The method of claim 41, wherein the solution is cooled.

43. A method of preparing the solid form of any one of claims 14 to 23:

comprising

(a) combining Compound (I) with 2-methyl THF; and

(b) evaporating the 2-methyl THF to yield the solid form of Compound (I).