Crystalline forms of 7-((2r,4s)-4-((2,3-dihydrobenzo[b][1,4] dioxin-6-YL-2,2,3,3-d 4)OXY)-2-methylpiperidin-1-YL)-8-methyl-4h-pyrimido[1,2-b]pyridazin -4-one

Abstract

Disclosed herein are solid forms of 7-((2R,4S)-4-((2,3-Dihydrobenzo[b][1,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-1-yl)-8-methyl-4H-pyrimido[1,2-b]pyridazin-4-one hydrochloride, including a crystalline Form X of exhibiting at least X-ray lines (in degrees 2θ ± 0.2°) at 6.69, 8.52, 10.29, 17.42, 20.64, 21.08, 26.22 and 29.52 in a powder diffraction pattern when measured using Cu Kα radiation. Also disclosed herein are pharmaceutical compositions containing the same, and to methods of their use and preparation.

Description

[0001] CRYSTALLINE FORMS OF 7-((2R,4S)-4-((2,3-DIHYDROBENZO[b][l,4] DIOXIN-6-YL-2,2,3 ,3 -D4)OXY)-2-METHYLPIPERIDIN- 1 -YL)-8-METHYL-4H- P YR.IM IDO[ 1 ,2-b]P YRID AZ IN-4-ONE

[0002] FIELD OF THE INVENTION

[0003] The invention relates to crystalline forms of 7-((2R,4S)-4-((2,3-dihydro benzo[b][l,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-l-yl)-8-methyl-4H-pyrimido[l,2-b] pyridazin-4-one, as well as products containing the same, and methods of their use and preparation.

[0004] BACKGROUND

[0005] Muscarinic acetylchloline receptors (mAChRs) are members of the family A-G protein-coupled receptors (GPCRs) and include five subtypes, designated M1-M5. The Mi, M3 and Ms subtypes mainly couple to Gqand activate phospholipase C, whereas the M2 and M4 subtypes mainly couple to Gi / 0and associated effector systems. These five distinct mAChR subtypes have been identified in the mammalian central nervous system where they are prevalent and differentially expressed. M1-M5 mAChRs have varying roles in cognitive, sensory, motor and autonomic functions. Thus, without wishing to be bound by a particular theory, it is believed that selective agonists of mAChR subtypes that regulate processes involved in cognitive function could prove to be superior therapeutics for treatment of psychosis, schizophrenia and related disorders. The muscarinic M4 receptor has been shown to have a major role in cognitive processing and is believed to have a major role in the pathophysiology of psychotic disorders, including schizophrenia.

[0006] Considerable effort has been focused on developing selective M4 agonists for treatment of these disorders. Unfortunately, these efforts have been largely unsuccessful because of an inability to develop compounds that are highly selective for the mAChR M4. Consequently, mAChR M4 agonists that have been tested in clinical studies have been found to induce a range of adverse effects by activation of peripheral mAChRs. To fully understand the physiological roles of individual mAChR subtypes, and to further explore the therapeutic utility of mAChR ligands in psychosis, including schizophrenia, cognition disorders and other disorders, significant efforts have been undertaken to develop compounds that are highly selective activators of mAChR M4 and other individual mAChR subtypes.

[0007] Muscarinic agonists including xanomeline have been shown to be active in animal models with similar profiles to known antipsychotic drugs, but without causing catalepsy (Bymaster et al., Eur. J. Pharmacol. (1998), 356(2-3), 109-119; Bymaster et al., Life Sci. (1999), 64(6-7), 527-534; Shannon et al., J. Pharmacol. Exp. Ther. (1999), 290(2), 901-907; Shannon et al., Schizophrenia Res. (2000), 42(3), 249-259). Further, xanomeline was shown to reduce psychotic behavioral symptoms such as delusions, suspiciousness, vocal outbursts, and hallucinations in Alzheimer's disease patients (Bodick et al., Arch. Neural. (1997), 54(4), 465- 473), however treatment induced side effects, e.g., gastrointestinal effects, have severely limited the clinical utility of this compound.

[0008] WO 2018 / 118736 Al by Gao et al. discloses 6,5-fused heteroaryl piperidine ether compounds that are allosteric modulators of mAChR M4.

[0009] A promising class of allosteric modulators of mAChR M4 is provided in WO 2022 / 015988 Al by Lindsley et al., the entire contents of which are incorporated herein by reference, which discloses 6,6-fused heteraryl piperidine ether compounds that are also allosteric modulators of mAChR M4. The 6,6-fused heteroaryl compounds disclosed in this reference are analogues of the following formula (I):

[0010] Within the genus of formula (I), the Compound 129 shown below — i.e., 7-((2R,4S)-

[0011] 4-((2,3-dihydrobenzo[b][l,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-l-yl)-8-methyl-4H- pyrimido[l,2-b]pyridazin-4-one — has been found to be a selective mAChR M4 agonist.

[0012] (Compound 129)

[0013] A need exists to discover solid forms of Compound 129 that can potentially be selected for clinical development as selective mAChR M4 agonists in the context of treating, for example, neurological and / or psychiatric disorders. SUMMARY OF THE INVENTION

[0014] The present invention is directed to solid forms of 7-((2R,4S)-4-((2,3-di hydrobenzo[Z>][l,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-l-yl)-8-methyl-4H-pyrimido [l,2-Z>]pyridazin-4-one (Compound 129), as well as compositions containing solid forms of Compound 129 and related methods.

[0015] The objective was to discover solid forms of Compound 129 that may be suitable as clinical candidates for the development of selective mAChR M4 agonists for the treatment of, for example, neurological and / or psychiatric disorders. As illustrated in the experimental section below, it was surprisingly discovered that hydrochloride salts of Compound 129 exhibit preferable characteristics compared to other salts based on stability testing (Example 10) and biorelevant solubility (Example 11). It was also discovered that hydrochloride salts of Compound 129 can be formed as different crystalline polymorphs having different stabilities, wherein a so-called “Form X” of Compound 129 exhibits favorable characteristics for drug development in terms of stability (Example 12), organic solubility (Example 13), aqueous solubility (Example 14), and lipophilicity as measured by LogD (Example 15).

[0016] In one embodiment, a crystalline hydrochloride salt of 7-((2R,4S)-4-((2,3-dihydro benzo[Z>] [ 1 ,4]dioxin-6-yl-2,2,3 ,3 -d4)oxy)-2-methylpiperidin- 1 -yl)-8-methyl-4H-pyrimido[ 1 ,2-Z>] pyridazin-4-one (Compound 129) has a Form X which exhibits at least X-ray lines (in degrees 29 ± 0.2°) at 6.69, 8.52, 10.29, 17.42, 20.64, 21.08, 26.22 and 29.52 in a powder diffraction pattern when measured using Cu Ka radiation.

[0017] In another embodiment, a pharmaceutical composition comprises the crystalline hydrochloride Form X of Compound 129 and at least one additive or auxiliary substance.

[0018] In another embodiment, a method is provided for modulating muscarinic acetylcholine receptor (mAChR) M4 activity in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of the crystalline hydrochloride Form X of Compound 129, or an effective amount of a pharmaceutical composition comprising the crystalline hydrochloride Form X of Compound 129.

[0019] In another embodiment, a method is provided for treating a neurological and / or psychiatric disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the crystalline hydrochloride Form X of Compound 129, or with an effective amount of a pharmaceutical composition comprising the crystalline hydrochloride Form X of Compound 129.

[0020] In another embodiment, the crystalline hydrochloride Form X of Compound 129 is provided for use in the treatment of a neurological and / or psychiatric disorder. In another embodiment, a pharmaceutical composition comprising the crystalline hydrochloride Form X of Compound 129 is provided for use in the treatment of a neurological and / or psychiatric disorder.

[0021] Another embodiment relates to use of the crystalline hydrochloride Form X of Compound 129 in the manufacture of a medicament for the treatment of a neurological and / or psychiatric disorder.

[0022] Another embodiment relates to use of a pharmaceutical composition comprising the crystalline hydrochloride Form X of Compound 129 in the manufacture of a medicament for the treatment of a neurological and / or psychiatric disorder.

[0023] BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 shows an overlay of the powder X-ray diffraction (PXRD) spectra for crystalline hydrochloride salts of Compound 129.

[0025] Figure 2 shows a differential scanning calorimetry (DSC) / thermogravimetric analysis (TGA) overlay for a crystalline hydrochloride salt of Compound 129 having a Form B that was obtained using aqueous hydrochloric acid in ethanol.

[0026] Figure 3 shows a DSC / TGA overlay for a crystalline hydrochloride salt of Compound 129 having a Form A that was obtained using aqueous hydrochloric acid in tetrahydrofuran.

[0027] Figure 4 shows a DSC / TGA overlay for a crystalline hydrochloride salt of Compound 129 having a Form A that was obtained at 100 mg scale using aqueous hydrochloric acid in acetone.

[0028] Figure 5 shows a DSC / TGA overlay for a crystalline hydrochloride salt of Compound 129 having a Form A that was obtained at 300 mg scale using aqueous hydrochloric acid in acetone.

[0029] Figure 6 shows a DSC / TGA overlay for a crystalline hydrochloride salt of Compound 129 having a Form C.

[0030] Figure 7 shows an overlay of DSC plots of Figures 2-6.

[0031] Figure 8 shows a polarized light microscopy (PLM) image of a crystalline hydrochloride salt of Compound 129 having the Form B that was obtained using aqueous hydrochloric acid in ethanol.

[0032] Figure 9 shows a PLM image of a crystalline hydrochloride salt of Compound 129 having a Form A that was obtained using aqueous hydrochloric acid in tetrahydrofuran. Figure 10 shows a PLM image of a crystalline hydrochloride salt of Compound 129 having a Form A that was obtained at 300 mg scale using aqueous hydrochloric acid in acetone.

[0033] Figure 11 shows a PLM image for a crystalline hydrochloride salt of Compound 129 having a Form C.

[0034] Figure 12 shows dynamic vapor sorption (DVS) plots of weight change versus relative humidity for a crystalline hydrochloride salt of Compound 129 having a Form B that was obtained using aqueous hydrochloric acid in ethanol.

[0035] Figure 13 shows dynamic vapor sorption (DVS) plots of weight change versus relative humidity for a crystalline hydrochloride salt of Compound 129 having a Form A that was obtained using aqueous hydrochloric acid in tetrahydrofuran.

[0036] Figure 14 shows a nuclear magnetic resonance (NMR) spectrum of a crystalline hydrochloride salt of Compound 129 having a Form A that was obtained at 100 mg scale using aqueous hydrochloric acid in acetone.

[0037] Figure 15 shows an overlay of the powder X-ray diffraction (PXRD) spectra for crystalline sulfate salts of Compound 129.

[0038] Figure 16 shows a DSC / TGA overlay for a crystalline sulfate salt of Compound 129 that was obtained using sulfuric acid in aqueous ethanol.

[0039] Figure 17 shows a DSC / TGA overlay for a crystalline sulfate salt of Compound 129 that was obtained at 100 mg scale using sulfuric acid in aqueous acetone.

[0040] Figure 18 shows a DSC / TGA overlay for a crystalline sulfate salt of Compound 129 that was obtained at 300 mg scale using sulfuric acid in aqueous acetone.

[0041] Figure 19 shows a DSC / TGA overlay for a crystalline sulfate salt of Compound 129 that was obtained at 10 g scale.

[0042] Figure 20 shows a PLM image of a crystalline sulfate salt of Compound 129 that was obtained at 300 mg scale using sulfuric acid in aqueous acetone.

[0043] Figure 21 shows a PLM image of a crystalline sulfate salt of Compound 129 that was obtained at 10 g scale.

[0044] Figure 22 shows DVS plots of weight change versus relative humidity for a crystalline sulfate salt of Compound 129 that was obtained using sulfuric acid in aqueous ethanol.

[0045] Figure 23 shows an overlay of the PXRD spectra for crystalline phosphate salts of Compound 129 obtained at 100 mg scale.

[0046] Figure 24 shows the PXRD spectrum for a crystalline phosphate salt of Compound 129 obtained at 350 g scale. Figure 25 shows a DSC / TGA overlay for a crystalline phosphate salt of Compound 129 that was obtained using phosphoric acid in aqueous ethanol and heptane (as antisolvent).

[0047] Figure 26 shows a DSC / TGA overlay for a crystalline phosphate salt of Compound 129 that was obtained using phosphoric acid in aqueous acetone.

[0048] Figure 27 shows a DSC / TGA overlay for a crystalline phosphate salt of Compound 129 obtained at 350 g scale.

[0049] Figure 28 shows DVS plots of weight change versus relative humidity for a crystalline phosphate salt of Compound 129 that was obtained using phosphoric acid in aqueous ethanol and heptane (as antisolvent).

[0050] Figure 29 shows DVS plots of weight change versus relative humidity for a crystalline phosphate salt of Compound 129 that was obtained at 350 g scale.

[0051] Figure 30 shows a PLM image of a crystalline sulfate salt of Compound 129 that was obtained at 350 g scale.

[0052] Figure 31 shows an NMR spectrum of a crystalline phosphate salt of Compound 129 that was obtained at 350 g scale.

[0053] Figure 32 shows an overlay of the PXRD spectra for esylate salts of Compound 129.

[0054] Figure 33 shows a DSC / TGA overlay for a crystalline esylate salt of Compound 129 that was obtained using ethanesulfonic acid in aqueous ethanol and heptane (as antisolvent).

[0055] Figure 34 shows a DSC / TGA overlay for a crystalline esylate salt of Compound 129 that was obtained using ethanesulfonic acid in aqueous THF and heptane (as antisolvent).

[0056] Figure 35 shows a DSC / TGA overlay for a crystalline esylate salt of Compound 129 that was obtained at 300 mg scale using ethanesulfonic acid in aqueous acetone and heptane (as anti solvent).

[0057] Figure 36 shows a PLM image of a crystalline esylate salt of Compound 129 that was obtained at 300 mg scale using ethanesulfonic acid in aqueous acetone and heptane (as antisolvent).

[0058] Figure 37 shows DVS plots of weight change versus relative humidity for a crystalline esylate salt of Compound 129 that was obtained using ethanesulfonic acid in aqueousethanol and heptane (as anti solvent).

[0059] Figure 38 shows DVS plots of weight change versus relative humidity for a crystalline esylate salt of Compound 129 that was obtained using ethanesulfonic acid in aqueous THF and heptane (as anti solvent).

[0060] Figure 39 shows kinetic solubility data for different crystalline salts of Compound 129. Figure 40 shows plots of average concentration versus time relating to biorelevant solubility testing of crystalline salts of Compound 129.

[0061] Figure 41 shows the PXRD spectrum for the Form C crystalline hydrochloride salt of Compound 129.

[0062] Figure 42 shows the PXRD spectrum for the Form B crystalline hydrochloride salt of Compound 129.

[0063] Figure 43 shows the PXRD spectrum for the Form E crystalline hydrochloride salt of Compound 129.

[0064] Figure 44 shows the PXRD spectrum for the Form F crystalline hydrochloride salt of Compound 129.

[0065] Figure 45 shows the PXRD spectrum for the Form G crystalline hydrochloride salt of Compound 129.

[0066] Figure 46 shows the PXRD spectrum for the Form H crystalline hydrochloride salt of Compound 129.

[0067] Figure 47 shows the PXRD spectrum for the Form D crystalline hydrochloride salt of Compound 129.

[0068] Figure 48 shows the PXRD spectrum for the Form X crystalline hydrochloride salt of Compound 129.

[0069] Figure 49 shows a DSC / TGA overlay for a crystalline hydrochloride salt of Compound 129 having the Form X.

[0070] Figure 50 shows a PLM image of a crystalline hydrochloride salt of Compound 129 having the Form X.

[0071] Figure 51 shows DVS plots of weight change versus relative humidity for a crystalline hydrochloride salt of Compound 129 having the Form X.

[0072] Figure 52 shows the PXRD spectrum for the Form X crystalline hydrochloride salt of Compound 129.

[0073] DETAILED DESCRIPTION OF THE INVENTION

[0074] The present invention is directed to solid forms of 7-((2R,4S)-4-((2,3-di hydrobenzo[Z>][l,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-l-yl)-8-methyl-4H-pyrimido [l,2-Z>]pyridazin-4-one (Compound 129 shown below), as well as compositions containing solid forms of Compound 129, and methods of use and preparation.

[0075] (Compound 129)

[0076] As illustrated in the experimental section below, it was surprisingly discovered that hydrochloride salts of Compound 129 exhibit preferable characteristics compared to other salts based on stability testing (Example 10) and biorelevant solubility (Example 11). It was also discovered that hydrochloride salts of Compound 129 can be formed as different crystalline polymorphs having different stabilities, wherein a so-called “Form X” of Compound 129 exhibits favorable characteristics for drug development in terms of stability (Example 12), organic solubility (Example 13), aqueous solubility (Example 14), and lipophilicity as measured by LogD (Example 15).

[0077] The Form X of Compound 129 may be suitable as a clinical candidate for the development of a selective mAChR M4 agonist for the treatment of neurological and / or psychiatric disorders.

[0078] Definitions

[0079] As used herein, ranges and amounts can be expressed as “about” a particular value or range. “About” also includes the exact amount. Hence “about lOOpL” means “about lOOpL” and also “lOOpL.” In some embodiments, “about” means within 5% of the value. Hence, “about 100 pL” means 95-105 pL. In some embodiments, “about” means within 4% of the value. In some embodiments, “about” means within 3% of the value. In some embodiments, “about” means within 2% of the value. In some embodiments, “about” means within 1% of the value. Generally, the term “about” includes an amount that would be expected to be within experimental error.

[0080] As used herein, the phrase “Compound 129” refers to the compound 7-((2R,4S)-4- ((2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidin-l-yl)-8-methyl-4H- pyrimido[l,2-Z>]pyridazin-4-one as a free base.

[0081] As used herein, the phrases “solid form disclosed herein” and “solid forms disclosed herein” refer to one or more solid forms of Compound 129.

[0082] As used herein, the phrase “substantially the same” means that the value of a described parameter (e.g., X-ray line angle) may vary by a percentage as low as 5% below the described value, or may vary by a percentage as high as 5% above the described value. In some embodiments, the phrase “substantially the same” means that the value of a described parameter (e.g., X-ray line angle) may vary by a percentage as low as 4% below the described value, or may vary by a percentage as high as 4% above the described value. In some embodiments, the phrase “substantially the same” means that the value of a described parameter (e.g., X-ray line angle) may vary by a percentage as low as 3% below the described value, or may vary by a percentage as high as 3% above the described value. In some embodiments, the phrase “substantially the same” means that the value of a described parameter (e.g., X-ray line angle) may vary by a percentage as low as 2% below the described value, or may vary by a percentage as high as 2% above the described value. In some embodiments, the phrase “substantially the same” means that the value of a described parameter (e.g., X-ray line angle) may vary by a percentage as low as 1% below the described value, or may vary by a percentage as high as 1% above the described value.

[0083] As used herein, the phase “essentially the same” means that the X-ray line angles of an X-ray pattern may individually vary by a percentage as low as 5% below the value illustrated in the described X-ray pattern, or may individually vary by a percentage as high as 5% above the value illustrated in the described X-ray pattern. In some embodiments, the phase “essentially the same” means that the X-ray line angles of an X-ray pattern may individually vary by a percentage as low as 4% below the value illustrated in the described X-ray pattern, or may individually vary by a percentage as high as 4% above the value illustrated in the described X-ray pattern. In some embodiments, the phase “essentially the same” means that the X-ray line angles of an X-ray pattern may individually vary by a percentage as low as 3% below the value illustrated in the described X-ray pattern, or may individually vary by a percentage as high as 3% above the value illustrated in the described X-ray pattern. In some embodiments, the phase “essentially the same” means that the X-ray line angles of an X-ray pattern may individually vary by a percentage as low as 2% below the value illustrated in the described X-ray pattern, or may individually vary by a percentage as high as 2% above the value illustrated in the described X-ray pattern. In some embodiments, the phase “essentially the same” means that the X-ray line angles of an X-ray pattern may individually vary by a percentage as low as 1% below the value illustrated in the described X-ray pattern, or may individually vary by a percentage as high as 1% above the value illustrated in the described X-ray pattern.

[0084] A. Crystalline Form X of Compound 129

[0085] In one embodiment, a crystalline hydrochloride salt of 7-((2R,4S)-4-((2,3-dihydro benzo[Z>] [ 1 ,4]dioxin-6-yl-2,2,3 ,3 -d4)oxy)-2-methylpiperidin- 1 -yl)-8-methyl-4H-pyrimido[ 1 ,2-Z>] pyridazin-4-one (Compound 129) has a Form X which exhibits at least X-ray lines (in degrees 29 ± 0.2°) at the same or substantially the same angles of 6.69, 8.52, 10.29, 17.42, 20.64, 21.08, 26.22 and 29.52 in a powder diffraction pattern when measured using Cu Ka radiation. In one embodiment, a crystalline hydrochloride salt of 7-((2R,4S)-4-((2,3-dihydro benzo[Z>] [ 1 ,4]dioxin-6-yl-2,2,3 ,3 -d4)oxy)-2-methylpiperidin- 1 -yl)-8-methyl-4H-pyrimido[ 1 ,2-Z>] pyridazin-4-one (Compound 129) has a Form X which exhibits at least X-ray lines (in degrees 29 ± 0.2°) at the same or substantially the same angles of 6.71, 8.58, 10.21, 11.06, 17.42, 20.39, 20.84, 24.85, 29.25 and 30.50 in a powder diffraction pattern when measured using Cu Ka radiation.

[0086] In another embodiment, the powder diffraction pattern of the crystalline Form X exhibits at least X-ray lines (in degrees 29 ± 0.2) at the same or substantially the same angles of

[0087] 6.69, 8.52, 10.29, 17.42, 20.64, 21.08, 26.22 and 29.52, and at least one X-ray line selected from the group consisting of the same or substantially the same angles of 11.15, 14.67, 14.95, 20.90, 25.02, 26.46 and 30.76.

[0088] In another embodiment, the powder diffraction pattern of the crystalline Form X exhibits at least X-ray lines (in degrees 29 ± 0.2°) at the same or substantially the same angles of

[0089] 6.69, 8.52, 10.29, 17.42, 20.64, 21.08, 26.22 and 29.52, and at least two X-ray lines selected from the group consisting of the same or substantially the same angles of 11.15, 14.67, 14.95, 20.90, 25.02, 26.46 and 30.76.

[0090] In another embodiments, the powder diffraction pattern of the crystalline Form X exhibits at least X-ray lines (in degrees 29 ± 0.2°) at the same or substantially the same angles of

[0091] 6.69, 8.52, 10.29, 11.15, 14.67, 14.95, 17.42, 20.64, 20.90, 21.08, 25.02, 26.22, 26.46, 29.52 and

[0092] 30.76.

[0093] In another embodiment, the powder diffraction pattern of the crystalline Form X exhibits at least X-ray lines (in degrees 29 ± 0.2°) at the same or substantially the same angles of

[0094] 6.69, 8.52, 10.29, 11.15, 14.67, 14.95, 17.42, 20.64, 20.90, 21.08, 25.02, 26.22, 26.46, 29.52 and

[0095] 30.76, and at least one X-ray line selected from the group consisting of the same or substantially the same angles of 15.54, 16.40, 17.03, 17.93, 19.68, 20.90, 21.08, 22.59, 22.67, 23.71 and 26.12.

[0096] In another embodiment, the powder diffraction pattern of the crystalline Form X exhibits at least X-ray lines (in degrees 29 ± 0.2°) at the same or substantially the same angles of

[0097] 6.69, 8.52, 10.29, 11.15, 14.67, 14.95, 17.42, 20.64, 20.90, 21.08, 25.02, 26.22, 26.46, 29.52 and

[0098] 30.76, and at least two X-ray lines selected from the group consisting of the same or substantially the same angles of 15.54, 16.40, 17.03, 17.93, 19.68, 20.90, 21.08, 22.59, 22.67, 23.71 and 26.12.

[0099] In another embodiment, the powder diffraction pattern of the crystalline Form X exhibits at least X-ray lines (in degrees 29 ± 0.2) at the same or substantially the same angles of

[0100] 6.69, 8.52, 10.29, 11.15, 14.67, 14.95, 15.54, 16.40, 17.03, 17.42, 17.93, 19.68, 20.64, 20.90, 21.08, 22.59, 22.67, 23.71, 25.02, 26.12, 26.22, 26.46, 29.52 and 30.76.

[0101] In another embodiment, the powder diffraction pattern of the crystalline Form X exhibits at least X-ray lines (in degrees 29 ± 0.2) at the same or substantially the same angles of 6.69, 8.17, 8.52, 9.94, 10.29, 11.15, 13.35, 13.75, 14.67, 14.95, 15.54, 16.03, 16.40, 17.03, 17.42, 17.64, 17.93, 18.99, 19.34, 19.68, 19.92, 20.18, 20.64, 20.90, 21.08, 21.47, 21.62, 21.92, 22.59, 22.67, 23.06, 23.71, 24.43, 25.02, 25.38, 25.58, 26.12, 26.22, 26.46, 27.64, 28.15, 28.91, 29.52,

[0102] 29.78, 29.84, 30.01, 30.42, 30.76, 31.13, 31.33, 33.12, 33.26, 34.38, 36.10, 36.73, 37.55, 37.66 and 38.87.

[0103] In another embodiment, the powder diffraction pattern of the crystalline Form X exhibits the same or substantially the same X-ray line angles (in degrees 29 ± 0.2), the same or substantially the same D values, and the same or substantially the same relative intensities as shown in the following table:

[0104] In another embodiment, the powder diffraction pattern of the crystalline Form X exhibits an X-ray pattern essentially the same as that provided in Figure 48.

[0105] B. Pharmaceutical Compositions

[0106] Solid forms of the invention may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non-human). Solid forms of the invention may also be provided as formulations, such as spray-dried dispersion formulations.

[0107] The pharmaceutical compositions may include a “therapeutically effective amount” or a “ prophy lactically effective amount” of the agent. A “therapeutically effective amount” refers to an amount effective, at single or multiple dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of solid form (e.g., the crystalline Form X of Compound 129) are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount may be less than the therapeutically effective amount.

[0108] The pharmaceutical compositions may include pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier,” as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0109] Thus, solid forms of the invention may be formulated for administration by, for example, solid dosing, eye drop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration. Techniques and formulations may generally be found in "Remington's Pharmaceutical Sciences," (Meade Publishing Co., Easton, Pa.). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.

[0110] The route by which the solid forms of the invention are administered, and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g.., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis).

[0111] Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others commonly use in the art. All carriers are optional in the compositions.

[0112] Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90 weight% of the total composition weight.

[0113] Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10% of the total composition weight.

[0114] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition Is typically about 5 to about 50% of the total composition weight.

[0115] Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10% of the total composition weight.

[0116] Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a systemic or topical composition Is typically about 0.005 to about 0.1% of the total composition weight.

[0117] Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor (s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0% of the total composition weight.

[0118] Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s) in a systemic or topical composition is typically about 0.001 to about 1% of the total composition weight.

[0119] Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5% of the total composition weight.

[0120] Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0001 to about 5% of the total composition weight.

[0121] Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5% of the total composition weight.

[0122] Suitable solvents include water, isotonic saline, ethyl oleate, glycerine, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent(s) in a systemic or topical composition is typically from about Oto about 100% of the total composition weight.

[0123] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8% of the total composition weight.

[0124] Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington's Pharmaceutical Sciences, 22th Ed. 2013; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant(s) in the systemic or topical composition Is typically about 0.1% to about 5% of the total composition weight.

[0125] Although the amounts of components in systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01 to 50 weight% of the total composition weight of an solid form (e.g., the crystalline Form X of Compounds 129) and 50 to 99.99 weight % of the total composition weight of one or more carriers. Compositions for parenteral administration typically include 0.1 to 10 weight% of the total composition weight of actives and 90 to 99.9 weight% of the total composition weight of a carrier including a diluent and a solvent.

[0126] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5 weight% of the total composition weight, and more particularly from about 25 to about 50 weight% of the total composition weight of actives. The oral dosage compositions include about 50 to about 95 weight% of carriers of the total composition weight, and more particularly, from about 50 to about 75 weight% of the total composition weight.

[0127] Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof.

[0128] Capsules (including implants, time release and sustained release formulations) typically include a solid form (e.g., the crystalline Form X of Compound 129), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics, Implants can be of the biodegradable or the non-biodegradable type.

[0129] The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention.

[0130] Solid compositions may be coated by conventional methods, typically with pH or time-dependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes and shellac.

[0131] Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non- effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.

[0132] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.

[0133] Solid forms of the invention can be topically administered. Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions include: a solid form (e.g., the crystalline Form X of Compound 129), and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components.

[0134] The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modem Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0135] A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0136] The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.

[0137] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane- 1,2-diol, butane- 1,3 -diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin .. sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically about 5 to about 95 weight% of the total composition weight.

[0138] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically about 0 to about 95 weight% of the total composition weight.

[0139] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0 to about 95 weight% of the total composition weight.

[0140] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5- carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0 to 95 weight % of the total composition weight.

[0141] The amount of thickener(s) in a topical composition is typically about 0 to about 95 weight% of the total composition weight. Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0 to 95 weight% of the total composition weight.

[0142] The amount of fragrance in a topical composition is typically about 0 to about 0.5 weight%, particularly, about 0.001 to about 0.1 weight% of the total composition weight.

[0143] Suitable pH adjusting additives include HC1 or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition.

[0144] C. Methods of Use

[0145] Solid forms of the invention and pharmaceutical compositions may be used in methods for treatment of disorders, such as neurological and / or psychiatric disorders, associated with muscarinic acetylcholine receptor dysfunction. The solid forms of the invention and pharmaceutical compositions may also be used in methods for the potentiation of muscarinic acetylcholine receptor activity in patient, and in methods for enhancing cognition in a patient. The methods further include co-therapeutic methods for improving treatment outcomes in the context of cognitive or behavioral therapy. In the methods of use described herein, additional therapeutic agent(s) may be administered simultaneously or sequentially with the compounds of the invention and compositions.

[0146] 1. Treating Disorders

[0147] Solid forms of the invention, pharmaceutical compositions thereof and formulations thereof may be used in methods for treatment of disorders, such as neurological and / or psychiatric disorders, associated with muscarinic acetylcholine receptor dysfunction. The methods of treatment may comprise administering to a subject in need of such treatment a therapeutically effective amount of a solid form (e.g., the crystalline Form X of Compound 129), or a pharmaceutical composition comprising a therapeutically effective amount of the solid form (e.g., the crystalline Form X of Compound 129).

[0148] In some embodiments, the invention provides to a method for enhancing cognition in a patient comprising the step of administering to the patient a therapeutically effective amount of a solid form disclosed herein (e.g., the crystalline Form X of Compound 129), or a pharmaceutical composition comprising a therapeutically effective amount of a solid form disclosed herein (e.g., the crystalline Form X of Compound 129).

[0149] The solid forms of the invention and compositions thereof may be useful for treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders associated with selective mAChR M4 receptor activation. For example, a treatment can include selective mAChR M4 receptor activation to an extent effective to affect cholinergic activity. A disorder can be associated with cholinergic activity, for example cholinergic hypofunction. Thus, provided are methods of treating or preventing a disorder in a subject comprising the step of administering to the subject at least one solid form of the invention (e.g., the crystalline Form X of Compound 129) or at least one disclosed pharmaceutical composition, in an amount effective to treat the disorder in the subject.

[0150] Also provided is a method for the treatment of one or more disorders associated with mAChR M4 receptor activity in a subject comprising the step of administering to the subject a therapeutically effective amount of a solid form disclosed herein (e.g., the crystalline Form X of Compound 129), or a pharmaceutical composition comprising a therapeutically effective amount of the solid form.

[0151] In some embodiments, the invention provides a solid form (e.g., the crystalline Form X of Compound 129) for use in a method for the treatment of a disorder associated with the mAChR M4 receptor. In some embodiments, the invention provides a pharmaceutical composition comprising a solid form disclosed herein (e.g., the crystalline Form X of Compound 129) for use in a method for the treatment of a disorder associated with the mAChR M4 receptor.

[0152] In some embodiments, the invention provides a solid form disclosed herein (e.g., the crystalline Form X of Compound 129) for use in the manufacture of a medicament for the treatment of a disorder associated with the mAChR M4 receptor.

[0153] In some embodiments, the invention provides a method for the treatment of a disorder associated with muscarinic acetylcholine receptor dysfunction in a patient, comprising the step of administering to the patient an effective amount of at least one solid form disclosed herein (e.g., the crystalline Form X of Compound 129), or a pharmaceutical composition comprising at least one solid form disclosed herein (e.g., the crystalline Form X of Compound 129).

[0154] In some embodiments, the solid form of the invention and compositions thereof have utility in treating a variety of neurological, psychiatric and cognitive disorders associated with the mAChR M4 receptor, including one or more of the following conditions or diseases: schizophrenia, psychotic disorder NOS, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, shared psychotic disorder, catastrophic schizophrenia, postpartum psychosis, psychotic depression, psychotic break, tardive psychosis, myxedematous psychosis, occupational psychosis, menstrual psychosis, secondary psychotic disorder, bipolar I disorder with psychotic features, and substance-induced psychotic disorder.

[0155] In some embodiments, the psychotic disorder is a psychosis associated with an illness selected from major depressive disorder, affective disorder, bipolar disorder, electrolyte disorder, Alzheimer's disease, neurological disorder, hypoglycemia, AIDS, lupus, and post- traumatic stress disorder.

[0156] In some embodiments, the disorder is schizophrenia. In some embodiments, the disorder is psychotic depression. In some embodiments, the disorder is agitation and psychosis in Alzheimer's disease. In some embodiment, the disorder is a bipolar disorder.

[0157] In some embodiments, the disorder is a neurological disorder is selected from brain tumor, dementia with Lewy bodies, multiple sclerosis, sarcoidosis, Lyme disease, syphilis, Alzheimer's disease, Parkinson's disease, and anti-NMDA receptor encephalitis.

[0158] In some embodiments, the disorder is a psychotic disorder is selected from schizophrenia, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, and shared psychotic disorder. In some embodiments, the schizophrenia is selected from catastrophic schizophrenia, catatonic schizophrenia, paranoid schizophrenia, residual schizophrenia, disorganized schizophrenia, and undifferentiated schizophrenia. In some embodiments, the disorder is selected from schizoid personality disorder, schizotypal personality disorder, and paranoid personality disorder. In some embodiments, the psychotic disorder is due to a general medical condition and is substance induced or drug induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants, and cocaine).

[0159] In some embodiments, the present invention provides a method for treating a neurodevelopmental disorder, comprising administering to a patient in need thereof an effective amount of a solid form disclosed herein (e.g., the crystalline Form X of Compound 129), or a pharmaceutical composition thereof. In some embodiments, the neurodevelopmental disorder is fragile X syndrome.

[0160] In some embodiments, the present invention provides a method for treating a cognitive disorder, comprising administering to a patient in need thereof an effective amount of a solid form disclosed herein (e.g., the crystalline Form X of Compound 129), or a pharmaceutical composition thereof. In some embodiments, cognitive disorders include dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse), delirium, amnestic disorder, substance-induced persisting delirium, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, Parkinsonian-ALS dementia I complex, dementia of the Alzheimer's type, age-related cognitive decline, and mild cognitive impairment. In some embodiments, the cognitive disorder is Huntington's disease.

[0161] The text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes cognitive disorders including dementia, delirium, amnestic disorders and age-related cognitive decline. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (2013, American Psychiatric Association, Washington DC) provides a diagnostic tool for neurocognitive disorders (NCDs) that include delirium, followed by the syndromes of major NCD, mild NCD, and their etiological subtypes. The major or mild NCD subtypes include NCD due to Alzheimer's disease, vascular NCD, NCD with Lewy bodies, NCD due to Parkinson's disease, frontotemporal NCD, NCD due to traumatic brain injury, NCD due to HIV infection, substance / medication-induced NCD, NCD due to Huntington's disease, NCD due to prion disease, NCD due to another medical condition, NCD due to multiple etiologies, and unspecified NCD. The NCD category in DSM-S encompasses the group of disorders in which the primary clinical deficit is in cognitive function, and that are acquired rather than developmental. As used herein, the term “cognitive disorders” includes treatment of those cognitive disorders and neurocognitive disorders as described in DSM-IV-TR or DSM-5. The skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for mental disorders, and that these systems evolve with medical and scientific progress. Thus the term “cognitive disorders” is intended to include like disorders that are described in other diagnostic sources.

[0162] In some embodiments, the present invention provides a method for treating sleep disorder, comprising administering to a patient in need thereof an effective amount of a solid form disclosed herein (e.g., the crystalline Form X of Compound 129), or a pharmaceutical composition thereof.

[0163] In some embodiments, the sleep disorder is associated with sleep disturbance in a patient having schizophrenia.

[0164] In some embodiments, the present invention provides a method for treating schizophrenia or psychosis, comprising administering to a patient in need thereof an effective amount of a solid form disclosed herein (e.g., the crystalline Form X of Compound 129), or a pharmaceutical composition thereof. Particular schizophrenia or psychosis pathologies are paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorder. DSM-IV-TR provides a diagnostic tool that includes paranoid, disorganized, catatonic, undifferentiated or residual schizophrenia, and substance-induced psychotic disorder. DSM-5 eliminated the subtypes of schizophrenia, and instead includes a dimensional approach to rating severity for the core symptoms of schizophrenia, to capture the heterogeneity in symptom type and severity expressed across individuals with psychotic disorders. As used herein, the term “schizophrenia or psychosis” includes treatment of those mental disorders as described in DSM- IV-TR or DSM-5. The skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for mental disorders, and that these systems evolve with medical and scientific progress. Thus, the term “schizophrenia or psychosis” is intended to include like disorders that are described in other diagnostic sources.

[0165] In some embodiments, the present invention provides a method for treating pain, comprising administering to a patient in need thereof a therapeutically effective amount of a solid form disclosed herein (e.g., the crystalline Form X of Compound 129), or a pharmaceutical composition thereof. Particular pain embodiments are bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological}, chronic pain and neuropathic pain.

[0166] The solid form and compositions disclosed herein may be further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The solid forms disclosed herein (e.g., the crystalline Form X of Compound 129) and pharmaceutical composition thereof may be further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions, in combination with other agents.

[0167] In the treatment of conditions which require activation of mAChR M4, an appropriate dosage level may be about 0.001 mg / kg to about 100 mg / kg patient body weight per day, which can be administered in single or multiple doses. In particular, daily dosages may be in the range of 0.01 mg / kg body weight to about 50 mg / kg body weight per day. The dosage level may be about 0.1 to about 30 mg / kg per day, or more particular about 1 to about 10 mg / kg per day. A suitable dosage level can be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range, the dosage can be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg per day. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The solid forms can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosage regimen can be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[0168] Thus, in some embodiments, the present invention relates to a method for activating mAChR M4 receptor activity in at least one cell, comprising the step of contacting the at least one cell with at least one solid form disclosed herein (e.g., the crystalline Form X of Compound 129) or pharmaceutical composition thereof in an amount effective to activate mAChR M4 in the at least one cell. In some embodiments, the cell is mammalian, for example, human. In some embodiments, the cell has been isolated from a subject prior to the contacting step. In some embodiments, contacting Is via administration to a subject.

[0169] In some embodiments, the invention relates to a method for activating mAChR M4 activity in a subject, comprising the step of administering to the subject at least one solid form disclosed herein (e.g., the crystalline Form X of Compound 129) or a pharmaceutical composition thereof in a dosage and amount effective to activating mAChR M4 activity in the subject. In some embodiments, the subject is patient. In some embodiments, the patient has been diagnosed with a need for mAChR M4 agonism prior to the administering step. In some embodiments, the patient has been diagnosed with a need for mAChR M4 activation prior to the administering step. In some embodiments, the method further comprises the step of identifying a subject in need of mAChR M4 agonism.

[0170] In some embodiments, the invention relates to a method for the treatment of a disorder associated with selective mAChR M4 activation, for example, a disorder associated with cholinergic activity, in a patient comprising the step of administering to the patient at least one solid form disclosed herein (e.g., the crystalline Form X of Compound 129) or pharmaceutical composition thereof in a dosage and amount effective to treat the disorder in the patient. In some embodiments, the patient is a human. In some embodiments, the patient has been diagnosed with a need for treatment for the disorder prior to the administering step. In some embodiments, the method further comprises the step of identifying a subject in need of treatment for the disorder.

[0171] In some embodiments, the disorder can be selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, autistic disorder, movement disorders, Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia, drug induced and neurodegeneration based dyskinesias, attention deficit hyperactivity disorder, obsessive-compulsive disorder, cognitive disorders, dementias, and memory disorders.

[0172] In some embodiments, the disorder is Alzheimer's disease. In some embodiments, the disorder is Tourette's syndrome. In some embodiments, the disorder is tardive dyskinesia. In some embodiments, the disorder is obsessive-compulsive disorder. In some embodiments, the disorder is bipolar disorder.

[0173] 2. Modulating Muscarinic Acetylcholine Receptor Activity

[0174] In some embodiments, the invention relates to a method for potentiation of muscarinic acetylcholine receptor activity in a patient comprising the step of administering to the patient an effective amount of at least one solid form disclosed herein (e.g., the crystalline Form X of Compound 129) or a pharmaceutical composition thereof.

[0175] In some embodiments, the invention provides a solid form disclosed herein (e.g., the crystalline Form X of Compound 129), for use in a method for the potentiation of muscarinic acetylcholine receptor activity in patient. In some embodiments, the invention provides a pharmaceutical composition comprising a solid form disclosed herein (e.g., the crystalline Form X of Compound 129), for use in a method for the potentiation of muscarinic acetylcholine receptor activity in a patient.

[0176] In some embodiments, the invention provides a solid form disclosed herein (e.g., the crystalline Form X of Compound 129), for use in the manufacture of a medicament for the potentiation of muscarinic acetylcholine receptor activity in a patient.

[0177] In some embodiments, potentiation of muscarinic acetylcholine receptor activity increases muscarinic acetylcholine receptor activity. In some embodiments, potentiation of muscarinic acetylcholine receptor activity is partial agonism of the muscarinic acetylcholine receptor. In some embodiments, potentiation of muscarinic acetylcholine receptor activity is positive allosteric modulation of the muscarinic acetylcholine receptor.

[0178] In some embodiments, potentiation of muscarinic acetylcholine receptor activity in a patient is associated with the treatment of a neurological and / or psychiatric disorder associated with a muscarinic receptor dysfunction, such as a neurological or psychiatric disorder disclosed herein. In some embodiments, the muscarinic receptor is mAChR M4.

[0179] 3. Enhancing Cognition

[0180] In some embodiments, the invention relates to a method for enhancing cognition in a patient comprising the step of administering to the patient an effective amount of least one solid form disclosed herein (e.g., the crystalline Form X of Compound 129).

[0181] In some embodiments, the invention provides a solid form disclosed herein (e.g., the crystalline Form X of Compound 129), for use in a method for the enhancement of cognition in a patient. In some embodiments, the invention provides a pharmaceutical composition comprising a solid form disclosed herein (e.g., the crystalline Form X of Compound 129) for use in a method for the enhancement of cognition in a patient.

[0182] In some embodiments, the invention provides a solid form disclosed herein (e.g., the crystalline Form X of Compound 129) for use in the manufacture of a medicament for the enhancement of cognition in a patient.

[0183] In some embodiments, the patient has been diagnosed with a need for cognition enhancement prior to the administering step. In some embodiments, the method further comprises the step of identifying a patient in need of cognition enhancement. In some embodiments, the need for cognition enhancement is associated with a muscarinic receptor dysfunction. In some embodiments, the muscarinic receptor is mAChR M4.

[0184] Cognitive deficits or cognitive impairment include a decline in cognitive functions or cognitive domains, e.g., working memory, attention and vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving, e.g., executive function, speed of processing and / or social cognition. In particular, cognitive deficits or cognitive impairment may indicate deficits in attention, disorganized thinking, slow thinking, difficulty in understanding, poor concentration, impairment of problem solving, poor memory, difficulties in expressing thoughts and / or difficulties in integrating thoughts, feelings and behavior, or difficulties in extinction of irrelevant thoughts. The terms “cognitive deficits” and “cognitive impairment” are intended to indicate the same and are used interchangeably.

[0185] Cognitive functions are, as mentioned above, often impaired in schizophrenic patients. Studies have also concluded that cognitive functioning is associated with vocational functioning in schizophrenia (Scizophrenia Res., 4.5, 17.5-184, 2000). In one embodiment, the patient to be treated for cognitive impairment is schizophrenic.

[0186] The skilled person is familiar with various test for measuring the enhancement of cognition. Examples of test for measuring the enhancement of cognition are but not limited to the Novel Object Recognition and the Wisconsin Card Sorting Test.

[0187] 4. Co-Therapeutic Methods

[0188] The present invention is further directed to administration of a selective mAChR M4 activator for improving treatment outcomes in the context of cognitive or behavioral therapy. That is, in some embodiments, the invention relates to a co-therapeutlc method comprising a step of administering to a patient an effective amount and dosage of a solid form disclosed herein (e.g., the crystalline Form X of Compound 129).

[0189] In some embodiments, the invention provides a solid form disclosed herein (e.g., the crystalline Form X of Compound 129) for use in a co-therapeutic method with cognitive or behavioral therapy in a patient. In some embodiments, the invention provides a pharmaceutical composition comprising solid form disclosed herein (e.g., the crystalline Form X of Compound 129) for use in a co-therapeutic method with cognitive or behavioral therapy in a patient.

[0190] In some embodiments, the invention provides a solid form disclosed herein (e.g., the crystalline Form X of Compound 129) for use in the manufacture of a medicament for a co- therapeutic method with cognitive or behavioral therapy in a patient.

[0191] In some embodiments, administration improves treatment outcomes in the context of cognitive or behavioral therapy. Administration in connection with cognitive or behavioral therapy can be continuous or intermittent. Administration need not be simultaneous with therapy and can be before, during, and / or after therapy. For example, cognitive or behavioral therapy can be provided within 1, 2, 3, 4, 5, 6, 7 days before or after administration of the compound. As a further example, cognitive or behavioral therapy can be provided within 1, 2, 3, or 4 weeks before or after administration of the compound. As a still further example, cognitive or behavioral therapy can be provided before or after administration within a period of time of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 half-lives of the administered solid form.

[0192] It is understood that the disclosed co-therapeutic methods can be used in connection with the compounds of the inventions, compositions, kits, and uses.

[0193] 5. Combination Therapies

[0194] In the methods of use described herein, additional therapeutic agent(s) may be administered simultaneously or sequentially with solid forms disclosed herein (e.g., the crystalline Form X of Compound 129) and pharmaceutical compositions thereof. Sequential administration includes administration before or after the solid forms of the invention and compositions thereof. In some embodiments, the additional therapeutic agent or agents may be administered in the same composition as the compounds of the invention. In other embodiments, there may be an interval of time between administration of the additional therapeutic agent and the solid form. In some embodiments, administration of an additional therapeutic agent with a solid form disclosed herein (e.g., the crystalline Form X of Compound 129) may allow lower doses of the other therapeutic agents and / or administration at less frequent intervals. When used in combination with one or more other active ingredients, the solid forms disclosed herein (e.g., the crystalline Form X of Compound 129) and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to solid forms disclosed herein (e.g., the crystalline Form X of Compound 129) and pharmaceutical compositions thereof. The above combinations include combinations of a solid form disclosed herein (e.g., the crystalline Form X of Compound 129) not only with one other active compound, but also with two or more other active compounds.

[0195] The solid forms disclosed herein (e.g., the crystalline Form X of Compound 129) of the invention can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of the aforementioned diseases, disorders and conditions for which the compound or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone. The other drug(s) can be administered by a route and in an amount commonly used therefore, contemporaneously or sequentially with a solid form disclosed herein (e.g., the crystalline Form X of Compound 129). When a solid form disclosed herein (e.g., the crystalline Form X of Compound 129) is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the solid form may be used. However, the combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and a solid form disclosed herein (e.g., the crystalline Form X of Compound 129) may be more efficacious than either independently as a single agent. Thus, when used in combination with one or more other active ingredients, the solid form disclosed herein (e.g., the crystalline Form X of Compound 129) and the other active ingredients may be used in lower doses than when each is used singly.

[0196] The pharmaceutical compositions and methods of the present invention can further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above-mentioned pathological conditions.

[0197] The above combinations include combinations of solid forms disclosed herein (e.g., the crystalline Form X of Compound 129) not only with one other active compound, but also with two or more other active compounds. Likewise, solid forms disclosed herein can be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the invention are useful. Such other drugs can be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a solid form of the present invention. Hence, in an embodiment, the pharmaceutical compositions contain one or more other active ingredients, in addition to a solid form disclosed herein (e.g., the crystalline Form X of Compound 129).

[0198] The weight ratio of a solid form disclosed herein (e.g., the crystalline Form X of Compound 129) to the second active ingredient can be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a solid form disclosed herein (e.g., the crystalline Form X of Compound 129) is combined with another agent, the weight ratio of the solid form to the other agent will generally range from 200: 1 to about 1 :200. Combinations of a solid form disclosed herein and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

[0199] In such combinations a solid form disclosed herein (e.g., the crystalline Form X of Compound 129) and other active agents can be administered separately or in conjunction. In addition, the administration of one element can be prior to, concurrent to, or subsequent to the administration of other agent(s).

[0200] Accordingly, the solid forms disclosed herein (e.g., the crystalline Form X of Compound 129) can be used alone or in combination with other agents which are known to be beneficial in the subject indications or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects of the compounds of the invention. The solid forms disclosed herein and the other agent can be co-administered, either in concomitant therapy or in a fixed combination.

[0201] In some embodiments, the solid forms disclosed herein (e.g., the crystalline Form X of Compound 129) und can be employed in combination anti-Alzheimer's agents, beta-secretase inhibitors, cholinergic agents, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, Ml allosteric agonists, Ml positive allosteric modulators, NSAIDs including ibuprofen, vitamin E, and anti-amyloid antibodies. In another embodiment, solid forms disclosed herein (e.g., the crystalline Form X of Compound 129) can be employed in combination with sedatives, hypnotics, anxiolytics, antipsychotics (typical and atypical), antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, brexpiprazole, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, clorethate, chlorpromazine, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, donepezil, memantine, galantamine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, zuflupentixol, flupentixol, fluphenazine, flurazepam, fluvoxarnine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone, roletamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, thiothixene, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimlpramine, uldazepam, zaleplon, zlprasldone, zolazepam, zolpidem, and salts thereof, and combinations thereof, and the like, or a solid form disclosed herein (e.g., the crystalline Form X of Compound 129) can be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.

[0202] In some embodiments, the solid forms disclosed herein (e.g., the crystalline Form X of Compound 129) can be employed in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors such as azilect, antioxidants, A2a adenosine receptor antagonists such as istradefylline, cholinergic agonists, NMD A receptor antagonists such as ketamine, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole. It will be appreciated that the dopamine agonist can be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate. Lisuride and pramipexol are commonly used in a non-salt form.

[0203] In some embodiments, the solid forms disclosed herein (e.g., the crystalline Form X of Compound 129) can be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indoIone classes of neuroleptic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indoIone is molindolone. Other neuroleptic agents include loxapine, sulpiride and risperidone. It will be appreciated that the neuroleptic agents when used in combination with a solid form disclosed herein (e.g., the crystalline Form X of Compound 129) can be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form. Thus, a solid form disclosed herein (e.g., the crystalline Form X of Compound 129) can be employed in combination with acetophenazine, alentemol, amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, deutetrabenazine, trihexyphenidyl, thioridazine, thiothixene, trifluoperazine, or ziprasidone.

[0204] In some embodiments, the solid forms disclosed herein (e.g., the crystalline Form X of Compound 129) can be employed in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRls), monoamine oxidase inhibitors (MAOls), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRls), corticotropin releasing factor (CRF) antagonists, a- adrenoreceptor antagonists, neurokinin- 1 receptor antagonists, atypical anti-depressants, benzodiazepines, 5-HT1A agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists. Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, vortioxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, escitalopram, tranylcypromine and selegiline; moclobemide: venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.

[0205] In some embodiments, the solid forms disclosed herein (e.g., the crystalline Form X of Compound 129) can be co-administered with orthosteric muscarinic agonists, muscarinic potentiators, or cholinesterase inhibitors. In some embodiments, the compounds can be coadministered with GlyTl inhibitors and the like such as, but not limited to: risperidone, quetiapine, clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbitol, and salts thereof and combinations thereof.

[0206] 6. Modes of Administration

[0207] Methods of treatment may include any number of modes of administering a solid form disclosed herein (e.g., the crystalline Form X of Compound 129) or pharmaceutical composition thereof. Modes of administration may include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in- water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders. For the preparation of pharmaceutical compositions for oral administration, the solid form may be admixed with commonly known and used adjuvants and excipients such as for example, gum arable, talcum, starch, sugars (such as, e.g., mannitose, methyl cellulose, lactose), gelatin, surface-active agents, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, crosslinking agents, dispersants, emulsifiers, lubricants, conserving agents, flavoring agents (e.g., ethereal oils), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol} or bioavailability enhancers (e.g., Gelucire.TM.). In pharmaceutical composition, the solid form may also be dispersed in a microparticle, e.g., a nanoparticulate composition.

[0208] For parenteral administration, solid forms disclosed herein (e.g., the crystalline Form X of Compound 129) can be dissolved or suspended in a physiologically acceptable diluent, such as, e.g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers. As oils, for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used. More generally, for parenteral administration, the solid form can be in the form of an aqueous, lipid, oily or other kind of solution or suspension or even administered in the form of liposomes or nano-suspensions.

[0209] The term “parenterally,” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

[0210] The solid forms and processes of the invention will be better understood by reference to the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.

[0211] EXAMPLES

[0212] The invention is further illustrated by the following examples. The examples below are non-limiting and are merely representative of various aspects of the invention.

[0213] Abbreviations used in the examples and reaction schemes that follow include the following: AB PR is automatic back-pressure regulator, ACN is acetylnitrile, DCE is 1,2- di chloroethane, BSM is binary solvent management, CH-A is column heater with active preheating, DCM is dichloromethane, DMSO is dimethyl sulfoxide, Dowtherm A is a eutectic mixture of 26.5% diphenyl + 73.5% diphenyl oxide, EtOH is ethanol, EtOAc is ethyl acetate, IPA is isopropyl alcohol, MeCN is acetylnitrile, MeOH is methanol, MTBE is methyl tert-butyl ether, PDA is photodiode array detector, PPhs is triphenylphosphine, RH is relative humidity, RT is room temperature, SM-FL is sample manage with a fixed loop, THF is tetrahydrofuran, TFA is trifluoroacetic acid.

[0214] NMR Analyses: All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer a 400 MHz Bruker Avance AV-III-400 spectrometer or a Varian MR400 spectrometer. 'H chemical shifts are reported in 5 values in ppm. Data are reported as follows: chemical shift, multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, ABq = AB quartet), coupling constant, integration.

[0215] “Method A” LCMS Analyses: Reverse-phase LCMS (liquid chromatography mass spectrometry) analyses under Method A were performed using an Agilent 1200 system comprised of a binary pump with degasser, high-performance autosampler, thermostatted column compartment, C18 column, diode-array detector (DAD) and an Agilent 6150 MSD with the following parameters. The gradient conditions were 5% to 95% acetonitrile with the aqueous phase 0.1% TFA In water over 1.4 minutes, hold at 95% acetonitrile for 0.1 min, 0.5 ml / min, 55 °C (“90 sec method”). Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 pm, 1.0 x 50 mm) at 0.5 ml / min, with column and solvent temperatures maintained at 55 °C. The DAD was set to scan from 190 to 300 nm, and the signals used were 220 nm and 254 nm (both with a band width of 4nm). The MS detector was configured with an electrospray ionization source, and the low-resolution mass spectra were acquired by scanning from 140 to 700 AMU with a step size of 0.2 AMU at 0.13 cycles / second, and peak width of 0.008 minutes. The drying gas flow was set to 13 liters per minute at 300 °C and the nebulizer pressure was set to 30 psi. The capillary needle voltage was set at 3000 V, and the fragmentor voltage was set at 100V. Data acquisition was performed with Agilent Chemstation and Analytical Studio Reviewer software.

[0216] “Method B” HPLC analyses: HPLC (high pressure liquid chromatography) analyses under Method B were performed using the conditions summarized in Table 1 and 2.

[0217] Table 1

[0218] (HPLC Method B: General Conditions) Table 2

[0219] (HPLC Method B: Mobile Phase Gradient)

[0220] “Method C” IPC Analyses: IPC (ion pair chromatography) analyses under Method C were performed using the conditions summarized in Table 3 and 4.

[0221] Table 3

[0222] (IPC HPLC Method: General Conditions)

[0223] Table 4

[0224] (IPC HPLC Method: Gradient Conditions) EXAMPLE 1-1

[0225] Preparation of 7-((2R,4S)-4-((2,3-Dihydrobenzo[ / >][l,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2- methylpiperidin-l-yl)-8-methyl-4H-pyrimido[l,2- / >]pyridazin-4-one (Compound 129) a. Preparation of 5-(((6-Chloro-5-methylpyridazin-3-yl)amino)methylene)-2,2- dimethyl-L3-dioxane-4,6-dione (Intermediate A)

[0226] To a solution of 6-chloro-5-methylpyridazin-3-amine (1 g) in ethanol (12 ml) were added triethyl orthoformate (1.16 ml) and isopropylidene malonate (1.04 g) at ambient temperature. The mixture was then heated to 60 °C for 18 hours. The mixture was filtered and the cake was washed with ethanol (0.5 ml x 3) to afford the intermediate 5-[[(6-chloro-5-methyl- pyridazin-3-yl)amino]methylene]-2,2-dimethyl-l,3-dioxane-4, 6-dione (Intermediate A) (1.59 g, 77% yield). ES-MS (Method A) [M+H]+: 298.2 b. Prep of 7-Chloro-8-methyl-4H-pyrimidolL2-b1pyridazin-4-one (Intermediate B)

[0227] A solution of 5-[[(6-chloro-5-methyl-pyridazin-3-yl)amino]methylene]-2,2- dimethyl-l,3-dioxane-4, 6-dione (Intermediate A) (1.59 g) in Dowtherm A (8 ml) was stirred at 220 °C for 1 hour. After cooling, the mixture was added to water and acidified using IM HC1. The aqueous layer was extracted with hexanes (3 x 125 ml) to remove Dowtherm A. The aqueous layer was neutralized with aq. NaHCCh and the mixture was extracted with chloroform / IPA (4: 1) (3x). The combined organic layers were dried over magnesium sulfate, concentrated to give the Intermediate B (908 mg, 67% yield). 'H NMR (400 MHz, DMSO) 5 8.23 (d, J= 6.5 Hz, 1H), 8.03 (q, J= 1.3 Hz, 1H), 6.54 (d, J= 6.4 Hz, 1H), 2.44 (d, J= 1.3 Hz, 3H). ES-MS (Method A) [M+l]+: 196. c. Prep of 2,2,3, 3-Tetradeuterio-l,4-benzodioxine-6-carbaklehyde (Intermediate AG)

[0228] In a 500 ml round bottom flask were combined 3,4-dihydroxybenzaldehyde (21.3 g), l,2-dibromoethane-D4 (14.1ml), and potassium carbonate (65.0g) in acetone (515ml). The reaction was heated to reflux for 18 h. The reaction was diluted with EtOAc, filtered through celite, and the filtrate was concentrated in vacuo. The crude sample was purified by flash chromatography on silica gel (0-40% EtOAc / Hexanes) to afford the title compound (15.4 g).JH NMR (400 MHz, CDCh) 3 9.82 (s, 1H), 7.41-7.38 (m, 2H), 6.97 (d, J= 8.8 Hz, 1H). ES-MS (Method A) [M+l]+: 169. d. Preparation of 2,2,3, 3-Tetradeuterio-l,4-benzodioxin-6-ol (Intermediate AH)

[0229] Step 1 : To a solution of 2,2,3,3-tetradeuterio-l,4-benzodioxine-6-carbaldehyde (15.4 g) in DCE (250 ml) was added 3 -chloroperoxybenzoic acid (47.6 g, <77% CAS#937-14-4; Sigma- Aldrich). The reaction mixture was heated to 50 °C for 18 h. The reaction was diluted with DCM and saturated NaHCCh solution. The layers were separated. The aqueous layer was extracted with DCM (2 x) and the combined organic layers were washed with brine, dried (MgSCh), filtered, and concentrated to afford 2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl-2,2,3,3-d4 formate (15.1 g). ESMS (Method A) [M+l]+185.

[0230] Step 2: 2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl-2,2,3,3-d4 formate (15.1 g) was dissolved in methanol (250 ml) and potassium carbonate (15.5 g) was added. After 3 h, the solvent was removed and water / DCM (1 : 1) were added. The aqueous layer was slowly acidified by dropwise addition of 6 N aqueous HC1 to pH < 4. The layers were separated, and the aqueous layer was extracted with DCM (2 x) and the combined organic layers were washed with brine, dried (MgSCh), filtered, and concentrated. The filtrate was purified by flash chromatography on silica gel (0-40% EtOAc / Hexanes). The desired fractions were concentrated and co-evaporated (2 x with toluene) to afford the title compound (12.3 g). 'H NMR (400 MHz, CDCh) 3 6.72 (d, J= 8.8 Hz, 1H), 6.39 (d, J = 2.9 Hz, 1H), 6.34-6.31 (dd, J= 8.7, 2.9 Hz, 1H), 4.64 (s, 1H). ES-MS (Method A) [M+l]+: 157. e. Preparation of tert-butyl (2R,4S)-4-((2,3-DihvdrobenzolZ>irL41dioxin-6-yl-2,2,3,3- d4)oxy)-2-methylpiperidine-l -carboxylate (Intermediate BO)

[0231] To a mixture of 2,3-dihydrobenzo[Z>][l,4]dioxin-2,2,3,3-d4-6-ol (5 g, 32.02 mmol), (2R,4R)-tert-butyl 4-hydroxy-2-methylpiperidine-l -carboxylate (6.89 g) and PPhs (10.93 g) in THF (100 ml) was added slowly DIAD (8.1 ml) at 20 °C and the reaction was stirred at 20 °C for 16 hours. The reaction was concentrated and the residue was purified by Combi Flash (silica gel, from 0 to 30%, ethyl acetate in petroleum ether) to give tert-butyl (2R,45)-4-((2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidine-l-carboxylate (3.7 g). 'H NMR (400MHz, CDCh) 5 6.77 (d, J= 8.8 Hz, 1H), 6.46 (s, 1H), 6.42 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 4.61 - 4.46 (m, 1H), 4.41 - 4.31 (m, 1H), 4.13 - 4.06 (m, 1H), 2.96 - 2.89 (m, 1H), 2.14 - 2.04 (m, 1H), 2.01 - 1.90 (m, 1H), 1.74-1.64 (m, 1H), 1.52-1.42 (s, 10H), 1.19 (d, J= 7.2 Hz, 3H). f. Preparation of (2R,4S)-4-((2,3-DihydrobenzolZ>iri,41dioxin-6-yl-2,2,3,3-d4)oxy)- 2-methylpiperidine (Intermediate BP)

[0232] 8P

[0233] To a solution of tert-butyl (2R,4S)-4-((2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl- 2,2,3,3-d4)oxy)-2-methylpiperidine-l-carboxylate (3.7 g) in DCM (20 ml) was added TFA (4 mL) and the reaction was stirred at 20 °C for 3 hours. The reaction was quenched with sat. aq. Na2COs to pH 8~9 at 0 °C and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (20 ml), dried over Na2SO4 and concentrated to give (2R,4S)-4-((2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidine (2.6 g, crude). ES-MS (Method A) [M+l]+: 254.2. g. Preparation of 7-((2R,4S)-4-((2,3-DihvdrobenzolbirL41dioxin-6-yl-2,2,3,3- d4)oxy)-2-methylpiperid in- 1 -yl)-8-methyl-4H-pyrimidol 1 ,2-b1pyridazin-4-one To a solution of 7-chloro-8-methyl-4J / -pyrimido[l,2-Z>]pyridazin-4-one (3.91 g), (2A,45)-4-((2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl-2,2,3,3-t / 4)oxy)-2-methylpiperidine (3.9 g) in DMSO (70 mL) was added CsF (2.82 g) and DIEA (5.36 mL). The reaction was heated to 80°C for 18 hours. The mixture was diluted with H2O (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over MgSCh, filtered and concentrated. The residue was purified by Combi Flash (silica gel, from 0 to 4%, MeOH / DCM). The resulting solid was re-purified by reverse-phase ISCO (10-60% MeCN / water / 0.05%NH40H) to give 7-((2A,45)-4-((2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl-2,2,3,3- t / 4)oxy)-2-methylpiperidin-l-yl)-8-methyl-4J / -pyrimido[l,2-Z>]pyridazin-4-one as an amorphous solid. ‘H NMR (400MHz, CDCh) 5 8.10 (d, J=6.4 Hz, 1H), 7.50 (d, J= 1.2 Hz, 1H), 6.77 (d, J= 8.8 Hz, 1H), 6.53 (d, J= 6.4 Hz, 1H), 6.48 (d, J = 2.8 Hz, 1H), 6.44 (d, J = 8.8 Hz, 2.8 Hz, 1H), 4.56 - 4.48 (m, 1H), 4.18 - 4.11 (m, 1H), 3.61 - 3.55 (m, 1H), 3.39 - 3.32 (m, 1H), 2.44 (s, 3H), 2.21 - 2.12 (m, 1H), 2.07 - 1.97 (m, 2H), 1.93 - 1.84 (m, 1H), 1.27 (d, J = 6.8 Hz, 3H). ES-MS (Method A) [M+l]+: 413.0.

[0234] Compound 129 was found to have a purity of > 98% by the following LCMS method. Low-resolution mass spectra were obtained on a Waters QDa (Performance) SQ MS with ESI source. MS parameters were as follows: cone voltage: 15 V, capillary voltage: 0.8 kV, probe temperature: 600° C. Samples were introduced via an Acquity I-Class PLUS UPLC comprised of a BSM, FL-SM, CH- A, and PDA. UV absorption was generally observed at 215 nm and 254 nm; 4 nm bandwidth. Column: Phenomenex EVO C18, 1.0 x 50 mm, 1.7 um. Column temperature: 55° C. Flow rate: 0.4 mL / min. Gradient: 5% to 95% CH3CN (0.05% TFA) in H2O (0.05% TFA) over 1.4 min (curve 6), hold at 95% CH3CN for 0.1 min.

[0235] EXAMPLE 1-2

[0236] Preparation of 7-((2R,4S)-4-((2,3-Dihydrobenzo[ / >][l,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2- methylpiperidin-l-yl)-8-methyl-4H-pyrimido[l,2- / >]pyridazin-4-one (Compound 129) a. Preparation of tert-butyl (2A,4A)-2-methyl-4-((methylsulfonyl)oxy)piperidine-l- carboxylate Tert-butyl (2R,4R)-4-hydroxy-2-methylpiperidine-l -carboxylate and dichloro methane are charged to the reactor and cooled to -5 ± 5 °C. A,7V-Diisopropylethylamine is added, followed by methanesulfonyl chloride while maintaining the temperature < 5 °C. The mixture is then stirred > 0.5 h, after which IM hydrochloric acid solution and water are added to the reaction and the aqueous layer is separated. The organic layer is washed with saturated sodium bicarbonate solution and water. The organic layer is slurried in heptane and stirred. The slurry is filtered, washed with heptane, and dried to provide tert-butyl (2A,4A)-2-methyl-4- ((m ethyl sulfonyl)oxy )piperi dine- 1 -carboxylate. b. Preparation of tert-butyl (2A,4M-4-((2,3-dihydrobenzolbirL41dioxin-6-yl-2,2,3,3- d4)oxy)-2-methylpiperidine- 1 -carboxylate

[0237] 2,3-dihydrobenzo[b][l,4]dioxin-2,2,3,3-d4-6-ol, tert-butyl (2R,4R)-2-methyl-4- ((methylsulfonyl)oxy)piperidine-l -carboxylate and cesium carbonate are stirred in 1,4-dioxane at 96 ± 5 °C for > 7 h, after which a second portion of tert-butyl (2R,4R)-2-methyl-4- ((methylsulfonyl)oxy)piperidine-l -carboxylate is added. The mixture is stirred an additional > 36 h, then sampled for reaction completion The reaction is cooled, filtered and washed with 1,4- dioxane. The filtrates are vacuum distilled, redissolved in ethyl acetate and washed with water. The organic layer is distilled, heptane is added, and the mixture is cooled and isolated. The mixture is filtered, washed with heptane and dried. The resulting oil is crystallized from cold heptane, filtered, washed with heptane and dried to afford tert-butyl (27?,45)-4-((2,3- dihydrobenzo[b][l,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiperidine-l-carboxylate. c. Preparation of (2A,4M-4-((2,3-dihydrobenzolbirL41dioxin-6-yl-2,2,3,3-d4)oxy)- 2-methylpiperidin-l-ium chloride tert-butyl-(2A,45)-4-((2,3-dihydrobenzo[b][l,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2- methylpiperidine-1 -carboxylate is stirred in 1,4-dioxane. 4M hydrogen chloride in dioxane is charged, and the mixture is heated to 55 ± 5 °C. After stirring > 5 h, the mixture is sampled for reaction completion. The mixture is then cooled, stirred, and filtered. The resultant solids are washed with 1,4-dioxane and dried to afford (27?,45)-4-((2,3-dihydrobenzo[b][l,4]dioxin-6-yl- 2,2,3,3-d4)oxy)-2-methylpiperidin-l-ium chloride. d. Preparation of 7-((2R,4S)-4-((2,3-DihvdrobenzolbirE41dioxin-6-yl-2,2,3,3- d4)oxy)-2-methylpiperid in-l-yl)-8-methyl-4H-pyrimidolE2-b1pyridazin-4-one (Compound 129)

[0238] (27?,45)-4-((2,3-dihydrobenzo[b][l,4]dioxin-6-yl-2,2,3,3-d4)oxy)-2-methylpiper idin-l-ium chloride, 7-chloro-8-methyl-4H-pyrimido[l,2-b]pyridazin-4-one, cesium fluoride, dimethyl sulfoxide and / f-diisopropylethylamine are stirred at 80 ± 5 °C for > 16 h, then sampled for reaction completion. The cooled mixture is diluted with dichloromethane and washed with water and saturated brine. The organic layer is distilled and added to a silica gel plug. The silica gel plug is eluted with dichloromethane:acetone (1 : 1), and the eluted fractions are distilled to give 7-((27?,45)-4-((2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl-2,2,3,3-t / 4)oxy)-2-methylpiperidin-l-yl)-8- methyl-4J / -pyrimido[l,2-Z>]pyridazin-4-one.

[0239] EXAMPLE 2

[0240] Solubility Screen of Compound 129 Free Base

[0241] Solid-state screening experiments were carried out on the free base of the Compound 129 prepared in Example 1-1. To determine optimal solvent systems for crystallization, solubility screens were carried out with common organic solvents and water. To ensure scalability for potential drug substance production, Class 3 organic solvents were primarily used. To carry out solubility screening, approximately 10 mg of Compound 129 free base was added to 4 ml glass vial. Solvents were added in 100 ml increments to visually determine miscibility. The results shown in Table 5 indicate >30mg / ml solubility in many organic solvents, including MeOH, acetone, ACN, DCM and toluene, with poor aqueous solubility and minimal solubility in typical antisolvents such as heptane and MTBE. Table 5

[0242] (Visual Solubility Results, Compound 129 Free Base)

[0243] EXAMPLE 3 Crystallization Screen of Compound 129 Free Base

[0244] Crystallization screening experiments focused mainly on heat cycling and slurries.

[0245] A summary of experimental conditions is summarized in Table 6. Samples 3-1 and 3-4 were crystalline; whereas the other samples were amorphous solids.

[0246] Table 6 (Results of Crystallization Screen of Compound 129 Free Base) EXAMPLE 4

[0247] Salt Screen of Compound 129

[0248] The Compound 129 free base of Example 1-1 was salt screened using different acids and different solvent conditions to determine salt formation properties under various reaction conditions. Solubility data from Table 5 guided these experiments. Experimental and crystallization conditions focused on direct precipitation, slow cooling, and precipitation by antisolvent addition. All experiments were conducted at 100 mg scale. Salt formation conditions are summarized in Table 7, and the qualitative results are summarized in Table 8.

[0249] Table 7 (Compound 129 Salt Screen Conditions)

[0250] Table 8

[0251] (Compound 129 Salt Screen Results) EXAMPLE 5

[0252] Crystalline Hydrochloride Salts of Compound 129

[0253] Hydrochloride salts of Compound 129 were obtained using the conditions summarized in Table 9. Samples 5-1, 5-2 and 5-3 were prepared at 100 mg scale using the same conditions of Samples 4-1, 4-2 and 4-3 respectively in Table 7. Sample 5-4 was prepared using the conditions of Sample 4-3 in Table 7 except that the scale was increased to 300 mg.

[0254] Sample 5-5 was prepared using the following synthetic procedure.

[0255] The free base of Compound 129 prepared in Example 1-1 (theor. 12.1 g, 29.3 mmols, 1.0 eq) was dissolved in dioxane (97.0 mL, 8X vol) and added to a round bottom reactor with overhead stirring. The stirring mixture was treated dropwise at RT with 4M HC1 in dioxane solution (7.33 mL, 29.3 mmols, 1.0 eq) over a 5-minute period. The resulting immediate slurry was aged at RT for three hours before isolation by filtration. The resulting wet cake was displacement washed first with dioxane (48.4 mL, 4X vol) and then MTBE (60.5 mL, 5X vol) before oven-drying at 40 °C to constant mass.

[0256] Table 9 (Compound 129 HC1 Salt Screen Conditions)

[0257] Samples 5-1, 5-2, 5-3, 5-4 and 5-5 were analyzed using powder X-ray diffraction (PXRD). In each case 2-50 mg of material is transferred to a zero-background sample holder coated with a thin layer of petroleum jelly and leveled with a glass plate, XRD data was obtained using the PXRD parameters in Table 10.

[0258] Table 10

[0259] (PXRD Measurement Parameters)

[0260] Figure 1 shows an overlay of the PXRD spectra for Samples 5-1, 5-2, 5-3, 5-4 and 5-5. As shown in the overlay, the powder diffraction patterns of Samples 5-2, 5-3 and 5-4 are nearly identical. The crystalline form of Samples 5-2, 5-3 and 5-4 are designated as Form A. By contrast, the powder diffraction patterns of Samples 5-1 and 5-5 are substantially different from the powder diffraction pattern of Form A. The crystalline form of Sample 5-1 is designated as Form B, and the crystalline form of Sample 5-5 is designated as Form C.

[0261] Samples 5-1, 5-2, 5-3, 5-4 and 5-5 were also analyzed using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), and Figures 2-6 show DSC / TGA overlays for Samples 5-1, 5-2, 5-3, 5-4 and 5-5 respectively. Figure 7 shows an overlay of the DSC plots of Samples 5-1, 5-2, 5-3, 5-4 and 5-5. Results indicate a consistent endothermic event which is associated with a melt and HC1 exsolvation at 180°C to 190°C. The endotherm temperature is slightly variable which is consistent with a complex thermal event involving a melt and exsolvation. TGA indicates a >7% weight loss associated with the endotherm, which is consistent with an approximate mono-HCl salt.

[0262] Polarized light microscopy (PLM) was also carried out on the Samples 5-1, 5-2, 5- 4 and 5-5. PLM images for the Samples 5-1, 5-2, 5-4 and 5-5 are shown in Figures 8-11 respectively. The PLM images show an undefined morphology for all of Samples 5-1, 5-2, 5-4 and 5-5.

[0263] Dynamic Vapor Sorption (DVS) was also performed on Samples 5-1 and 5-2. The resulting DVS plots showing weight change versus relative humidity for Samples 5-1 and 5-2 are shown in Figures 12 and 13 respectively, and indicate an approximate 7.5% and 12% adsorption at 95% RH for Samples 5-1 and 5-2 respectively. To investigate whether the TGA weight loss is due to solvent evaporation or HC1 exsolvation, nuclear magnetic resonance (NMR) spectroscopy was performed on Sample 5-3. The NMR spectrum of Sample 5-3 is shown in Figure 14 and does not indicate the presence of organic solvent.

[0264] Karl-Fisher (KF) analysis was performed on Sample 5-5 to ascertain whether the crystalline hydrochloride salt of Compound 129 having Form C is a hydrate. KF results are shown in Table 11 and indicate an average 0.118% water content. Considering lack of organic solvents and water, the TGA weight loss associated with the melting endotherm appears to be due to salt splitting / gaseous HC1 exsolvation.

[0265] Table 11

[0266] (KF Analysis of Sample 5-5 (Form C))

[0267] EXAMPLE 6

[0268] Crystalline Sulfate Salts of Compound 129

[0269] Sulfate salts of Compound 129 were obtained using the same conditions used to prepare Samples 4-4 and Sample 4-6 in Table 7. Sample 6-1 was prepared using the process of Sample 4-4 at 100 mg scale. Sample 6-2 was prepared using the process of Sample 4-6 at 100 mg scale. Sample 6-3 was preparation using the process of Sample 4-6 at 300 mg scale. Sample 6-4 was prepared at 10 g scale using Dioxane / MTBE conditions. Table 12 summarizes the sulfate salts Compound 129.

[0270] Table 12

[0271] (Sulfate Salts of Compound 129) Samples 6-1, 6-2, 6-3 and 6-4 were analyzed by PXRD using the conditions described in Example 5 by reference to Table 10. Figure 15 shows an overlay of the PXRD spectra for Samples 6-1, 6-2, 6-3 and 6-4. As shown in the overlay, the powder diffraction patterns show that Samples 6-1, 6-2, 6-3 and 6-4 are all crystalline with the same crystalline form.

[0272] Samples 6-1, 6-2, 6-3 and 6-4 were also analyzed using DSC and TGA, and Figures 16-19 show DSC / TGA overlays for Samples 6-1, 6-2, 6-3 and 6-4 respectively. Results indicate a consistent melting point of approximately 197 °C for all of Samples 6-1, 6-2, 6-3 and 6-4, which is consistent with identical PXRD patterns. TGA does not indicate the presence of bound or adsorbed solvent.

[0273] PLM was also carried out on the Samples 6-3 and 6-4. PLM images for the Samples 6-3 and 6-4 are shown in Figures 20 and 21 respectively. The PLM images of Samples 6-3 and 6- 4 indicate a rod-like morphology.

[0274] DVS was also performed on Sample 6-1, and the DVS plot is shown in Figure 22. The DVS plot of Sample 6-1 indicates a +6.3% weight gain at 95% RH.

[0275] Overall, the physical properties of the sulfate salts of Compound 129 were considered desirable and the sulfate salt was progressed into further solubility and stability testing.

[0276] EXAMPLE 7

[0277] Crystalline Phosphate Salts of Compound 129

[0278] Phosphate salts of Compound 129 were obtained using the same conditions used to prepare Samples 4-7 and Sample 4-9 in Table 7. Sample 7-1 was prepared using the process of Sample 4-7, and Sample 7-2 was prepared using the process of Sample 4-9. Sample 7-3 was prepared as a 350 g scaled-up salt from the free base of Example 1-2 using dioxane / MTBE conditions. Table 13 summarizes the phosphate salts Compound 129.

[0279] Table 13

[0280] (Phosphate Salts of Compound 129)

[0281] Samples 7-1, 7-2 and 7-3 were analyzed by PXRD using the conditions described in Example 5 by reference to Table 7. Figure 23 shows an overlay of the PXRD spectra for Samples 7-1 and 7-2. The PXRD overlay of Samples 7-1 and 72 indicates distinct XRD patterns within each sample, with some peak overlap. Each sample is likely a mixture of a primary polymorph with a small quantity of a differing polymorph within the mixture. Figure 24 shows the PXRD spectrum for Sample 7-3, and appears to include a mixture of the different polymorphs contained in Samples 7-1 and 7-2.

[0282] Samples 7-1, 7-2 and 7-3 were also analyzed using DSC and TGA, and Figures 25- 27 show DSC / TGA overlays for Samples 7-1, 7-2 and 7-3 respectively. DSC / TGA results indicate that each pattern maintains a similar melting point at approximately 137°C. A small endotherm exists at 98.3°C and 112.9°C in Samples 7-1 and 7-3, respectively. Considering that no TGA weight loss is associated with such endotherms, they likely represent a melt of a minor quantity of a differing polymorph than that of the main melt; z.e., each pattern represents a mixture of forms. The DSC / TGA overlay of Sample 7-3 indicates that this sample contains a mixture of forms, which is consistent with the PXRD data.

[0283] DVS was also performed on Samples 7-1 and 7-3, and the DVS plots of Samples 7-1 and 7-3 are shown in Figures 28 and 29 respectively. The DVS plots indicate an approximate +22% weight gain upon exposure to 95% RH, and significant hysteresis upon desorption to a +4.5% weight gain at 0% RH, likely indicating formation of hydrates.

[0284] PLM was also carried out on Sample 7-3. The PLM image for Sample 7-3 is shown in Figure 30. NMR was also carried out on Sample 7-3. The NMR spectrum for Sample 7-3 is shown in Figure 31.

[0285] Due to complex physical properties, including the presence of solvates, hydrates, and mixtures of forms, phosphate salts of Compound 129 were not considered to be strong candidates for further salt development.

[0286] EXAMPLE 8

[0287] Esylate Salts of Compound 129

[0288] Esylate salts of Compound 129 were obtained using the same conditions used to prepare Samples 4-21, 4-22 and 4-23 in Table 7. Sample 8-1 was prepared using the process of Sample 4-21, Sample 8-2 was prepared using the process of Sample 4-22, and Samples 8-3 and 8- 4 were prepared using the process of Sample 4-23 at 100 mg and 300 mg scales respectively. Samples 8-1 and 8-2 were crystalline solids after 1-4 days of slurrying at RT. Sample 8-3 also produced crystalline solids; however, these solids became gummy after isolating and were not characterized. Table 14 summarizes the esylate salts Compound 129. Table 14

[0289] (Esylate Salts of Compound 129)

[0290] Samples 8-1, 8-2 and 8-4 were analyzed by PXRD using the conditions described in Example 5 by reference to Table 10. Figure 32 shows an overlay of the PXRD spectra for Samples 8-1, 8-2 and 8-4. The PXRD overlay indicates each sample is a consistent crystalline form.

[0291] Samples 8-1, 8-2 and 8-4 were also analyzed using DSC and TGA, and Figures 33- 35 show DSC / TGA overlays for Samples 8-1, 8-2 and 8-4 respectively. DSC / TGA results indicate that Samples 8-1 and 8-2 have sharp endotherms and similar melting points at approximately 189 °C; whereas Sample 8-4 contains a broader endotherm with a slightly lower melting point at 184 °C.

[0292] PLM was also performed on Sample 8-4 and is shown in Figure 36 indicating an undefined morphology.

[0293] DVS was also performed on Samples 8-1 and 8-2, and the DVS plots for Samples 8-1 and 8-2 are shown in Figures 37 and 38 respectively. The DVS plots indicate that Sample 8- 2 adsorbs a greater quantity of water compared to Sample 8-1 at > 80% RH. This may be due to differences in crystallinity or the presence of amorphous material, as the DSC endotherm of 8-2 is relatively broad.

[0294] Due to favorable physical properties, esylate salts of Compound 129 were progressed into solubility and stability testing.

[0295] EXAMPLE 9

[0296] Kinetic Solubility Testing of Crystalline Salts of Compound 129

[0297] Kinetic solubility testing was performed on the crystalline hydrochloride salt of Sample 5-4 (Example 5), the crystalline sulfate salt of Sample 6-3 (Example 6), the crystalline phosphate salt of Sample 7-3 (Example 7) and crystalline esylate salt of Sample 8-4 (Example 8). Table 15 summarizes the sample that were tested for kinetic solubility, and Table 16 summarizes the parameters for kinetic solubility. Samples were assayed at T=lhr, T=2hr and T-4hr.

[0298] Table 15 (Kinetic Solubility Testing of Crystalline Salts of Compound 129)

[0299] Table 16

[0300] (Kinetic Solubility Parameters)

[0301] The kinetic solubility results are summarized in Table 17 and Figure 39. The tests were conducted by saturating a 1.5 mL solution with each sample. After Ihr, 2hr and 4hr, each sample was filtered through a 0.45 micron PVDF syringe filter and the filtrate was assayed by HPLC Method B. Results indicate that the esylate salt (Sample 8-4) maintained overall higher solubility over the T=4hr experiment, with a maximum solubility of 302.0 pg / ml occurring at T=2hr, followed by a decrease to 147.0 pg / ml at T=4hr. Such data may indicate solubilization of a metastable polymorph, followed by precipitation to a more stable phase. The hydrochloride and sulfate salts, samples 5-4 and 6-3 and 5-4 respectively, maintained similar solubilities throughout the T=4hr experiment, whereas the phosphate salt (Sample 7-3) maintained <10pg / mL solubility at T=4hrs. Table 17

[0302] (Kinetic Solubility of Crystalline Salts of Compound 129)

[0303] EXAMPLE 10 Stability Testing of Crystalline Salts of Compound 129

[0304] Stability testing was performed on the crystalline hydrochloride salt of Sample 5-4 (Example 5), the crystalline sulfate salt of Sample 6-3 (Example 6), the crystalline phosphate salt of Sample 7-3 (Example 7) and crystalline esylate salt of Sample 8-4 (Example 8). Table 18 summarizes the samples that were tested for stability, Table 19 summarizes the stability protocol, and Table 20 summarizes the testing schedule.

[0305] Table 18

[0306] (Stability Testing of Crystalline Salts of Compound 129)

[0307] Table 19

[0308] (Stability Protocol for Testing Crystalline Salts of Compound 129) Table 20

[0309] (Stability Testing Schedule)

[0310] A - Assay, impurities by HPLC (Method C IPC Analysis) B - XRPD / DSC / TGA

[0311] Samples were analyzed using the IPC HPLC Method C described above.

[0312] Data for the stability testing is summarized in Table 21. The data shows that the hydrochloride and sulfate salts of Compound 129 (Samples 5-4 and 6-3) exhibited substantially greater stability compared to the phosphate and esylate salts of Compound 129 (Samples 7-3 and 8-4).

[0313] Table 21

[0314] (Stability Testing of Crystalline Salts of Compound 129)

[0315] EXAMPLE 11

[0316] Biorelevant Solubility Testing of Crystalline Salts of Compound 129

[0317] Biorelevant solubility testing was performed on the crystalline hydrochloride salt of Sample 5-5 (Example 5), the crystalline sulfate salt of Sample 6-4 (Example 6), and the crystalline phosphate salt of Sample 7-3 (Example 7). Table 22 summarizes the samples that were tested for biorelevant solubility. Media-exchange dissolution was conducted according to the procedure summarized in Table 23, and the results are graphically summarized in Figure 40. The results indicate that the crystalline hydrochloride salt of Sample 5-5 (Form C) maintains the highest solubility across all timepoints. After the media exchange and subsequent pH shift from gastric pH (approx. 2.5) to intestinal pH (approx. 7.1), the solubility slightly decreases for all salts.

[0318] Table 22

[0319] (Stability Testing of Crystalline Salts of Compound 129)

[0320] Table 23 (Media-Exchange Dissolution Testing Procedure) 4. If there is remaining sediment, collect and confirm with XRPD if disso results needs further

[0321] EXAMPLE 12

[0322] Polymorph Screening of Crystalline Hydrochloride Salts of Compound 129

[0323] Polymorph screening experiments were conducted with hydrochloride salts of Compound 129. As summarized in Table 24, additional hydrochloride solid forms of Compound 129 were discovered. Each of the hydrochloride solid forms of Compound 129 is further described below.

[0324] Table 24

[0325] (HC1 Salt Polymorph Screening Experiments of Compound 129)

[0326] 1. Form C

[0327] As described in Example 5, a hydrochloride salt of Compound 129 was obtained as a solid Form C in Sample 5-5. The PXRD spectrum of Sample 5-5 (obtained using the conditions described in Example 5 by reference to Table 10) is shown in Figure 41, and the DSC / TGA plot of Sample 5-5 is shown in Figure 6. The PXRD indicates that Form C is weakly crystalline. Because Sample 5-5 was prepared in dioxane solvent, Form C may be a dioxane solvate — which is consistent with the 1.892% weight loss at approximately 106 °C (see Figure 6). As explained below, competitive slurrying and trituration experiments summarized in Table 24 show that Form C can be converted to Form B.

[0328] 2. Form B

[0329] As described in Example 5, a hydrochloride salt of Compound 129 was obtained as a solid Form B in Sample 5-1. Figure 1 shows an overlay of PXRD spectra (obtained using the conditions described in Example 5 by reference to Table 10) including the Sample 5-1. Form B also resulted from slurrying the Form C (Sample 5-6-1) and the Form D (Sample 5-7), described below, in EtOH at 40°C and RT for T=1 day. Form B also resulted from competitive slurries between the Forms B / D (Sample 5-8), Forms A / B (Samples 5-9 and 5-10) and Forms A / B / C (Sample 5-11), suggesting that Form B is a relatively stable solid form.

[0330] The Form B hydrochloride salt of Sample 5-6-1 was also scaled-up to production process to obtain the Form B of Sample 5-6-2. In this process, 7.04 g of the Form C prepared in Sample 5-5 was added to 250 ml round bottom flask, and 93 ml of EtOH then added (75mg / ml target). Magnetic stirring was initiated, and the sample was slurried at 40°C for ~lhr, at which point the slurry became too thick to stir. 30ml EtOH then added, the resulting mixture was seeded with ~ lOmg of the Form B prepared as Sample 5-6-1. The resulting mixture was stirred at 40°C, filtered, and the filtrate was dried at ambient temperature to obtain ~7 g of the Form B hydrochloride salt of Compound 129. Figure 42 shows the PXRD spectrum of Sample 5-6-2 obtained using the conditions described in Example 5 by reference to Table 10. 3. Form A

[0331] As described in Example 5, hydrochloride salts of Compound 129 were obtained as a solid Form A in Samples 5-2, 5-3 and 5-4. Figure 1 shows an overlay of PXRD spectra (obtained using the conditions described in Example 5 by reference to Table 10) including the Samples 5-2, 5-3 and 5-4. Form A was not obtained when conducting stable form screening experiments. As illustrated in Table 24 (Samples 5-9, 5-10 and 5-11), the Form A was converted to Form B (described above) in EtOH, EtOAc or Acetone after varying lengths of slurry time at 40 °C or RT. In Samples 5-9 and 5-10, competitive slurries between Forms A and B in EtOAc and Acetone at 40°C resulted in Form B — indicating that Form A is a metastable form under such conditions. Form B was also obtained in Sample 5-11 when Form C was slurried in the presence of Forms A and B. In Sample 5-14, a competitive slurry between Forms A, B and C in ACN and RT resulted in primarily the Form F described below. These experiments suggests that the Form A is likely a metastable intermediate.

[0332] 4. Forms E, F, G and H

[0333] In Sample 5-12, Form E resulted from a slow cool (over 1 day) of a Compound 129 HC1 salt slurry in dioxane:EtOH (3: 1) and, in Sample 5-13, a slurry of Form C over a period of Iday at 40°C in Dioxane. The PXRD spectrum of Form E (obtained using the conditions described in Example 5 by reference to Table 10) is shown in Figure 43.

[0334] In Sample 5-14, Form F resulted from a one week competitive slurry of the Form C of Compound 129 HC1 salt in ACN at RT in the presence of Form A and B seeds. The PXRD spectrum of Form F (obtained using the conditions described in Example 5 by reference to Table 10) is shown in Figure 44. Based on the PXRD spectrum, Form F is weakly crystalline and appears to be a mixture of Form C with minor amounts of Forms A and B.

[0335] In Sample 5-15, Form G resulted from a slow cool / anti-solvent addition with EtOH and Heptane solvent / antisolvent of a Compound 129 HC1 salt slurry, involving a Ihr slurry time after heptane antisolvent addition at 65°C and slow cooling from 65°C to RT. The PXRD spectrum of Form G (obtained using the conditions described in Example 5 by reference to Table 10) is shown in Figure 45. Based on the PXRD spectrum, Form G is a mixture of Forms B and D. Continued slurrying of Form G at RT resulted in Form B, suggesting that the Form D (initially present in Form G) is kinetically metastable.

[0336] In Sample 5-16, Form H resulted from a slurry of Form C in EtOH over Iday. The PXRD spectrum of Form H (obtained using the conditions described in Example 5 by reference to Table 10) is shown in Figure 46. 5. Form D

[0337] In Samples 5-17, 5-18 and 5-19, Form D resulted from slow cool of a Compound 129 HC1 salt slurry in EtOH solvent optionally with IPA as antisolvent. The PXRD spectrum of Form D (obtained using the conditions described in Example 5 by reference to Table 10) is shown in Figure 47. As explained above, competitive slurrying of Forms B and D demonstrated that Form B is preferentially stable versus Form D (see Sample 5-8); Form D is likely kinetically metastable versus Form B.

[0338] 6. Form X

[0339] In Sample 5-20, the phosphate salt of Compound 129 (Sample 7-3 described in Example 7) was converted into the free-base on Compound 129 by adding Sample 7-3 (402.7 g) to a mixture of DCM (3.91 L) and water (1.56 L), and then adding a K3PO4 solution (357.7 g K3PO4 in 560 mL of water) with stirring overnight at RT. The resulting mixture having pH~8 was separated into organic (DCM) and aqueous phases, and the organic phase was washed with brine and combined with EtOH (~2L) (~5L total volume of DCM and EtOH). The resulting solution was filtered through a glass microfiber filter (GF / F) (25 mm), and the filtrate was evaporated to yield an amorphous solid. The amorphous solid was dissolved in EtOH (3.5L) to which concentrated HC1 (73 mL) was added, and a solid immediately formed at RT. After stirring overnight, the resulting mixture was filtered through a 3L fritted funnel (medium), and the filter cake was washed with EtOH (2 x 500 mL). The resulting filter cake was vacuum dried at RT to yield 346.83 g (~ 92.7%) of crystalline hydrochloride salt of Compound 129, which is designated as Form X.

[0340] Sample 5-20 was analyzed using PXRD using the conditions described in Example 5 by reference to Table 10. The PXRD spectrum of Sample 5-20, which is shown in Figure 48, indicates a distinctive Form X having the peaks (in degrees 29 ± 0.2°) listed in Table 25.

[0341] Table 25

[0342] (Peak-Peaked PXRD Data for Form X)

[0343] Sample 5-20 was analyzed using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), and Figure 49 shows the DSC / TGA overlay for Sample 5-20. The DSC / TGA overlay for Sample 5-20 indicates an onset point of 170.80°C and melting point of 191.33°C.

[0344] Polarized light microscopy (PLM) was also carried out on Sample 5-20. The PLM image for Sample 5-20 is shown in Figure 50. The PLM images show an undefined morphology for all of Samples 5-1, 5-2, 5-4 and 5-5. The PLM of Sample 5-20 indicates that Form X is comprised of needle-like crystalline material. Dynamic Vapor Sorption (DVS) was also performed on Sample 5-20. The resulting

[0345] DVS plot shown in Figure 51 indicates that Form X is moderately hygroscopic with low hysteresis upon sorption-desorption. In Sample 5-21, the free base of Compound 129 from Example 1-2 was dissolved in ethyl alcohol, 37% HC1 is added, and the mixture was stirred at RT for 48 h. The resulting heterogeneous mixture was then filtered and washed with ethyl alcohol, after which the filtered solid was dried to afford the crystalline hydrochloride salt of Compound 129 in the Form X.

[0346] Sample 5-21 was analyzed by PXRD using the conditions described in Example 5 by reference to Table 10. Figure 52 shows the PXRD spectrum of Sample 5-21.

[0347] Based on the experimental results above, Form X of Compound 129 exhibits favorable characteristics for drug development in terms of stability.

[0348] EXAMPLE 13

[0349] Solubility Testing of Form X in Organic Solvents

[0350] Sample 5-20 was also tested for visual solubility in the organic solvents listed in Table 26. For each test, approximately 10 g of Sample 5-20 was weighed into a 1 dram vial, and then the respective solvent was added in 100 pL to 1000 pL increments until the crystalline solid dissolved, or until 4mL solvent was added. Results are shown in Table 26.

[0351] Table 26

[0352] (Form X Estimated Solubility in Organic Solvents)

[0353] Based on these experimental results, Form X of Compound 129 exhibits favorable characteristics for drug development in terms of solubility in organic solvents.

[0354] EXAMPLE 14

[0355] Solubility Testing of Form X in Aqueous Media

[0356] Equilibrium solubility tests were also carried out using Sample 5-20 at RT in a variety of buffers, DI water, and Fasted-State Simulated Intestinal Fluid (FaSSIF), in order to measure the solubility of Form X at different pH values. The results of these tests are summarized in Table 27. Table 27

[0357] (Form X Equilibrium Solubility Tests)

[0358] Based on these experimental results, Form X of Compound 129 exhibits favorable characteristics for drug development in terms of solubility in aqueous media.

[0359] EXAMPLE 15

[0360] LogD Testing of Form X

[0361] LogD testing was also carried out on Sample 5-20 using a shake-flask method. Octanol was used as the lipophilic solvent, whereas 25 mM pH 7.4 phosphate buffer was used as the aqueous media. Results, shown in Table 28, indicate that the %RSD of triplicate samples at each partition was low, and that the average logD (7.4) result was consistent across all partitions tested. The measured logD (pH 7.4) for Form X (Sample 5-20) was 2.62 ± 0.02.

[0362] Table 28

[0363] (Form X LogD Testing Data)

[0364] Based on these experimental results, Form X of Compound 129 exhibits favorable characteristics for drug development in terms of lipophilicity as measured by LogD.

[0365] The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet, including U.S. Provisional Application No. 63 / 607,368, filed on December 7, 2023, are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments. These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

CLAIMSWe claim:

1. A crystalline Form X of 7-((2R,4S)-4-((2,3-Dihydrobenzo[Z>][l,4]dioxin-6- yl-2,2,3,3-d4)oxy)-2-methylpiperidin-l-yl)-8-methyl-4H-pyrimido[l,2-Z>]pyridazin-4-one hydrochloride exhibiting at least X-ray lines (in degrees 29 ± 0.2°) at 6.69, 8.52, 10.29, 17.42,20.64, 21.08, 26.22 and 29.52 in a powder diffraction pattern when measured using Cu Ka radiation.

2. The crystalline Form X of claim 1, wherein the powder diffraction pattern exhibits at least X-ray lines (in degrees 29 ± 0.2) at 6.69, 8.52, 10.29, 17.42, 20.64, 21.08, 26.22 and 29.52, and at least one X-ray line selected from the group consisting of 11.15, 14.67, 14.95, 20.90, 25.02, 26.46 and 30.76.

3. The crystalline Form X of claim 1, wherein the powder diffraction pattern exhibits at least X-ray lines (in degrees 29 ± 0.2°) at 6.69, 8.52, 10.29, 17.42, 20.64, 21.08, 26.22 and 29.52, and at least two X-ray lines selected from the group consisting of 11.15, 14.67, 14.95, 20.90, 25.02, 26.46 and 30.76.

4. The crystalline Form X of claim 1, wherein the powder diffraction pattern exhibits at least X-ray lines (in degrees 29 ± 0.2°) at 6.69, 8.52, 10.29, 11.15, 14.67, 14.95, 17.42,20.64, 20.90, 21.08, 25.02, 26.22, 26.46, 29.52 and 30.76.

5. The crystalline Form X of claim 1, wherein the powder diffraction pattern exhibits at least X-ray lines (in degrees 29 ± 0.2°) at 6.69, 8.52, 10.29, 11.15, 14.67, 14.95, 17.42,20.64, 20.90, 21.08, 25.02, 26.22, 26.46, 29.52 and 30.76, and at least one X-ray line selected from the group consisting of 15.54, 16.40, 17.03, 17.93, 19.68, 20.90, 21.08, 22.59, 22.67, 23.71 and 26.12.

6. The crystalline Form X of claim 1, wherein the powder diffraction pattern exhibits at least X-ray lines (in degrees 29 ± 0.2°) at 6.69, 8.52, 10.29, 11.15, 14.67, 14.95, 17.42,20.64, 20.90, 21.08, 25.02, 26.22, 26.46, 29.52 and 30.76, and at least two X-ray lines selected from the group consisting of 15.54, 16.40, 17.03, 17.93, 19.68, 20.90, 21.08, 22.59, 22.67, 23.71 and 26.12.

7. The crystalline Form X of claim 1, wherein the powder diffraction pattern exhibits at least X-ray lines (in degrees 29 ± 0.2) at 6.69, 8.52, 10.29, 11.15, 14.67, 14.95, 15.54, 16.40, 17.03, 17.42, 17.93, 19.68, 20.64, 20.90, 21.08, 22.59, 22.67, 23.71, 25.02, 26.12, 26.22, 26.46, 29.52 and 30.76.

8. The crystalline Form X of claim 1, wherein the powder diffraction pattern exhibits X-ray lines at the same angles (in degrees 29 ± 0.2) in Table 25.

9. The crystalline Form X of claim 1, wherein the powder diffraction pattern exhibits an X-ray pattern essentially the same as that provided in Figure 48.

10. A pharmaceutical composition, comprising the crystalline Form X of any one of claims 1-9, and a pharmaceutically acceptable carrier.

11. A method for modulating muscarinic acetylcholine receptor (mAChR) M4 activity in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a crystalline Form X of any one of claims 1-9, or an effective amount of a pharmaceutical composition of claim 19.

12. A method for treating a neurological and / or psychiatric disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a crystalline Form X of any one of claims 1-9, or with an effective amount of a pharmaceutical composition of claim 19.

13. The method of claim 12, wherein the disorder is Alzheimer's disease, a schizophrenia, a sleep disorder, a borderline personality disorder, Tourette's syndrome, a bipolar disorder, a tardive dyskinesia, Huntington's disease, a pain disorder, a cognitive disorder, or a combination thereof.

14. The method of claim 12, wherein the disorder is a psychosis, a schizophrenia, a conduct disorder, a disruptive behavior disorder, a bipolar disorder, a psychotic episode of anxiety, an anxiety associated with psychosis, a mood disorder associated with psychotic disorders, an acute mania, a depression associated with bipolar disorder, a mood disorder associated with schizophrenia, a behavioral manifestation of mental retardation, an autistic disorder, a movement disorders, Tourette's syndrome, an akinetic-rigid syndrome, a movementdisorder associated with Parkinson's disease, a tardive dyskinesia, a drug induced and neurodegeneration based dyskinesias, an attention deficit hyperactivity disorder, a cognitive disorder, a dementia, a memory disorder, or a combination thereof.

15. The method of any one of claims 12-14, wherein the disorder is associated with muscarinic acetylchloline receptor M4 dysfunction.

16. A crystalline Form X of any one of claims 1-9, or a pharmaceutical composition of claim 10, for use in the treatment of a neurological and / or psychiatric disorder.

17. The crystalline Form X or pharmaceutical composition of claim 16, wherein the disorder is Alzheimer's disease, a schizophrenia, a sleep disorder, a borderline personality disorder, Tourette's syndrome, a bipolar disorder, a tardive dyskinesia, Huntington's disease, a pain disorder, a cognitive disorder, or a combination thereof.

18. The crystalline Form X or pharmaceutical composition of claim 16, wherein the disorder is a psychosis, a schizophrenia, a conduct disorder, a disruptive behavior disorder, a bipolar disorder, a psychotic episode of anxiety, an anxiety associated with psychosis, a mood disorder associated with psychotic disorders, an acute mania, a depression associated with bipolar disorder, a mood disorder associated with schizophrenia, a behavioral manifestation of mental retardation, an autistic disorder, a movement disorders, Tourette's syndrome, an akinetic-rigid syndrome, a movement disorder associated with Parkinson's disease, a tardive dyskinesia, a drug induced and neurodegeneration based dyskinesias, an attention deficit hyperactivity disorder, a cognitive disorder, a dementia, a memory disorder, or a combination thereof.

19. The crystalline Form X or pharmaceutical composition of any one of claims 16-18, wherein the disorder is associated with muscarinic acetylchloline receptor M4 dysfunction.

20. Use of a crystalline Form X of any one of claims 1-9, or a pharmaceutical composition of claim 10, in the manufacture of a medicament for the treatment of a neurological and / or psychiatric disorder.

21. The use of claim 20, wherein the disorder is Alzheimer's disease, a schizophrenia, a sleep disorder, a borderline personality disorder, Tourette's syndrome, a bipolardisorder, a tardive dyskinesia, Huntington's disease, a pain disorder, a cognitive disorder, or a combination thereof.

22. The use of claim 20, wherein the disorder is a psychosis, a schizophrenia, a conduct disorder, a disruptive behavior disorder, a bipolar disorder, a psychotic episode of anxiety, an anxiety associated with psychosis, a mood disorder associated with psychotic disorders, an acute mania, a depression associated with bipolar disorder, a mood disorder associated with schizophrenia, a behavioral manifestation of mental retardation, an autistic disorder, a movement disorders, Tourette's syndrome, an akinetic-rigid syndrome, a movement disorder associated with Parkinson's disease, a tardive dyskinesia, a drug induced and neurodegeneration based dyskinesias, an attention deficit hyperactivity disorder, a cognitive disorder, a dementia, a memory disorder, or a combination thereof.

23. The use of any one of claims 20-22, wherein the disorder is associated with muscarinic acetylchloline receptor M4 dysfunction.

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