MEK immune oncology inhibitor pharmaceutical compositions

Abstract

Solid forms of 4-((dimcthylamino)mcthyl)-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (Compound A), polymorphs, salt forms, compositions, pharmaceutical compositions, their use and preparation as therapeutic agents. Some embodiments disclosed herein relate to crystalline free base polymorphs and crystalline salt forms of Compound A having the following structure useful for inhibiting MEK, and related methods of treatment of certain forms of cancer:

Description

MEK IMMUNE ONCOLOGY INHIBITOR PHARMACEUTICAL COMPOSITIONSINCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] This patent application claims the benefit of, and priority to, U.S. Provisional Patent Application No. 63 / 511,778, filed July 3, 2024; and U.S. Provisional Patent Application No. 63 / 625,044, filed January 25, 2024; each of which are incorporated by reference herein in their entirety.TECHNICAL FIELD

[0002] The present disclosure relates to the fields of chemistry and medicine. More particularly, the present disclosure relates to compositions comprising a compound useful for inhibiting MEK, and related methods of treatment of certain forms of cancer with MEK inhibitor therapies.BACKGROUND

[0003] In all cells, signaling pathways govern how cells regulate themselves as well as direct activities in relation to other cells in the body. One of the most commonly altered signaling pathways in cancer is the Mitogen Activated Protein Kinase (MAPK) pathway. RAS is a family of related oncogenes found upstream in the MAPK pathway that codes for four highly related protein isoforms: HRAS, NRAS, KRAS4A and KRAS4B. In many solid tumors, the MAPK pathway is inappropriately activated, often through mutations in the key members of the pathway, including RAS. When RAS is switched “on” through the activation of the membrane-bound receptor tyrosine kinase, or RTK, the MAPK pathway functions to drive cell proliferation, differentiation, survival, and a variety of other cellular functions that are critical for the formation of tumors.

[0004] Through the widespread adaptation of molecular profiling, it is now recognized that up to one in two cancer patients harbor tumors which are inappropriately activated through the MAPK pathway. Many of these patients display tumors with activation mutations in RAS or RAF, which lie upstream of MEK and ERK. Because inappropriate activation of the MAPK pathway supports many of the core tumor capabilities described above, efforts to create new therapeutics to target this pathway have been a high priority incancer drug research. However, to date, nearly all therapeutics that target the MAPK pathway have been limited to narrow patient subpopulations and have struggled to balance tolerability, durability of response, and efficacy. Nearly all targeted therapeutics against the MAPK pathway have been designed for sustained pathway suppression, which has resulted in on- target drug-related toxicities that limit clinical durability and potential drug-drug combinations.

[0005] Activating mutations of RAS and / or RAF in the MAPK pathway are observed in approximately 30% of all cancer patients, and inappropriate activation of this pathway is observed in up to 50% of all tumors and represents one of the most highly utilized signaling pathways in oncology. In aggressive solid tumors of the pancreas, skin, lungs and colon, mutations in RAS and / or RAF are even more common. For example, approximately 40% of lung cancers and approximately 90% of pancreatic cancers are due to RAS and / or RAF mutations.

[0006] Traditional targeted oncology drug development generally seeks to chronically sustain pathway inhibition, by prioritizing drugs with long to moderate half-lives and dosing them at intervals that maintain a sufficient level of drug, even at trough, to maintain target occupancy. This prevailing chronic ablation approach can cause on-target drug-related toxicity and limit clinical durability as a result of drug holidays, treatment discontinuation, and / or adaptive resistance. To date, FDA-approved MEK inhibitors have been ineffective at treating RAS mutant tumors when compared to BRAF mutant tumors because of a well-known mechanism of resistance, CRAF-mediated MEK reactivation, also known as CRAF-bypass. In addition, a well-known limitation of current FDA approved MEK inhibitors are high rates of serious drug-related adverse events, or SAE’s, most often observed in over 50% of treated patients, which leads to drug intolerability. The longer half-life of these drugs (e.g., up to 2 to 4 days) with once per day or less frequent dosing, or moderate half-life (e.g., 3 to 6 hours) with increased dosing frequency, contributes to high rates of adverse events because these drugs systemically circulate for an extended period of time harming healthy normal cells, which also rely on the pathway for survival.

[0007] Compounds may exist in different solid forms. The selection of a solid form of a pharmaceutical compound may affect a variety of physical and chemical properties, which may provide benefits or drawbacks in processing, formulation, stability, and bioavailability,among other important pharmaceutical characteristics. Potential pharmaceutical solids include crystalline solids and amorphous solids. Amorphous solids arc characterized by a lack of long- range structural order, whereas crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solid depends upon the specific application; amorphous solids are sometimes selected on the basis of, e.g., an enhanced dissolution profile, while crystalline solids may be desirable for properties such as, e.g., physical or chemical stability.SUMMARY OF THE DISCLOSURE

[0008] Some embodiments disclosed herein relate to crystalline free base polymorphs and crystalline salt forms of Compound A having the following structure:(Compound A).

[0009] In some embodiments, the disclosure encompasses a solid form of a free base of Compound A. In some embodiments, a composition comprises the free base of Compound A, wherein the composition may be characterized by: (a) a solid form of the free base of Compound A characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.8°, 15.6°, 15.8°, 16.3°, and 21.8° 20 (±0.2 29); and / or (b) a solid form of the freebase of Compound A characterized by a TGA / DSC showing a melting event at Tpeak of about 150 °C and a decomposition event at Tonset of about 245-255 °C and a mass loss of about 35%. In some embodiments, the solid form of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.8°, 12.6°, 15.6°, 15.8°, 16.3°, and 21.8° 20 (±0.2 20). In some embodiments, the solid form of the freebase of Compound A is further characterized by a TGA / DSC showing a melting event at Tpeak of about 149.3-150.5 °C. In some embodiments, the solid form of the freebase of Compound A is further characterized by a decomposition event at Tonset of about 245.6-255.7 °C. In someembodiments, the solid form of the freebase of Compound A is further characterized by a mass loss of about 35.0-35.3%. In some embodiments, the solid form of the freebase of Compound A is further characterized by a TGA / DSC showing a melting event at Tpeak of about 149.3- 150.5 °C and a decomposition event at TOUSet of about 245.6-255.7 °C and a mass loss of about 35.0-35.3%. In some embodiments, the solid form of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 7. In some embodiments, the solid form of the freebase of Compound A is characterized by an XRPD pattern as substantially as shown in Figure 13 A. In some embodiments, the solid form of the freebase of Compound A is characterized by an XRPD pattern as substantially as shown in Figure 14A. In some embodiments, the solid form of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 7, or substantially as shown in Figure 13A or substantially as shown in Figure 14A. In some embodiments, the solid form is the solid Form 1 of the free base of Compound A.

[0010] In some embodiments, the disclosure encompasses a solid form of a free base of Compound A. In some embodiments, a composition comprises the free base of Compound A, wherein the composition may be characterized by: (a) a solid form of the free base of Compound A characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.0°, 9.2°, 9.6°, 13.4°, and 16.4° 20 (±0.2 20); and / or a solid form of the free base of Compound A characterized by a TGA / DSC showing a melting event at Tpeak of about 165.0 °C and a decomposition event at Tonset of about 260 °C and a mass loss of about 30%. In some embodiments, the solid form of the freebase of Compound A may be characterized by an X- ray powder diffraction (XRPD) pattern comprising peaks at 7.0°, 9.2°, 9.6°, 13.4°, and 16.4° 29 (±0.2 20). In some embodiments, the solid form is characterized by a TGA / DSC showing a melting event at Tpeak of about 165 °C. In some embodiments, the solid form is characterized by a TGA / DSC showing a decomposition event at Tonset of about 260 °C. In some embodiments, the solid form is characterized by a TGA / DSC showing a mass loss of about 29.7%. In some embodiments, the solid form is characterized by a TGA / DSC showing a melting event at Tpeak of about 165 °C and a decomposition event at Tonset of about 260 °C and a mass loss of about 29.7%. In some embodiments, the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 15A. In some embodiments, the solid form is the solid Form 2 of free base of Compound A.

[0011] In some embodiments, a salt form of Compound A is provided, wherein the salt form comprises a counter ion. In some embodiments, the counter ion may be, but is not limited to, potassium, sodium, chloride, sulfate, bisulfate, aspartate, maleate, phosphate, glutamate, tartrate, fumarate, citrate, L-malate, hippurate, D-gluconate, L-ascorbate, succinate, acetate, naphthalene- 1,5-disulfonate ethanesulfonate, ethane- 1,2-sufonate, p-toluenesulfonate, methanesulfonate and benzoate. In some embodiments, the salt of Compound A is selected from the group consisting of: a HC1 salt of Compound A, a sulfuric acid salt of Compound A, a phosphoric acid salt of Compound A, a citric acid salt of Compound A, a succinic acid salt of Compound A, an acetic acid salt of Compound A and a methanesulfonic acid salt of Compound A.

[0012] In some embodiments, the salt of Compound A is a galactaric acid salt of Compound A. In some embodiments, the galactaric acid salt of Compound A is optionally characterized by melting point of about 220.0 °C. In some embodiments, the salt of Compound A is a galactaric acid salt of Compound A characterized by a TGA / DSC showing a melting event at Tpeak of about 221.4°C. In some embodiments, the salt of Compound A is a galactaric acid salt of Compound A characterized by a TGA / DSC showing a melting event at Tpeak of about 149.6 °C. In some embodiments, the salt of Compound A is a galactaric acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP2. In some embodiments, the salt of Compound A is a galactaric acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP14.

[0013] In some embodiments, the salt of Compound A is a L- Aspartic acid salt of Compound A. In some embodiments, the salt of Compound A is a L-Aspartic acid salt of Compound A optionally characterized by a melting point of about 264.1 °C. In some embodiments, the salt of Compound A is a L-Aspartic acid salt of Compound A characterized by a TGA / DSC showing a desolvation event at about 69.9 °C and an exotherm at about 173.8 °C. In some embodiments, the salt of Compound A is a L-Aspartic acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP3.

[0014] In some embodiments, the salt of Compound A is a maleic acid salt of Compound A. In some embodiments, the salt of Compound A is a maleic acid salt of Compound A optionally characterized by a melting point of about 130.5 °C. In someembodiments, the salt of Compound A is a maleic acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP4. In some embodiments, the salt of Compound A is a maleic acid salt of Compound A characterized by a TGA / DSC showing a melt event at about 151.3 °C.In some embodiments, the salt of Compound A is a hippuric acid salt of Compound A. In some embodiments, the salt of Compound A is a hippuric acid salt of Compound A optionally characterized by a melting point of about 187.0 °C. In some embodiments, the salt of Compound A is a hippuric acid salt of Compound A characterized by a TGA / DSC showing a melt event at about 186.5 °C; or a hippuric acid salt of Compound A characterized by a TGA / DSC showing a melt event at about136.8 °C and an exotherm at about 165.2 °C. In some embodiments, the salt of Compound A is a hippuric acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP5; or a hippuric acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP8.

[0015] In some embodiments, the salt of Compound A is a L-ascorbic acid salt of Compound A. In some embodiments, the salt of Compound A is a L-ascorbic acid salt of Compound A characterized by a melting point of about 190.0 °C. In some embodiments, the salt of Compound A is a L-ascorbic acid salt of Compound A characterized by a TGA / DSC showing a melt / decompo sition event at about 189.3 °C; or a L-ascorbic acid salt of Compound A characterized by a TGA / DSC showing a melt event at about 150.3 °C and a melt / decompo sition event at about 186.8 °C; or a L-ascorbic acid salt of Compound A characterized by a TGA / DSC showing a melt / decomposition event at about 188.1 °C; or a L- ascorbic acid salt of Compound A characterized by a TGA / DSC showing a melt event at about146.9 °C and a melt / decomposition event at about 188.6°C. In some embodiments, the salt of Compound A is a L-ascorbic acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP6; or a L-ascorbic acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP7; or a L-ascorbic acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP12; or a L-ascorbic acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP13.

[0016] In some embodiments, the salt of Compound A is a glutamic acid salt of Compound A. In some embodiments, the salt of Compound A is a glutamic acid salt of Compound A optionally characterized by a melting point of about 199.0 °C. In some embodiments, the salt of Compound A is a glutamic acid salt of Compound A characterized by a TGA / DSC showing a melt / decompo sition event at about 198.8 °C; or a glutamic acid salt of Compound A characterized by a TGA / DSC showing a melt / decomposition event at about 196.9 °C; or a glutamic acid salt of Compound A characterized by a TGA / DSC showing a melt event at about 150.9 °C, and a melt / decomposition event at about 201.5 °C. In some embodiments, the salt of Compound A is a glutamic acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP9; or a glutamic acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP10.

[0017] In some embodiments, a salt of Compound A is a galactaric acid salt of Compound A characterized by a X-ray powder diffraction (XRPD) pattern comprising peaks at 13.5°, 15.6°, 15.8°, 16.5°, and 27.2° 29 (±0.2 29). In some embodiments, a salt of Compound A is a L-Aspartic acid salt of Compound A characterized by a X-ray powder diffraction (XRPD) pattern comprising peaks at 21.7°, 28.2°, and 31.1° 29 (±0.220). In some embodiments, a salt of Compound A is a maleic acid salt of Compound A characterized by a X-ray powder diffraction (XRPD) pattern comprising peaks at 21.6°, 28.2°, 31.1°, 32.2°, and 35.1° 29 (±0.2 20). In some embodiments, a salt of Compound A is a hippuric acid salt of Compound A characterized by a X-ray powder diffraction (XRPD) pattern comprising peaks at 21.8°, 21.9°, 22.2°, 28.0°, and 31.7° 29 (±0.2 29). In some embodiments, a salt of Compound A is a L-ascorbic acid salt of Compound A characterized by a X-ray powder diffraction (XRPD) pattern comprising peaks at 19.9°, 28.0°, and 30.9° 29 (±0.2 29); or a L- ascorbic acid salt of Compound A characterized by a X-ray powder diffraction (XRPD) pattern comprising peaks at 30.0°, and 19.7° 29 (±0.220). In some embodiments, a salt of Compound A is a glutamic acid salt of Compound A characterized by a X-ray powder diffraction (XRPD) pattern comprising peaks at 21.4°, 22.0°, and 25.6° 29 (±0.229).

[0018] In some embodiments, the salt of Compound A is a naphthalene-1 ,5- disulfonic acid salt of Compound A. In some embodiments, the salt of Compound A is anaphthalene-l ,5-disulfonic acid salt of Compound A optionally characterized by a melting point of about 242.5 °C. In some embodiments, the salt of Compound A is a napthalene-1,5- disulfonic acid salt of Compound A characterized by a TGA / DSC showing desolvation event at about 92.6 °C, a desolvation event at about 127.1 °C, and a melt event at about 213.8 °C; or a napthalene-1,5- disulfonic acid salt of Compound A characterized by a TGA / DSC showing desolvation event at about 119 °C; or

[0019] In some embodiments, a pharmaceutical composition comprising a salt or solid form of Compound A as described herein and at least one pharmaceutically acceptable carrier.

[0020] In some embodiments, a method of treating a patient with a RAS-mutated or RAF-mutated cancer, comprising administering a therapeutically effective amount of the pharmaceutical composition as described herein, wherein the Compound A is administered to the patient (a) in a dose amount that achieves a Cmax effective to inhibit pERK and pMEK and (b) with an interval between consecutive doses that is at least about seven times the plasma half-life of the dual-MEK inhibitor. In some embodiments, the patient is diagnosed with a cancer harboring a mutation in (a) KRAS optionally selected from G12C, G12S, G12D or G12V; (b) NRAS optionally selected from Q61L, Q61K, Q61R; (c) HRAS; or (d) BRAF optionally selected from V600E. In some embodiments, the patient is diagnosed with a cancer selected from the group consisting of: pancreatic cancer, human lung adenocarcinoma, human malignant melanoma, human NSCLC and human colon carcinoma.BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIGURE 1 is a XRPD pattern of an amorphous form of Compound A.

[0022] FIGURE 2 is a graph obtained from a DSC analysis of an amorphous form of Compound A.

[0023] FIGURE 3 is a graph obtained of a cycle-DSC of an amorphous form of Compound A.

[0024] FIGURE 4 is an overlay of XRPD pattern of an amorphous form of Compound A and an anhydrous Form 1.

[0025] FIGURE 5 is a graph obtained from a TGA / DSC analysis of an amorphous form of Compound A.

[0026] FIGURE 6 is an overlay of XRPD patterns of the Form 1 solid form prepared according to the method of Example 5 (Sample 1 A, Sample IB) and the Form 2 solid form prepared according to the method of Example 6 (Sample 2).

[0027] FIGURE 7 is an overlay of XRPD patterns of the Form 1 solid form prepared according to the method of Example 5 (Sample 1A, Sample IB and Sample 1C).

[0028] FIGURE 8 is an XRPD peak list from the XRPD pattern of Sample 1C shown in FIGURE 7.

[0029] FIGURE 9 is an overlay of XRPD patterns of the Form 1 solid form prepared according to the method of Example 6 (Sample IB) and Form 2 solid form.

[0030] FIGURE 10 is a graph obtained from a TGA / DSC analysis of Sample 1A.

[0031] FIGURE 11 is a graph obtained from a TGA / DSC analysis of Sample IB.

[0032] FIGURE 12 is a graph obtained from a TGA / DSC analysis of Sample 2.

[0033] FIGURE 13A is an XRPD pattern obtained from Sample 1A.

[0034] FIGURE 13B is an XRPD peak list from the XRPD pattern shown in FIGURE 13 A.

[0035] FIGURE 14A is an XRPD pattern obtained from Sample IB.

[0036] FIGURE 14B is an XRPD peak list form the XRPD pattern shown inFIGURE 14A.

[0037] FIGURE 15A is an XRPD pattern obtained from Sample 2.

[0038] FIGURE 15B is an XRPD peak list form the XRPD pattern shown inFIGURE 15 A.

[0039] FIGURE 16 is an overlay of XRPD patterns of Form 1 , galactaric acid, NP2, and NP14.

[0040] FIGURE 17 is an overlay of XRPD patterns of Form 1, aspartic acid, and NP3.

[0041] FIGURE 18 is an overlay of XRPD patterns of Form 1, maleic acid, and NP4.

[0042] FIGURE 19 is an overlay of XRPD patterns of Form 1, hippuric acid, NP5, and NP8.

[0043] FIGURE 20 is an overlay of XRPD patterns of Form 1, ascorbic acid, NP6, NP7, NP12, and NP13.

[0044] FIGURE 21 is an overlay of XRPD patterns of Form 1 , glutamic acid, NP9,NP10, and NP11.

[0045] FIGURE 22 is an overlay of XRPD patterns of Form 1, naphthalene- 1,5- disulfonic acid, NP15, and NP16.

[0046] FIGURE 23 is an overlay of XRPD patterns of Form 1, galactaric acid, experiment Galactaric Solid (NP17), and NP14.

[0047] FIGURE 24 is an overlay of XRPD patterns of Form 1, ascorbic acid, experiment Ascorbic Temp 2 (NP13), and NP13.

[0048] FIGURE 25 is an overlay of XRPD patterns of Form 1, naphthalene- 1,5- disulfonic acid, experiment Naphthalene Solid (NP18), and NP15.

[0049] FIGURE 26 is a XPRD pattern from a tablet formulation of Compound A free base in Table 18 in Example 13.

[0050] FIGURE 27 is a XRPD pattern of a placebo formulation of Table 19 in Example 13.

[0051] FIGURE 28 is a XRPD pattern of Compound A free base in solid Form 2 reference standard in Example 13.

[0052] FIGURE 29 is an overlay of XRPD patterns of the reference standard of Compound A free base in solid Form 2 (FIGURE 28) (top XRPD pattern), the tablet formulation of Compound A free base in Table 18 (FIGURE 26), and the placebo formulation of Table 19 (FIGURE 27) (bottom XRPD pattern).

[0053] FIGURE 30 is a graph showing the concentration of Compound A in dogs after administration of Compound A in solution with and without pentagastrin administration, and the tablet oral dosage form of Compound A administered with and pentagastrin.

[0054] FIGURE 31 A is a bar graph showing the AUC measurements from dogs after administration of Compound A in solution or in an oral dosage formulation tablet, with and without pentagastrin administration.

[0055] FIGURE 3 IB is a bar graph showing the Cmax measurements from dogs after administration of Compound A in solution or in an oral dosage formulation table, with and without pentagastrin administration.DETAILED DESCRIPTION

[0056] Applicant has discovered new solid forms of Compound A, and other related inventions as disclosed herein:(Compound A).

[0057] Compound A has a molecular weight of 506.55 g / mol and a molecular formula of C23H27FN4O6S. Compound A can be referred to as 4-((dimethylamino)methyl)-3- (2-fhioro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate. The preparation of Compound A is described in Example 1.

[0058] Some embodiments relate to a solid form of the free base of Compound A. Some embodiments relate to an anhydrous form of the free base of Compound A. In some embodiments, Compound A includes one or more counter ions. In some embodiments, the counter ion may be selected from, but not limited to, potassium, sodium, chloride, sulfate, bisulfate, aspartate, maleate, phosphate, galactarate, glutamate, tartrate, fumarate, citrate, L- malate, hippurate, D-gluconate, L-ascorbate, succinate, acetate, naphthalene- 1,5-disulfonate, ethanesulfonate, ethane- 1,2- sufonate, p-toluenesulfonate, methanesulfonate and benzoate.

[0059] In some embodiments, the free base of Compound A is a crystalline form. In some embodiments, a crystalline form of a Compound A exhibits an X-ray powder diffraction pattern comprising peaks selected from about 15.8°, 16.3°, and 21.8° 20. In some embodiments, a crystalline form of a Compound A exhibits an X-ray powder diffraction pattern comprising peaks selected from about 10.8°, 12.6°, 15.6°, 16.3°, 15.8°, and 21.8° 20. In some embodiments, a crystalline form of a Compound A exhibits an X-ray powder diffraction pattern comprising peaks selected from about 10.8°, 12.6°, 13.5°, 15.6°, 15.8°, 16.3°, 16.5°, 16.8°, 18.2°, 20.6°, 21.8° and 27.2° 20. In some embodiments, a crystalline form of a Compound A includes an X-ray powder diffraction pattern substantially as shown in FIGURE 7. In some embodiments, a crystalline form of a Compound A includes an X-raypowder diffraction pattern substantially as shown in FIGURE 8. Tn some embodiments, a crystalline form of a Compound A includes a crystalline form exhibiting an X-ray powder diffraction pattern comprising peaks selected from FIGURE 5. In some embodiments, a crystalline form of a Compound A includes a crystalline form exhibiting an X-ray powder diffraction pattern comprising at least three peaks selected from FIGURE 5. In some embodiments, a crystalline form of a Compound A includes a crystalline form exhibiting an X-ray powder diffraction pattern comprising at least five peaks selected from FIGURE 5. In some embodiments, a crystalline form of a Compound A includes a crystalline form exhibiting an X-ray powder diffraction pattern comprising peaks selected from FIGURE 13B. In some embodiments, a crystalline form of a Compound A includes a crystalline form exhibiting an X-ray powder diffraction pattern comprising at least three peaks selected from FIGURE 13B. In some embodiments, a crystalline form of a Compound A includes a crystalline form exhibiting an X-ray powder diffraction pattern comprising at least five peaks selected from FIGURE 13B. In some embodiments, a crystalline form of a Compound A includes a crystalline form exhibiting an X-ray powder diffraction pattern comprising peaks selected from FIGURE 14B. In some embodiments, the crystalline form is Form 1. In some embodiments, a crystalline form of a Compound A includes a crystalline form exhibiting an X-ray powder diffraction pattern comprising at least three peaks selected from FIGURE 14B. In some embodiments, a crystalline form of a Compound A includes a crystalline form exhibiting an X-ray powder diffraction pattern comprising at least five peaks selected from FIGURE 14B.

[0060] In some embodiments, a crystalline form of Compound A includes a crystalline form exhibiting an X-ray powder diffraction pattern comprising peaks selected from about 9.1°, 9.5°, and 17.8° 29. In some embodiments, a crystalline form of a Compound A includes a crystalline form exhibiting an X-ray powder diffraction pattern comprising peaks selected from about 9.1°, 9.5°, 13.3°, 16.4°, 17.8° and 23.7° 20. In some embodiments, a crystalline form of a Compound A includes a crystalline form exhibiting an X-ray powder diffraction pattern comprising peaks selected from about 7.1°, 9.1°, 9.5°, 13.3°, 16.4°, 17.8°, 19.3°, 20.7°, 21.3°, 21.5°, 22.4°, 23.7°, and 23.4° 29. In some embodiments, a crystalline form of a Compound A includes an X-ray powder diffraction pattern substantially as shown in Figure 15 A. In some embodiments, a crystalline form of a Compound A includes a crystalline form exhibiting an X-ray powder diffraction pattern comprising peaks selected from FIGURE15B. Tn some embodiments, a crystalline form of a Compound A includes a crystalline form exhibiting an X-ray powder diffraction pattern comprising at least three peaks selected from FIGURE 15B. In some embodiments, a crystalline form of a Compound A includes a crystalline form exhibiting an X-ray powder diffraction pattern comprising at least five peaks selected from FIGURE 15B. In some embodiments, the crystalline form is Form 2.

[0061] In some embodiments, a pharmaceutical composition of Compound A exhibits an X-ray powder diffraction pattern comprising characteristic peaks at 7.0°, 9.2°, 9.6°, 13.4°, and 16.4° 29 (±0.2 29). In some embodiments, the pharmaceutical composition is an oral dosage form. In some embodiments, the pharmaceutical composition of Compound A exhibits an X-ray powder diffraction pattern comprising characteristic peaks at 9.1°, 9.5°, 13.3°, 16.4°, 17.8° and 23.7° 29 (±0.2 29). In some embodiments, the pharmaceutical composition of Compound A exhibits an X-ray powder diffraction pattern comprising characteristic peaks at 7.1°, 9.1°, 9.5°, 13.3°, 16.4°, 17.8°, 19.3°, 20.7°, 21.3°, 21.5°, 22.4°, 23.7°, and 23.4° 29 (±0.2 29). In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0062] In some embodiments, a salt of Compound A is a galactaric acid salt of Compound A characterized by a X-ray powder diffraction (XRPD) pattern comprising peaks at 13.5°, 15.6°, 15.8°, 16.5°, and 27.2° 29 (±0.220).

[0063] In some embodiments, a salt of Compound A is a L-Aspartic acid salt of Compound A characterized by a X-ray powder diffraction (XRPD) pattern comprising peaks at 21.7°, 28.2°, and 31.1° 29 (±0.2 29).

[0064] In some embodiments, a salt of Compound A is a maleic acid salt of Compound A characterized by a X-ray powder diffraction (XRPD) pattern comprising peaks at 21.6°, 28.2°, 31.1°, 32.2°, and 35.1° 29 (±0.2 29).

[0065] In some embodiments, a salt of Compound A is a hippuric acid salt of Compound A characterized by a X-ray powder diffraction (XRPD) pattern comprising peaks at 21.8°, 21.9°, 22.2°, 28.0°, and 31.7° 29 (±0.2 29).

[0066] In some embodiments, a salt of Compound A is a L-ascorbic acid salt of Compound A characterized by a X-ray powder diffraction (XRPD) pattern comprising peaks at 19.9°, 28.0°, and 30.9° 29 (±0.220); or a L-ascorbic acid salt of Compound A characterizedby a X-ray powder diffraction (XRPD) pattern comprising peaks at 30.0°, and 19.7° 20 (±0.2 20).

[0067] In some embodiments, a salt of Compound A is a glutamic acid salt of Compound A characterized by a X-ray powder diffraction.

[0068] As is well understood in the art, because of the experimental variability when X-ray diffraction patterns are measured on different instruments, the peak positions are assumed to be equal if the two theta (20) values agree to within 0.2° (i.e., ±0.20). For example, the United States Pharmacopeia states that if the angular setting of the 10 strongest diffraction peaks agree to within ±0.2° with that of a reference material, and the relative intensities of the peaks do not vary by more than 20%, the identity is confirmed. Accordingly, peak positions within 0.2° of the positions recited herein are assumed to be identical. Unless otherwise indicated, all X-ray diffraction angles recited herein are based on a copper K-alpha source.Compositions

[0069] Some embodiments relate to a composition including a crystalline form of Compound A as described herein. In some embodiments, the composition includes a free base form of Compound A. In some embodiments, the free base form is Form 1. In some embodiments, the free base form is Form 2. In some embodiments, the composition includes Compound A in both Form 1 and Form 2. Some embodiments relate to a composition with low levels of impurities. The term “impurity” as used herein refers to one or more components of the composition that are different from Compound A and water. In some embodiments, the impurity can include one or more chemical compounds introduced during the synthesis of Compound A. In some embodiments, the impurity can include a residual solvent.

[0070] Some embodiments relate to a composition that includes more than about 50% by weight of the Compound A described herein, based on the total weight of the composition. In some embodiments, the composition includes more than about 75% of the Compound A described herein. In some embodiments, the composition includes more than about 90% of the Compound A described herein. In some embodiments, the composition includes more than about 95% of the Compound A described herein. In some embodiments, the composition includes more than about 98% of the Compound A described herein. In some embodiments, the composition includes more than about 99% of the Compound A describedherein. In some embodiments, the composition includes the Compound A described herein in the range of about 50% to about 99%, about 60% to about 99%, about 70% to about 99%, about 80% to about 99%, about 90% to about 99%, about 95% to about 99%, or about 97.5% to about 99%, based on the total weight of the composition. The remaining portion of the composition may be other forms of Compound A and / or other chemical entities. In some embodiments, Compound A in the composition is present, at least in part, in a free base form as described herein. In some embodiments, Compound A in the composition is present, at least in part, in a crystalline form as described herein.

[0071] Some embodiments relate to a composition with a high purity. In particularly, some embodiments relate to a composition having more than about 90% by weight of Compound A, based on the total weight of the composition. In some embodiments, the composition includes more than about 92% of Compound A. In some embodiments, the composition includes more than 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 96.5%, 96%, 98%, 99%, or 99.5% of Compound A, or ranges including and / or spanning the aforementioned values. In some embodiments, the composition includes more than about 99% by weight of Compound A, based on the total weight of non-solvent molecules in the composition. In some embodiments, the composition includes more than about 95%, 96%, 97%, 98%, 99%, or 99.5% by weight of Compound A, or ranges including and / or spanning the aforementioned values, based on the total weight of non- solvent molecules in the composition. In some embodiments, Compound A in the composition is present, at least in part, in a free base form as described herein. In some embodiments, Compound A in the composition is present, at least in part, in a crystalline form as described herein.

[0072] In some embodiments, the composition includes more than about 99% by weight of Compound A, based on the total weight of molecules in the composition other solvents. In some embodiments, the solvents may include, but are not limited to, acetone, acetonitrile, alcohol, ether, heptane, water, toluene, triethylamine, or a combination thereof. In some embodiments, the alcohol includes methanol, ethanol, propanol, and benzyl alcohol. In some embodiments, the ether is cyclopentyl methyl ether. In some embodiments, the Compound A composition includes more than about 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 96.5%, 96%, 98%, 99%, or 99.5% by weight of Compound A, or ranges including and / or spanning the aforementioned values, based on the total weightof molecules in the composition other than solvents. In some embodiments, the composition includes more than about 99% by weight of Compound A, based on the total weight of nonsolvent molecules in the composition. In some embodiments, the composition includes more than about 95%, 96%, 97%, 98%, 99%, or 99.5% by weight of Compound A, or ranges including and / or spanning the aforementioned values, based on the total weight of solvent molecules in the composition. In some embodiments, Compound A in the composition is present, at least in part, in a free base form as described herein. In some embodiments, Compound A in the composition is present, at least in part, in a crystalline form as described herein.

[0073] In some embodiments, the composition includes more than about 99% by weight of a Compound A, based on a HPLC analysis. In some embodiments, the composition includes more than about 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 96.5%, 96%, 98%, 99%, or 99.6% of a Compound A, or ranges including and / or spanning the aforementioned values by weight, based on a HPLC analysis. In some embodiments, Compound A in the composition is present, at least in part, in a free base form as described herein. In some embodiments, Compound A in the composition is present, at least in part, in a crystalline form as described herein.

[0074] In some embodiments, the composition includes no more than about 10% by weight of impurities, based on the total weight of the composition. In some embodiments, the composition includes no more than about 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.6%, 0.4%, or 0.2% by weight of impurities, or ranges including and / or spanning the aforementioned values, based on the total weight of the composition. In some embodiments, the composition includes no more than about 5% by weight of impurities, based on the total weight of non-solvent molecules in the composition. In some embodiments, the composition includes no more than about 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.6%, 0.4%, or 0.2% by weight of impurities, or ranges including and / or spanning the aforementioned values, based on the total weight of non-solvent molecules in the composition. In some embodiments, Compound A in the composition is present, at least in part, in a free base form as described herein. In some embodiments, Compound A in the composition is present, at least in part, in a crystalline form as described herein.

[0075] In some embodiments, the composition includes no more than about 5% by weight of impurities, based on the total weight of the composition other than water. In some embodiments, the composition includes no more than about 15%, 14°%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.6%, 0.4%, or 0.2% by weight of impurities, or ranges including and / or spanning the aforementioned values, based on the total weight of the composition other than water. In some embodiments, the composition includes no more than about 3% by weight of impurities, based on the total weight of non-solvent molecules in the composition other than water. In some embodiments, the composition includes no more than about 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.6%, 0.4%, or 0.2% by weight of impurities, or ranges including and / or spanning the aforementioned values, based on the total weight of non- solvent molecules in the composition other than water. In some embodiments, Compound A in the composition is present, at least in part, in a free base form as described herein. In some embodiments, Compound A in the composition is present, at least in part, in a crystalline form as described herein.

[0076] In some embodiments, the composition includes no more than about more than about 1% by weight of impurities other than solvent impurities, based on the total weight of molecules in the composition other than water. In some embodiments, the composition includes no more than about more than about 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.6%, 0.4%, or 0.2% by weight of impurities other solvent impurities, or ranges including and / or spanning the aforementioned values. In some embodiments, Compound A in the composition is present, at least in part, in a free base form as described herein. In some embodiments, Compound A in the composition is present, at least in part, in a crystalline form as described above.

[0077] In some embodiments, the composition includes no more than about more than about 1% by weight of impurities, based on a HPLC analysis. In some embodiments, the composition includes no more than about more than about 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.6%, 0.4% or 0.2% by weight of impurities, based on a HPLC analysis. In some embodiments, Compound A in the composition is present, at least in pail, in a free base form as described herein. In some embodiments, Compound A in the composition is present, at least in part, in a crystalline form as described herein.

[0078] One aspect of the disclosure relates to salts of Compound A, which may also be referred to as “salt forms of Compound A” or “Compound A salts.” In some embodiments, the solid may be amorphous, crystalline, or a mixture of such forms. In some embodiments, the salt is at least 50% in crystalline form. In further embodiments, the salt can be at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, and 100% crystalline. In some embodiments, the crystalline form can be chosen from NP3, NP4, NP7, NP8, NP11, NP13, NP14, NP15, NP16, NP17, and NP18.

[0079] In some embodiments, a salt form of Compound A includes crystalline NP3 characterized by an XRPD pattern substantially similar to the XRPD in FIGURE 17. In some embodiments, a salt form of Compound A includes crystalline NP4 characterized by an XRPD pattern substantially similar to the XRPD in FIGURE 18. In some embodiments, a salt form of Compound A includes crystalline NP7 characterized by an XRPD pattern substantially similar to the XRPD in FIGURE 20. In some embodiments, a salt form of Compound A includes crystalline NP8 characterized by an XRPD pattern substantially similar to the XRPD in FIGURE 19. In some embodiments, a salt form of Compound A includes crystalline NP11 characterized by an XRPD pattern substantially similar to the XRPD in FIGURE 21. In some embodiments, a salt form of Compound A includes crystalline NP13 characterized by an XRPD pattern substantially similar to the XRPD in FIGURE 20. In some embodiments, a salt form of Compound A includes crystalline NP14 characterized by an XRPD pattern substantially similar to the XRPD in FIGURE 16. In some embodiments, a salt form of Compound A includes crystalline NP15 characterized by an XRPD pattern substantially similar to the XRPD in FIGURE 22. In some embodiments, a salt form of Compound A includes crystalline NP16 characterized by an XRPD pattern substantially similar to the XRPD in FIGURE 22. In some embodiments, a salt form of Compound A includes crystalline NP17 characterized by an XRPD pattern substantially similar to the XRPD in FIGURE 23. In some embodiments, a salt form of Compound A includes crystalline NP18 characterized by an XRPD pattern substantially similar to the XRPD in FIGURE 25.Administration and Pharmaceutical Compositions

[0080] Some embodiments include compositions comprising a crystalline form of Compound A described herein and a pharmaceutically acceptable carrier. Such a composition can be administered to a subject as part of a therapeutic treatment.

[0081] Standard pharmaceutical formulation techniques can be used to make the pharmaceutical compositions described herein, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), incorporated herein by reference in its entirety. Accordingly, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of Compound A, or a crystalline form as described herein, or pharmaceutically acceptable salts thereof, and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0082] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.

[0083] Some examples of substances, which can serve as pharmaceutically- acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0084] The compositions described herein may be provided in unit dosage form. As used herein, a “unit dosage form” is a composition containing an amount of a compound or composition that is suitable for administration to an animal, preferably a mammalian subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, although a single administration is not specifically excluded. The skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.

[0085] The compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, sublingual, buccal, nasal, rectal, topical (including transdermal and intradermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration. The skilled artisan will appreciate that oral and nasal compositions include compositions that are administered by inhalation, and made using available methodologies. Depending upon the particular route of administration desired, a variety of pharmaceutically- acceptable carriers well-known in the ail may be used. Pharmaceutically-acceptable earners include, for example, solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the activity of the compound or composition. The amount of carrier employed in conjunction with the compound or composition is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

[0086] Various oral dosage forms can be used, including such solid forms as tablets, capsules (c.g., liquid gel capsule and solid gel capsule), granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.Methods and Uses

[0087] Without wanting to be bound by theory, it is believed that Compound A is a dual-MEK inhibitor that inhibits ERK and MEK. Compound A allosterically inhibits MEK by targeting the site lying adjacent to the binding pocket of adenosine triphosphate, or ATP, which would result in downstream inhibition of ERK. Compound A has a short plasma halflife, with a near-zero steady state drug trough concentration to enable deep, cyclic inhibition of the MAPK pathway. Compound A is a potent, non- ATP competitive, small molecule dual inhibitor of MEK. Compound A is a dual MEKi with a new approach to MEK inhibition that is differentiated from first-generation MEKi by allosterically disrupting the activation of MEK itself, instead of inhibiting the ability of MEK to activate ERK. In contrast to first-generation MEK inhibitors, Compound A blocks both MEK phosphorylation as well as downstream phosphorylation of ERK (i.e., dual MEK). Without being bound by theory, it is believed that Compound A prevents RAF-mediated MEK activation and further disrupts KSR by also engaging the RAF activation loop on MEK. In contrast, first-generation MEK inhibitors are believed to engage the allosteric pocket of MEK to prevent the downstream phosphorylation of ERK. Phosphorylation of MEK through the RAF activation pathway is left unimpeded. Depleting intracellular' pools of pERK is believed to remove the negative feedback signal on CRAF, which in turn is believed to hyperactivate phosphorylated MEK (pMEK) through CRAF leading to CRAF bypass.

[0088] In some embodiments, the dual MEK inhibitor is Compound A and the method of treatment comprises administering a pharmaceutical composition comprising a solidform of Compound A once-daily to a patient in need thereof, for the treatment of a solid tumor harboring RAS mutations. Compound A may be formulated as a pharmaceutical composition comprising one or more solid form(s) of Compound A (e.g., solid Form 1, solid Form 2, salt forms, or a combination thereof, as disclosed herein) using a pharmaceutically acceptable excipients and administered by a variety of routes. In some embodiments, the compositions are for oral administration. Such pharmaceutical compositions and processes for preparing them are well known in the art. (See, e.g., Remington: The Science and Practice of Pharmacy, L. V. Allen, Editor, 22nd Edition, Pharmaceutical Press, 2012). In a particular’ embodiment, the pharmaceutical composition comprises 4-((dimethylamino)methyl)-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

[0089] In some embodiments, methods of treating a patient diagnosed with a cancer harboring a RAS mutation, comprising administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a solid form of Compound A once daily. In some embodiments, the patient is diagnosed with a cancer selected from the group consisting of: NRAS-mutated melanoma, KRAS-mutated PDAC, KRAS- mutated NSCLC and KRAS-mutated, and APC-wildtype CRC. In some embodiments, the cancer is NRAS-mutated melanoma. In some embodiments, the cancer is KRAS-mutated PDAC. In some embodiments, the cancer is KRAS-mutated NSCLC. In some embodiments, the cancer is KRAS-mutated CRC. In some embodiments, the cancer is APC-wildtype CRC. In some embodiments, the cancer is pancreatic cancer with a KRAS G12C mutation. In some embodiments, the cancer is pancreatic cancer with a G12D mutation. In some embodiments, the cancer is pancreatic cancer with a G12V mutation. In some embodiments, the cancer is colorectal cancer with a NRAS Q61L mutation. In some embodiments, the cancer is colorectal cancer with a NRAS Q61K mutation. In some embodiments, the cancer is colorectal cancer with a KRAS G12D mutation. In some embodiments, the cancer is melanoma with a NRAS Q61R mutation. In some embodiments, the cancer is melanoma with a KRAS G12S mutation. In some embodiments, the cancer melanoma with a BRAF V600E mutation. In some embodiments, the cancer is non-small cell lung cancer (NSCLC) with a KRAS G12S mutation.

[0090] In some embodiments, methods of treating a patient with a RAS-mutated cancer can comprise the administration of a therapeutically effective amount of a dual-MEKinhibitor inhibiting both the phosphorylation of mitogen-activated protein kinase kinase MEK1 and MEK2 (MEK) and the phosphorylation of mitogen-activated protein kinase (pERK), wherein the dual-MEK inhibitor is administered to the patient (a) in a dose amount that achieves a Cmax effective to inhibit pERK and MEK and (b) with an interval between consecutive doses that is at least about seven times the plasma half-life of the dual-MEK inhibitor. The Cmax measured on the day of initial administration of the dual-MEK inhibitor is may be at least 2,000 ng / mL. The dual-MEK inhibitor can have at least about 1 micromolar dual-MEK inhibitor free fraction. The Cmin, about 0.1 micromolar free fraction, of the dual- MEK inhibitor may occur more than about 6 hours after the administration of the dual-MEK inhibitor. For example, the Cmin of about 0.1 micromolar free fraction occurs about 6-8 hours after the administration of the dual-MEK inhibitor, or later. In some embodiments, the interval between consecutive doses of the dual-MEK inhibitor that is about seven to eighteen times the plasma half-life of the dual-MEK inhibitor. In some embodiments, the dual-MEK inhibitor is a solid form of Compound A free base or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the cancer has a RAS mutation that is a KRAS G12D or G12V mutation or a NRAS Q61L or Q61K mutation. In some embodiments, the cancer has a KRAS G12D mutation. In some embodiments, the cancer has a KRAS G12V mutation. In some embodiments, the cancer has a NRAS Q61L mutation. In some embodiments, the cancer has a NRAS Q61K mutation.

[0092] As used herein, the terms “deg C” and “°C” refer interchangeably to degrees Centigrade.Additional Embodiments

[0093] In some embodiments, the solid form of the free base of Compound A is Solid Form 1 as disclosed herein. In some embodiments, the solid form of the free base of Compound A is a crystalline solid form as disclosed herein. In some embodiments, the crystalline form is Form 1. In some embodiments, Form 1 exhibits an X-ray powder diffraction pattern comprising peaks selected from about 15.8°, 16.3°, and 21.8° 20 (±0.2 20). In some embodiments, Form 1 exhibits an X-ray powder diffraction pattern comprising at least three peaks at about 10.8°, 12.6°, 15.6°, 16.3°, 15.8°, and 21.8° 20 (±0.220). In some embodiments, Form 1 exhibits an X-ray powder diffraction pattern comprising the peaks at about 10.8°, 12.6°,15.6°, 15.8°, 16.3°, and 21.8° 20 (±0.2 20). In some embodiments, Form 1 exhibits an X-ray powder diffraction pattern comprising at least three peaks at about 10.8°, 12.6°, 13.5°, 15.6°, 15.8°, 16.3°, 16.5°, 16.8°, 18.2°, 20.6°, 21.8° and 27.2° 20 (±0.2 20). In some embodiments, Form 1 exhibits an X-ray powder diffraction pattern comprising the peaks at about 10.8°, 12.6°, 13.5°, 15.6°, 15.8°, 16.3°, 16.5°, 16.8°, 18.2°, 20.6°, 21.8° and 27.2° 20 (±0.2 20). In some embodiments, the solid form of the free base of Compound A is characterized by an X-ray powder diffraction pattern comprising peaks at 20 values (±0.2) of 10.8°, 12.6°, 15.8°, 16.3°, and 21.8°. In some embodiments, the Form 1 of Compound A exhibits an X-ray powder diffraction pattern substantially as shown in Figure 7. In some embodiments, the Form 1 of Compound A exhibits an X-ray powder diffraction pattern substantially as shown in Figure 8. In some embodiments, the Form 1 of Compound A exhibits an X-ray powder diffraction pattern substantially as shown in Figure 9. In some embodiments, Form 1 is further characterized by a TGA / DSC showing a melting event at Tpcak of about 150 °C and a decomposition event at TonSet of about 245-255 °C and a mass loss of about 35%. In some embodiments, Form 1 is further characterized by a TGA / DSC showing a melting event at Tpeak of about 149.3-150.5 °C and a decomposition event at Tonset of about 245.6-255.7 °C and a mass loss of about 35.0-35.3%. In some embodiments, the solid form of the free base of Compound A is characterized by a TGA / DSC showing a melting event at Tpeak of about 150 °C and a decomposition event at Tonsetof about 245-255 °C and a mass loss of about 35%. In some embodiments, the solid form of Compound A is characterized by a TGA / DSC showing a melting event at Tpeak of about 149.3-150.5 °C and a decomposition event at Tonset of about 245.6-255.7 °C and a mass loss of about 35.0-35.3%.

[0094] Some embodiments disclosed herein relate to a crystalline form of of Compound A having the following structure:(Compound A).

[0095] In some embodiments, the solid form of the free base of Compound A is Solid Form 2 as disclosed herein. In some embodiments, the solid form of the free base of Compound A is a crystalline solid form as disclosed herein. In some embodiments, the crystalline form is Form 2. In some embodiments, Form 2 exhibits an X-ray powder diffraction pattern comprising peaks selected from about 9.1°, 9.5°, and 17.8° 29 (±0.2 20). In some embodiments, Form 2 exhibits an X-ray powder diffraction pattern comprising the peaks at about of 9.1°, 9.5°, 16.4° and 17.8° 29 (±0.2 20). In some embodiments, Form 2 exhibits an X-ray powder diffraction pattern comprising at least three peaks at about 9.1°, 9.5°, 13.3°, 16.4°, 17.8° and 23.7° 20 (±0.2 20). In some embodiments, Form 2 exhibits an X-ray powder diffraction pattern comprising peaks at about 9.1°, 9.5°, 13.3°, 16.4°, 17.8° and 23.7° 20 (±0.2 20). In some embodiments, Form 2 exhibits an X-ray powder diffraction pattern comprising at least five peaks at about 7.1°, 9.1°, 9.5°, 13.3°, 16.4°, 17.8°, 19.3°, 20.7°, 21.3°, 21.5°, 22.4°, 23.7°, and 23.4° 20 (±0.2 20). In some embodiments, Form 2 exhibits an X-ray powder diffraction pattern comprising peaks at about 7.1°, 9.1°, 9.5°, 13.3°, 16.4°, 17.8°, 19.3°, 20.7°, 21.3°, 21.5°, 22.4°, 23.7°, and 23.4° 29 (±0.2 20). In some embodiments, Form 2 exhibits an X-ray powder diffraction pattern substantially as shown in Figure 15A. In some embodiments, Form 2 is further characterized by a TGA / DSC showing a melting event at Tpeak of about 165.0 °C and a decomposition event at Tonsetof about 260 °C and a mass loss of about 30%. In some embodiments, Form 2 is further characterized by a TGA / DSC showing a melting event at Tpeak of about 165 °C and a decomposition event at Tonset of about 260 °C and a mass loss of about 29.7%. In some embodiments, the solid form of the free base of Compound A is characterized by an X-ray powder diffraction pattern comprising peaks at 20 values (±0.2) of 9.1°, 9.5°, 13.3°, 16.4° and 17.3°. In some embodiments, the solid form of the free base of Compound A is characterized by a TGA / DSC showing a melting event at Tpeak of about 165.0 °C and a decomposition event at Tonset of about 260 °C and a mass loss of about 30%. In some embodiments, the solid form of Compound A is characterized by a TGA / DSC showing a melting event at Tpeak of about 165 °C and a decomposition event at Tonsetof about 260 °C and a mass loss of about 29.7%.

[0096] Some embodiments relate herein to a composition comprising a solid form of the free base of Compound A, selected from the group consisting of Form 1 of a free base of Compound A and Form 2 of a free base of Compound A having the following structure:(Compound A).

[0097] In some embodiments, the Form 1 of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at about 15.8°, 16.3°, and 21.8° 20 (±0.220), and the Form 2 of the free base of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at about 9.1°, 9.5°, and 17.8° 20 (±0.220).

[0098] In some embodiments, the solid form of the free base of Compound A is Form 1. In some embodiments, the Form 1 of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 2-theta angles of 10.8, 12.6, 15.6, 16.3, 15.8, and 21.8 (±0.2 20). In some embodiments, the Form 1 of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 2-theta angles of 10.8, 12.6, 13.5, 15.6, 15.8, 16.3, 16.5, 16.8, 18.2, 20.6, 21.8 and 27.2 (±0.2 20). In some embodiments, the solid form is further characterized by a TGA / DSC showing a melting event at Tpeak of about 150 °C and a decomposition event at Tonset of about 245-255 °C and a mass loss of about 35%. In some embodiments, the solid form is further characterized by a TGA / DSC showing a melting event at Tpeak of about 149.3-150.5 °C and a decomposition event at Tonset of about 245.6-255.7 °C and a mass loss of about 35.0-35.3%. In some embodiments, the Form 1 of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 7, Figure 8, or Figure 9.

[0099] In some embodiments, Form 2 of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 2-thetaangles of 9.1, 9.5, 16.4 and 17.8 (+0.2 20). In some embodiments, the Form 2 of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 2-theta angles of 9.1 , 9.5, 13.3, 16.4, 17.8 and 23.7 (±0.2 20). In some embodiments, the Form 2 of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 2-theta angles of 7.1, 9.1, 9.5, 13.3, 16.4, 17.8, 19.3, 20.7, 21.3, 21.5, 22.4, 23.7, and 23.4 (±0.2 20). In some embodiments, the solid form is further characterized by a TGA / DSC showing a melting event at Tpeak of about 165.0 °C and a decomposition event at Tonset of about 260 °C and a mass loss of about 30%. In some embodiments, the solid form is further characterized by a TGA / DSC showing a melting event at Tpeak of about 165 °C and a decomposition event at TOUset of about 260 °C and a mass loss of about 29.7%. In some embodiments, the Form 2 of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 15A.

[0100] In some embodiments, pharmaceutical composition are provided, including oral dosage forms of Compound A. In some embodiments, a pharmaceutical composition comprises the free base of Compound A in solid Form 2. In some embodiments, the pharmaceutical composition can be formed into a tablet or other unit dosage form. In some embodiments, the pharmaceutical composition comprises the free base of Compound A, and is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 2-theta angles of 7.0, 9.2, 9.6, 13.4 and 16.4 (±0.2 20). In some embodiments, the pharmaceutical composition comprises compound A as a free base in solid Form 2; a disintegrant (e.g., an insoluble polymer of N-vinyl-2-pyrrolidone such as crospovidone); a tablet binder, thickening agent, viscosity-increasing agent, coating agent and / or film former (e.g., hydroxypropyl cellulose, such as HPC-SL and / or L-HPC); and a lubricant (e.g., magnesium stearate). In some embodiments, oral dosage forms (e.g., tablets, or capsules) having Compound A at a dosage strength of 120 mg or 160 mg are provided.

[0101] Some embodiments relate to crystalline salt forms of Compound A, including those derived from galactaric acid, aspartic acid, hippuric acid, ascorbic acid, glutamic acid, and l,5-naphthalcnc-l,5-disulfonic acid.

[0102] Some embodiments relate to a pharmaceutical composition comprising a pharmaceutically effective amount of the crystalline form as described herein or a composition as described herein, and at least one pharmaceutically acceptable carrier.

[0103] Some embodiments relate to a method of treating a patient with a RAS- mutated cancer, comprising administering a therapeutically effective amount of the pharmaceutical composition as described herein, wherein the Compound A is administered to the patient (a) in a dose amount that achieves a Cmax effective to inhibit pERK and pMEK and (b) with an interval between consecutive doses that is at least about seven times the plasma half-life of the dual-MEK inhibitor.

[0104] Some embodiments relate to a method of treating a patient with a cancer with a KRAS G12D or G12V mutation, or a cancer with a NRAS Q61L or Q61K mutation, the method consisting of orally administering to the patient in need thereof a therapeutically effective amount of Compound A, in the pharmaceutical composition of as described herein.

[0105] Some embodiments relate to a method of treating a patient with a cancer with a mutation in KRAS, NRAS, or HRAS, the method consisting of orally administering to the patient in need thereof with a therapeutically effective dose of Compound A in the pharmaceutical composition as described herein once daily to treat the cancer.

[0106] Some embodiments relate to a method of treating a patient with a RAS- mutated cancer, comprising administering once-daily orally a therapeutically effective amount of Compound A in the pharmaceutical composition of as described herein, wherein the, wherein the Compound A is administered to the patient (a) in a dose amount that achieves a Cmax, wherein, the Cmax is measured on day one of administering the dual-MEK inhibitor, wherein the Cmax at least 2,000 ng / mL and (b) with an interval between consecutive doses of the dual-MEK inhibitor is about seven to eight times a plasma half-life of the Compound A. In some embodiments, the cancer has a MAPK mutation selected from the group consisting of: KRAS-G12S, BRAF-V600E, NRAS-Q61R, KRAS-G12C, NRAS-Q61K, or KRAS-G12D. In some embodiments, the cancer has a KRAS, BRAF, NRAS, or MAPK mutation. In some embodiments, the cancer is selected from the group consisting of: human lung adenocarcinoma, human malignant melanoma, human NSCLC and human colon carcinoma.

[0107] In some embodiments, one or more of following compositions and methods are also provided.

[0108] 1. A crystalline form of a compound having the formula:(Compound A) wherein the crystalline form is Form 1 exhibiting an X-ray powder diffraction pattern comprising peaks selected from about 15.8°, 16.3°, and 21.8° 20 (±0.2 20).

[0109] 2. The crystalline form of embodiment 1, exhibiting an X-ray powder diffraction pattern comprising at least three peaks at about 10.8°, 12.6°, 15.6°, 15.8°, 16.3°, and 21.8° 20 (±0.2 2 0).

[0110] 3. The crystalline form of embodiment 1 or 2, exhibiting an X-ray powder diffraction pattern comprising the peaks at about 10.8°, 12.6°, 15.6°, 15.8°, 16.3°, and 21.8° 20 (±0.22 0).

[0111] 4. The crystalline form of embodiment 1 or 2, exhibiting an X-ray powder diffraction pattern comprising at least three peaks at about 10.8°, 12.6°, 13.5°, 15.6°, 15.8°, 16.3°, 16.5°, 16.8°, 18.2°, 20.6°, 21.8° and 27.2° 20 (±0.22 0).

[0112] 5. The crystalline form of embodiment 4, exhibiting an X-ray powder diffraction pattern comprising the peaks at about 10.8°, 12.6°, 13.5°, 15.6°, 15.8°, 16.3°, 16.5°, 16.8°, 18.2°, 20.6°, 21.8° and 27.2° 20 (±0.22 0).

[0113] 6. The crystalline form of any one of embodiments 1 to 5, wherein theCrystal Form 1 of Compound A exhibits an X-ray powder diffraction pattern substantially as shown in Figure 7.

[0114] 7. A solid form of a compound having the formula:(Compound A) wherein the solid form is characterized by one of the X-ray powder diffraction patterns substantially as shown in Figure 9.

[0115] 8. The crystalline form of any one of embodiments 1 to 7, wherein the crystalline form is further characterized by a TGA / DSC showing a melting event at Tpeak of about 150 °C and a decomposition event at Tonset of about 245-255 °C and a mass loss of about 35%.

[0116] 9. The crystalline form of embodiment 8, wherein the crystalline form is further characterized by a TGA / DSC showing a melting event at Tpeak of about 149.3-150.5 °C and a decomposition event at Tonset of about 245.6-255.7 °C and a mass loss of about 35.0- 35.3%.

[0117] 10. A crystalline form of a compound having the formula:(Compound A) wherein the crystalline form is crystalline Form 2 exhibiting an X-ray powder diffraction pattern comprising peaks selected from about 9.1°, 9.5°, and 17.8° 20 (±0.2 29).

[0118] 11. The crystalline form of embodiment 10, exhibiting an X-ray powder diffraction pattern comprising the peaks at about of 9.1°, 9.5°, 16.4° and 17.8° 20 (±0.22 0).

[0119] 12. The crystalline form of embodiment 10 or 11 , exhibiting an X-ray powder diffraction pattern comprising at least three peaks at about 9.1°, 9.5°, 13.3°, 16.4°, 17.8° and 23.7° 20 (±0.2 2 9).

[0120] 13. The crystalline form of embodiment 12, exhibiting an X-ray powder diffraction pattern comprising peaks at about 9.1°, 9.5°, 13.3°, 16.4°, 17.8° and 23.7° 20 (±0.2 2 0).

[0121] 14. The crystalline form of any one of embodiments 10 to 13, exhibiting anX-ray powder diffraction pattern comprising at least five peaks at about 7.1°, 9.1°, 9.5°, 13.3°, 16.4°, 17.8°, 19.3°, 20.7°, 21.3°, 21.5°, 22.4°, 23.7°, and 23.4° 20 (±0.2 20).

[0122] 15. The crystalline form of embodiment 14, exhibiting an X-ray powder diffraction pattern comprising peaks at about 7.1°, 9.1°, 9.5°, 13.3°, 16.4°, 17.8°, 19.3°, 20.7°, 21.3°, 21.5°, 22.4°, 23.7°, and 23.4° 20 (±0.2 2 0).

[0123] 16. The crystalline form of any one of embodiments 10 to 15, wherein theCrystal Form 2 of Compound A exhibits an X-ray powder diffraction pattern substantially as shown in Figure 15 A.

[0124] 17. The crystalline form of any one of embodiments 10 to 16, whereinCrystal Form 2 is further characterized by a TGA / DSC showing a melting event at Tpeak of about 165.0 °C and a decomposition event at Tonset of about 260 °C and a mass loss of about 30%.

[0125] 18. The crystalline form of embodiment 17, wherein Crystal Form 2 is further characterized by a TGA / DSC showing a melting event at Tpeak of about 165 °C and a decomposition event at Tonset of about 260 °C and a mass loss of about 29.7%.

[0126] 19. A composition comprising a solid form of the free base of CompoundA, selected from the group consisting of Form 1 of a free base of Compound A and Form 2 of a free base of Compound A,(Compound A) wherein, the Form 1 of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at about 15.8°, 16.3°, and 21.8° 20 (±0.220); and the Form 2 of the free base of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at about 9.1°, 9.5°, and 17.8° 20 (±0.2 20).

[0127] 20. The composition of embodiment 19, wherein the solid form of the free base of Compound A is Form 1.

[0128] 21. The composition of embodiment 20, wherein the Form 1 of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 2-theta angles of 10.8°, 12.6°, 15.6°, 16.3°, 15.8°, and 21.8° 2 0 (±0.2 29).

[0129] 22. The composition of any one of embodiments 20 to 21, wherein theForm 1 of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at about 10.8°, 12.6°, 13.5°, 15.6°, 15.8°, 16.3°, 16.5°, 16.8°, 18.2°, 20.6°, 21.8° and 27.2° 20 (±0.220).

[0130] 23. The composition of any one of embodiments 20 to 22, wherein the solid form is further characterized by a TGA / DSC showing a melting event at Tpeak of about 150 °C and a decomposition event at Tonset of about 245-255 °C and a mass loss of about 35%.

[0131] 24. The composition of embodiment 23, wherein the solid form is further characterized by a TGA / DSC showing a melting event at Tpeak of about 149.3-150.5 °C and a decomposition event at Tonset of about 245.6-255.7 °C and a mass loss of about 35.0-35.3%.

[0132] 25. The composition of any one of embodiments 20 to 24, wherein theForm 1 of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 7 with a peak list substantially as shown in Figure 8, or substantially as shown in Figure 13A or substantially as shown in Figure 14A.

[0133] 26. The composition of embodiment 19, wherein the Form 2 of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 2-theta angles of 9.1, 9.5, 16.4 and 17.8 20 (±0.220).

[0134] 27. The composition of embodiment 26, wherein the Form 2 of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at about 9.1°, 9.5°, 13.3°, 16.4°, 17.8° and 23.7° 20 (±0.2 20).

[0135] 28. The composition of embodiment 27, wherein the Form 2 of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at about 7.1°, 9.1°, 9.5°, 13.3°, 16.4°, 17.8°, 19.3°, 20.7°, 21.3°, 21.5°, 22.4°, 23.7°, and 23.4° 26 (±0.2 20).

[0136] 29. The composition of any one of embodiments 26to 28, wherein the solid form is further characterized by a TGA / DSC showing a melting event at Tpeak of about 165.0 °C and a decomposition event at Tonset of about 260 °C and a mass loss of about 30%.

[0137] 30. The composition of embodiment 29, wherein the solid form is further characterized by a TGA / DSC showing a melting event at Tpeak of about 165 °C and a decomposition event at Tonset of about 260 °C and a mass loss of about 29.7%.

[0138] 31. The composition of any one of embodiments 26to 30, wherein theForm 2 of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 15A.

[0139] 32. A pharmaceutical composition comprising a pharmaceutically effective amount of the crystalline form of any one of embodiments 1 to 18 or a composition of any one of embodiments 19 to 31, and at least one pharmaceutically acceptable carrier.

[0140] 33. A method of treating a patient with a RAS-mutated cancer, comprising administering a therapeutically effective amount of the pharmaceutical composition of embodiment 32, wherein the Compound A is administered to the patient (a) in a dose amount that achieves a Cmax effective to inhibit pERK and pMEK and (b) with an interval between consecutive doses that is at least about seven times the plasma half-life of the dual-MEK inhibitor.

[0141] 34. A method of treating a patient with a cancer with a KRAS G12D orG12V mutation, or a cancer with a NRAS Q61L or Q61K mutation, the method consisting of orally administering to the patient in need thereof a therapeutically effective amount of Compound A, in the pharmaceutical composition of embodiment 32.

[0142] 35. A method of treating a patient with a cancer with a mutation in KRAS,NRAS, or HRAS, the method consisting of orally administering to the patient in need thereof with a therapeutically effective dose of Compound A in the pharmaceutical composition of embodiment 32 once daily to treat the cancer.

[0143] 36. A method of treating a patient with a RAS-mutated cancer, comprising administering oncc-daily orally a therapeutically effective amount of Compound A in the pharmaceutical composition of embodiment 32, wherein the, wherein the Compound A is administered to the patient (a) in a dose amount that achieves a Cmax, wherein, the Cmax is measured on day one of administering the dual-MEK inhibitor, wherein the Cmax at least 2,000 ng / mL and (b) with an interval between consecutive doses of the dual-MEK inhibitor is about seven to eight times a plasma half-life of the Compound A.

[0144] 37. The method of any one of embodiments 33 to 36, wherein the cancer has a MAPK mutation selected from the group consisting of: KRAS-G12S, BRAF-V600E, NRAS-Q61R, KRAS-G12C, NRAS-Q61K, or KRAS-G12D.

[0145] 38. The method of any one of embodiments 33 to 37, wherein the cancer has a KRAS, BRAF, NRAS, or MAPK mutation.

[0146] 39. The method of any one of embodiments 33 to 38, wherein the cancer is selected from the group consisting of: human lung adenocarcinoma, human malignant melanoma, human NSCLC and human colon carcinoma.

[0147] 40. A crystalline form of a compound having the formula:(Compound A) wherein the crystalline exhibits an X-ray powder diffraction pattern comprising peaks selected from about 16.2°, 21.8°, and 27.2° 20 (±0.220).

[0148] 41. The crystalline form of embodiment 40, exhibits an X-ray powder diffraction pattern comprising at least three peaks at about 15.7°, 15.8°, 16.2°, 16.5°, 21.8°, and 27.2° 20 (±0.2 20).

[0149] 42. The crystalline form of embodiment 40 or 41, exhibits an X-ray powder diffraction pattern comprising the peaks at about 13.5°, 15.7°, 15.8°, 16.2°, 16.5°, 21.8°, and 27.2° 20 (±0.2 20).

[0150] 43. The crystalline form of embodiment 40 or 41 , exhibits an X-ray powder diffraction pattern comprising at least three peaks at about 10.8°, 12.6°, 13.5°, 15.6°, 15.7°, 15.8°, 16.2°, 16.5°, 21.8°, and 27.2° 29 (±0.2 29).

[0151] 44. The crystalline form of embodiment 40 or 41 , exhibits an X-ray powder diffraction pattern comprising at least three peaks at about 10.8°, 12.5°, 12.6°, 13.5°, 15.6°, 15.7°, 15.8°, 16.1°, 16.2°, 16.4°, 16.5°, 18.8°, 21.7°, 26.2°, and 27.2° 29 (±0.2 29).

[0152] 45. The crystalline form of any one of embodiments 40 to 44, wherein crystal form further characterized by a TGA / DSC showing a melting event at Tpeak of about 150 °C and a decomposition event at Tonset of about 245-255 °C and a mass loss of about 35%.

[0153] 46. The crystalline form of embodiment 45, wherein the crystalline form is further characterized by a TGA / DSC showing a melting event at Tpeak of about 149.3-150.5 °C and a decomposition event at Tonset of about 245.6-255.7 °C and a mass loss of about 35.0- 35.3%.

[0154] 47. A salt form of a compound having the formula:(Compound A).

[0155] 48. The salt form of embodiment 47, wherein the salt form comprises a counter ion selected from the group consisting of potassium, sodium, chloride, sulfate, bisulfate, aspartate, maleate, phosphate, glutamate, tartrate, fumarate, citrate, L-malate, hippurate, D-gluconate, L-ascorbate, succinate, acetate, naphthalene- 1,5-disulfonate ethanesulfonate, ethane- 1,2- sufonate, p-toluenesulfonate, methanesulfonate and benzoate.

[0156] 49. The salt form of embodiment 47 or 48, wherein the salt is at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% in crystalline form.

[0157] 50. The salt form of any one of embodiments 47to 49, wherein the salt form is characterized by an XRPD pattern of NP3 (aspartic acid salt) having an X-ray powder diffraction pattern substantially as shown in Figure 17.

[0158] 51. The salt form of any one of embodiments 47to 49, wherein the salt form is characterized by an XRPD pattern of NP4 (maleic acid) having an X-ray powder diffraction pattern substantially as shown in Figure 18.

[0159] 52. The salt form of any one of embodiments 47to 49, wherein the salt form is characterized by an XRPD pattern of NP7 (ascorbic acid) having an X-ray powder diffraction pattern substantially as shown in Figure 20.

[0160] 53. The salt form of any one of embodiments 47to 49, wherein the salt form is characterized by an XRPD pattern of NP8 (hippuric acid salt) having an X-ray powder diffraction pattern substantially as shown in Figure 19.

[0161] 54. The salt form of any one of embodiments 47 to 49, wherein the salt form is characterized by an XRPD pattern of NP11 (glutamic acid) having an X-ray powder diffraction pattern substantially as shown in Figure 21.

[0162] 55. The salt form of any one of embodiments 47 to 49, wherein the salt form is characterized by an XRPD pattern of NP13 (ascorbic acid) having an X-ray powder diffraction pattern substantially as shown in Figure 20 and Figure 24.

[0163] 56. The salt form of any one of embodiments 47 to 49, wherein the salt form is characterized by an XRPD pattern of NP14 (galactaric acid) having an X-ray powder diffraction pattern substantially as shown in Figure 16.

[0164] 57. The salt form of any one of embodiments 47 to 49, wherein the salt form is characterized by an XRPD pattern of NP15 (naphthalene- 1,5-disulfonic acid salt) having an X-ray powder diffraction pattern substantially as shown in Figure 22.

[0165] 58. The salt form of any one of embodiments 47 to 49, wherein the salt form is characterized by an XRPD pattern of NP16 (naphthalene- 1,5-disulfonic acid salt) having an X-ray powder diffraction pattern substantially as shown in Figure 22.

[0166] 59. The salt form of any one of embodiments 47 to 49, wherein the salt form is characterized by an XRPD pattern of NP17 (galactaric acid) having an X-ray powder diffraction pattern substantially as shown in Figure 23.

[0167] 60. The salt form of any one of embodiments 47to 49, wherein the salt form is characterized by an XRPD pattern of NP18 (naphthalene- 1,5-disulfonic acid) having an X- ray powder diffraction pattern substantially as shown in Figure 25.

[0168] 61. A 4-((dimethylamino)methyl)-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate galactaric acid salt solid form (NP14), wherein said salt solid form is characterized by an X-ray powder diffraction pattern (XRPD) substantially as shown in Figure 23.

[0169] 62. The 4-((dimethylamino)methyl)-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate galactaric acid salt crystal form of embodiment 61, wherein the galactaric acid salt solid form is at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% crystalline.

[0170] 63. The salt form of embodiment 61or 62, wherein the XRPD crystalline form is substantially similar to the XRPD pattern of NP14.

[0171] 64. A 4-((dimethylamino)methyl)-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate ascorbic acid solid form.

[0172] 65. The 4-((dimethylamino)methyl)-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate ascorbic acid salt crystal form of embodiment 64, wherein the ascorbic acid salt crystal form is at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% in crystalline form.

[0173] 66. The salt form of embodiment 64or 65, wherein the solid form is characterized by a XRPD pattern that is substantially similar to the XRPD pattern of NP7.

[0174] 67. The salt form of embodiment 64or 65, wherein the solid form is characterized by a XRPD pattern that is substantially similar to the XRPD pattern of NP13.

[0175] 68. A solid form of a free base of a compound having the formula:(Compound A) wherein the solid form is characterized by an X-ray powder diffraction pattern comprising peaks at 26 values (±0.2) of 10.8°, 12.6°, 15.8°, 16.3°, and 21.8°.

[0176] 69. The solid form of embodiment 68, further characterized by a TGA / DSC showing a melting event at Tpeak of about 150 °C and a decomposition event at Tonset of about 245-255 °C and a mass loss of about 35%.

[0177] 70. The solid form of embodiment 69, wherein the solid form is further characterized by a TGA / DSC showing a melting event at Tpeak of about 149.3-150.5 °C and a decomposition event at Tonset of about 245.6-255.7 °C and a mass loss of about 35.0-35.3%.

[0178] 71. A composition comprising solid Form 1 of the free base ofCompound A(Compound A).

[0179] 72. A solid form of a free base of a compound having the formula:(Compound A)wherein, the solid form is characterized by an X-ray powder diffraction pattern comprising peaks at 26 values (±0.2) of 9.1°, 9.5°, 13.3°, 16.4° and 17.3°.

[0180] 73. The solid form of embodiment 72, wherein the solid form is characterized by an X-ray powder diffraction pattern further comprising peaks at 26 values (±0.2) of 19.3°, 21.3° and 23.3° 26 (±0.2 26).

[0181] 74. The solid form of embodiment 73, wherein the solid form is characterized by an X-ray powder diffraction pattern further comprising peaks at 26 values (±0.2) of 7.1°, 19.6°, 21.5° 23.4°, and 23.8° 26 (±0.226).

[0182] 75. The solid form of any one of embodiments 72-74, wherein the solid form is further characterized by a TGA / DSC showing a melting event at Tpeak of about 165.0 °C and a decomposition event at Tonset of about 260 °C and a mass loss of about 30%.

[0183] 76. The solid form of embodiment 75, wherein the solid form is further characterized by a TGA / DSC showing a melting event at Tpeak of about 165 °C and a decomposition event at Tonset of about 260 °C and a mass loss of about 29.7%.

[0184] 77. A composition comprising solid Form 2 of the free base ofCompound A(Compound A).

[0185] 78. A solid form of a free base of a compound having the formula:(Compound A) characterized by a TGA / DSC showing a melting event at Tpeakof about 150 °C and a decomposition event at Tonset of about 245-255 °C and a mass loss of about 35%.

[0186] 79. The solid form of embodiment 78, wherein the solid form is further characterized by a TGA / DSC showing a melting event at Tpeak of about 149.3-150.5 °C and a decomposition event at Tonset of about 245.6-255.7 °C and a mass loss of about 35.0-35.3%.

[0187] 80. A solid form of a free base of a compound having the formula:(Compound A) characterized by a TGA / DSC showing a melting event at Tpeak of about 165.0 °C and a decomposition event at Tonset of about 260 °C and a mass loss of about 30%.

[0188] 81. The solid form of embodiment 80, wherein the solid form is further characterized by a TGA / DSC showing a melting event at Tpeak of about 165 °C and a decomposition event at Tonset of about 260 °C and a mass loss of about 29.7%.

[0189] 82. A pharmaceutical composition comprising a pharmaceutically effective amount of the salt form of any one of embodiments 1 to 81 at least one pharmaceu tic ally acceptable carrier.

[0190] 83. A method of treating a patient with a RAS-mutated cancer, comprising administering a therapeutically effective amount of the pharmaceutical composition of embodiment 82, wherein the Compound A is administered to the patient (a) ina dose amount that achieves a Cmax effective to inhibit pERK and pMEK and (b) with an interval between consecutive doses that is at least about seven times the plasma half-life of the dual-MEK inhibitor.

[0191] 84. A method of treating a patient with a cancer with a KRAS G12D orG12V mutation, or a cancer with a NRAS Q61L or Q61K mutation, the method consisting of orally administering to the patient in need thereof a therapeutically effective amount of Compound A, in the pharmaceutical composition of embodiment 82.

[0192] 85. A method of treating a patient with a cancer with a mutation in KRAS,NRAS, or HRAS, the method consisting of orally administering to the patient in need thereof with a therapeutically effective dose of Compound A in the pharmaceutical composition of embodiment 82 once daily to treat the cancer.

[0193] 86. A method of treating a patient with a RAS-mutated cancer, comprising administering once-daily orally a therapeutically effective amount of Compound A in the pharmaceutical composition of embodiment 82, wherein the, wherein the Compound A is administered to the patient (a) in a dose amount that achieves a Cmax, wherein, the Cmax is measured on day one of administering the dual-MEK inhibitor, wherein the Cmax at least 2,000 ng / mL and (b) with an interval between consecutive doses of the dual-MEK inhibitor is about seven to eight times a plasma half-life of the Compound A.

[0194] 87. The method of any one of embodiments 84 to86, wherein the cancer has a MAPK mutation selected from the group consisting of: KRAS-G12S, BRAF-V600E, NRAS-Q61R, KRAS-G12C, NRAS-Q61K, or KRAS-G12D.

[0195] 88. The method of any one of embodiments 84 to 87, wherein the cancer has a KRAS, BRAF, NRAS, or MAPK mutation.

[0196] 89. The method of any one of embodiments 84 to 88, wherein the cancer is selected from the group consisting of: human lung adenocarcinoma, human malignant melanoma, human NSCLC and human colon carcinoma.EXAMPLES

[0197] The following examples are given for the purpose of illustrating various embodiments of the disclosure and are not meant to limit the present disclosure in any fashion. One skilled in the art will appreciate readily that the present disclosure is well adapted to carryout the objects and obtain the ends and advantages mentioned, as well as those objects, ends and advantages inherent herein. Changes therein and other uses which arc encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art.EXAMPLE 1ASynthesis of Compound A

[0198] Compound A was prepared in 1 step:

[0199] 4-(bromomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2- oxo-2H-chromen-7-yl dimethylcarbamate (22.22 g, 34.79 mmol) was suspended in methanol. Dimethylamine 2M was added and the formed reaction mixture was stirred until full conversion was observed. After full conversion the reaction was concentrated under reduced pressure. IM HC1 was added to the residue and the water layer was extracted with CH2CI2. The water layer was made basic with solid Na CCE. The basic water layer was extracted with CH2CI2. The organic layer from the basic extraction was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the title compound (13.23 g, 25.7 mmol, yield: 74%) as a light yellow amorphous solid.

[0200] Yield: Compound A was isolated as a light yellow solid (74% over 1 step). Analysis: LCMS (Method T): tR = 1.53 min; m / z calculated for [M+H]+= 507.2, found = 507.2; 1H NMR (400 MHz, DMSO) d 9.38 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.28 (td, J = 8.0, 1.6 Hz, 1H), 7.25 - 7.18 (m, 2H), 7.15 (dd, J = 8.8, 2.4 Hz, 1H), 7.00 (t, J = 7.9 Hz, 1H), 6.90 - 6.77 (m, 1H), 4.04 (s, 2H), 3.64 (s, 2H), 3.06 (s, 3H), 2.93 (s, 3H), 2.52 (d, J = 4.9 Hz, 3H), 2.19 (s, 6H).EXAMPLE IBCompound A Nonclinical Pharmacology

[0201] Compound A is a potent, non-adenosine 5'-Triphosphate (ATP) competitive selective dual MEK inhibitor with the biochemical inhibitory half-maximal inhibitory concentration (IC50) for activated ERK of 24.2 nM to 83.2 nM across several cancer disease types. Compound A has been shown to have in vivo anti-tumor activity in mouse syngeneic and human xenograft models of activating MAPK pathway mutations in KRAS, NRAS, HRAS, BRAF, neurofibromatosis type 1 (NF1), and KSR, with the most sensitive being predominantly melanoma and pancreatic cancer cell lines that harbor activating MAPK pathway mutations in KRAS, NRAS, HRAS, BRAF, NF1, and KSR (Table 10).Table 1 (IC50 values for pERK in Multiple 2D Grown Cell Lines)

[0202] Corresponding reductions in phosphorylated MEK (pMEK) were observed within 2-hours following treatment of cells with 100 nM Compound A, confirming that Compound A was not sensitive to the MAPK pathway feedback reactivation events, such as CRAF-bypass, that are a known limitation of first generation MEK inhibitors currently in clinical use.EXAMPLE 2Polymorph Study

[0203] A polymorph study on Compound A was conducted using the following crystallization techniques: 1) slurry at 50 °C for 2 hours; 2) cooling crystallization, 50 °C- 10 °C; 3) precipitation; and 4) shake slurry at room temperature for 16 hours.

[0204] First the master plate was prepared: 20 mg of Compound A was dispensed in each well. The selected solvents and co-solvents (500 pl in total) were added to the specified wells in different amounts. All co-solvents (ethanol, cyclohexane, MtBE and toluene) were added to the specified wells in different amounts. The master plate was then placed on a thermoshaker 50°C for two hours and the cooling plate and precipitation plate were prepared. For the precipitation plate, 300 pl of the selected anti-solvent (water and n-heptane) was added to the specified wells. Then, 150 pl of the master plate was pipetted into the corresponding wells of the cooling plate and precipitation plate. The remaining liquids in the wells of the master plate were absorbed by filter paper and then, the master plate was stored in a vacuum oven until completely dry. The cooling plate was cooled to 5 °C and stored at this temperature for approximately 16 hours. The precipitation plate was stored in the fume hood for approximately 16 hours. After that, remaining liquids in the cooling plate and precipitation plate were absorbed by filter paper and were also placed in the vacuum oven until completely dry. The plates were all analyzed with XRPD.

[0205] The shake / slurry plate was prepared: 10 mg of Compound A was dispensed in each well. The selected solvents and co-solvents (250 pl in total) were added to the specified wells in different amounts. The shake / slurry plate was stored on the shaker for 16 hours atroom temperature. The remaining liquid was absorbed using filter paper and then, the plate was stored in the vacuum oven until completely dry. The plate was analyzed with XRPD.Table 21100%-0% solvent,280%-20% solvent,360%-40% solvent,440%-60% solvent,520%-80% solvent,65%-95% solventEXAMPLE 3Solubility Study

[0206] The solubility of the amorphous Compound A was determined by liquid chromatography (LC). The solvents were selected based on the Principal Component Analysis (PCA) of properties, which means that some pharmaceutically unattractive solvents were included to create a better understanding of the parameter space. The principal Component Analyses focusses on polarity, polarizability and hydrogen bonding.

[0207] The amorphous Compound A was slurried in the listed solvents (Table 3) for 24 hours before filtration and dilution (lOx) with acetonitrile for LC measurement. Determination of the concentration in the samples is performed based on a calibration line. The results are displayed in Table 3.Table 3

[0208] Based on these results, amorphous Compound A is very soluble in DMSO, freely soluble in acetonitrile, acetone, THF and dichloromethane, soluble in 2-methyl THF, sparingly soluble in ethyl acetate, slightly soluble in MIBK, methanol, ethyl salicylate, MTBE, 3-heptanone and isopropanol, very slightly soluble in water and toluene and insoluble in n- heptane. The solvents stated as freely soluble are suitable for evaporation experiments and the solvents in anti-solvent experiments. The solvents stated as soluble and sparingly soluble are good cooling crystallization solvent, stated as slightly soluble are good slurry solvents and the solvents stated as very slight soluble and insoluble are good anti- solvents.

[0209] Remaining solids and solids obtained after evaporation were measured using XRPD to see if different polymorphic forms were formed. Some samples formed an oil like material and could not be measured on XRPD. XRPD measurements of the other samples resulted in form 1 as found in the cycle-DSC measurement from Example 2.EXAMPLE 4Thermocycle Experiments

[0210] Thermocycle experiments were performed to determine the polymorphic behavior of Compound A. Therefore, 50 mg of Compound A was added to a vial and 1 ml of the specified solvent was added. The specified conditions are mentioned in Table 4. The 16 solvents tested were all the proposed solvents for the crystallization study.Table 4

[0211] After completing the thcrmocyclc protocol, all samples were centrifuged (4000 rpm, 5 minutes) and remaining solvent was removed. These samples were dried using a vacuum oven at RT. The acetone, 1,3 -Dioxolane, acetonitrile, 2-butanone, pyridine, 2-methyl THF, and hexafluorobenzene samples were clear solutions after thermocycle and were evaporated to dryness. Based on the XRPD results, no new patterns were found and are summarized in Table 5.Table 5EXAMPLE 5Preparing Solid Form 1 of Compound A free base

[0212] Crude Compound A was added to a flask equipped with a mechanical stirrer and SiliaMetsS in 2-butanone was added. The crude Compound A was mixed at 20 ± 5 °C for 1 h and filtered over Celpure®. The solids were rinsed with 2-butanone and the filtrate was returned to the flask with additional SiliaMetS and stirred at 20 ± 5 °C for 16 h. The mixture was filtered over Celpure® and rinsed with 2-butanone. The filtrate was concentrated under vacuum. Cyclopropyl methyl ether (CPME) was added and Compound A was concentrated under vacuum. Additional CPME was added to Compound A. The mixture was warmed to 50 °C, then allowed to cool to 20 °C over 2 to 3 h. Compound A was stirred for 20 h at 20 °C ± 5 and filtered. The product was rinsed with CPME and then air dried, yielding Form 1 .

[0213] Multiple samples of Compound A were prepared according to methods of Example 5, and subsequently analyzed with XRPD and TGA / DSC methods of Example 8. The TGA / DSC measurement was performed to determine the mass loss(es) and indicative endothermic and exothermic events.

[0214] Solid Form 1 of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 2-thcta angles of 16.3, 15.8, and 21.8 (±0.2 20).

[0215] Method 2A. Crude Compound A was added to a flask equipped with a mechanical stirrer and dimercaptotriazine functionalized silica (“SiliaMetS”) and 2-butanone were added. The mixture was mixed at 20 ± 5 °C for 1 h and filtered over Celpure®. The solids were washed with 2-butanone. The filtrate containing Compound A was returned to the flask and additional SiliaMetS was added and the mixture was stirred at 20 ± 5 °C for 16 h. The mixture was filtered over Celpure® and rinsed with 2-butanone. The filtrate containing Compound A was concentrated under vacuum. Cyclopentyl methyl ether (“CPME”) was added and the solution containing Compound A was concentrated under vacuum. Additional CPME was added and the solution was allowed to cool to 20 °C over 2 to 3 h, resulting in the crystallization of Compound A. The mixture was stirred for 20 h at 20 °C ± 5 and filtered. The solids were rinsed with CPME and air dried yielding Compound A, Sample 1A.

[0216] Sample 1 A is good crystalline material comprising form 1 of the Compound A free base. The TGA / DSC of Sample 1A showed a melting event at Tpeak of 150.5 °C, and a decomposition event at Tonset of 255.7 °C with a mass loss of 35.3%.

[0217] Method 2B. Crude Compound A was added to a flask equipped with a mechanical stirrer and dimercaptotriazine functionalized silica (“SiliaMetS”) in 2-butanone was added. The mixture was stirred at 20 ± 5 °C for 1 h, then filtered over Celpure®. The solids were rinsed with 2-butanone and the filtrate containing Compound A was returned to the flask. Additional SiliaMetS was added and the mixture was stirred at 20 ± 5 °C for 16 h. The mixture was filtered over Celpure® and rinsed with 2-butanone. The filtrate was concentrated under vacuum. Cyclopentyl methyl ether (“CPME”) was added and Compound A was concentrated under vacuum. Additional CPME was added to Compound A and the solution was allowed to cool to 20 °C over 2 to 3 h. The mixture was stirred for 20 h at 20 °C ± 5 and filtered. The solids were rinsed with CPME and air dried yielding Sample IB.

[0218] Sample IB is good crystalline material comprising form 1 of the Compound A free base. The TGA / DSC of Sample IB showed a melting event at Tpeak of 149.3 °C, and a decomposition event at Tonset of 245.6 °C with a mass loss of 35.0%.

[0219] The melting event of Sample 1 A is comparable to the melting event of Sample IB (150 °C).

[0220] Method 2C. Crude Compound A was added to a flask equipped with a mechanical stirrer and dimercaptotriazine functionalized silica (“SiliaMetS”) in 2-butanone was added. The mixture was stirred at 20 ± 5 °C for 1 h and filtered over Celpure®. The solids were rinsed and the fdtrate was returned to the flask. SiliaMetS was added and the mixture stirred at 20 ± 5 °C for 16 h. The mixture was filtered over Celpure® and rinsed with 2-butanone. An equal volume of n-heptane was added, resulting in the crystallization of Compound A. After stirring for 20 h at 20 °C ± 5, the mixture was filtered. The filtrate was rinsed 1:1 n-heptane:2-butanone and air dried yielding Sample 1C.EXAMPLE 6APreparing Solid Form 2 of Compound A free base

[0221] Sample 2 of Compound A was prepared according to methods of Example 6, and subsequently analyzed with XRPD and TGA / DSC methods of Example 8.

[0222] Solid Form 2 of the free base of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 2-theta angles of 9.1, 9.5, and 17.8 (±0.220).

[0223] Method. In an inert reactor, a charged solution of Compound A was stirred with 2-butanone (1 rel. vol.) and cyclopentyl methyl ether (8 rel. vol.). The charged solution was warmed to 50 ± 5°C. The total volume was adjusted in the reactor to approximately 8 relative volumes by distilling off a total of 15.9 relative volumes of volatiles at 50 ± 5 °C under vacuum. Cyclopcntyl methyl ether (8 rel. vol.) was added. The total volume in the reactor was adjusted to approximately 8 relative volumes by distilling off a total of 8 relative volumes of volatiles at 50 ± 5 °C under vacuum. The temperature was adjusted to 20 ± 5°C over 2.5 ± 0.5 h period. The reaction mixture was stirred at 20 ± 5°C for 18 - 72 hours. The solids were filtered off. The solids were washed twice with cyclopentyl methyl ether (2 x 2.0 rel. vol.). The product was dried at < 40°C for 12 - 96 h. The product formed was Sample 2.

[0224] Sample 2 is good crystalline material comprising form 2 of the Compound A free base. The TGA / DSC of Sample 2 showed a melting event at Tpeak of 165.0 °C, and a decomposition event at Tonset of 260.0 °C with a mass loss of 29.7%.

[0225] The melting event of Sample 2 is higher (165.0 °C) than the melting events of Sample 1A and Sample IB.EXAMPLE 6BPreparing Solid Form 2 of Compound A free base

[0226] Crude Compound A (3.64 kg), dimercaptotriazine functionalised silica (0.36 kg), and 2-butanone (29.3 kg) are combined and stirred at 25 ± 5 °C. Additional 2- butanone (6.4 kg) is added and the mixture warmed to 50 °C to dissolve all solids, then cooled to 30 °C. The mixture is filtered over a Celpure® plug (2.10 kg) and the solids rinsed with 2- butanone (2 x 6.3 kg). The filtrate is returned to the reactor and combined with dimercaptotriazine functionalised silica (0.36 kg) and stirred 25 - 30 °C for 2 h. The mixture is filtered over a Celpure® plug (2.10 kg) and the solids rinsed with 2-butanone (2 x 6.4 kg). The filtrate is returned to the reactor and combined with dimercaptotriazine functionalised silica (0.36 kg) and stirred 25 ± 5°C for 17 h. The mixture is filtered over a Celpure® plug (2.10 kg) and the solids rinsed with 2-butanone (2 x 6.2 kg). The filtrate is returned to the reactor and cyclopentyl methyl ether (25.2 kg) is added. The mixture is concentrated by vacuum distillation at 50 ± 5 °C to approximately 29 L. Cyclopentyl methyl ether (25.7 kg) is added and the contents distilled under vacuum at 50 ± 5 °C to a volume of approximately 29 L. The temperature is adjusted to 20 ± 5 °C over 2.5 ± 0.5 hour period and stirred at 20 ± 5°C for 18 hours. The solids are filtered and washed twice with cyclopentyl methyl ether (26.4 kg), the product is dried at 38 °C for 106 hours to afford 3.2 kg of Compound A, Form 2.EXAMPLE 7Characterization of Amorphous Form of Compound A and anhydrous Form 1

[0227] The amorphous form of Compound A was prepared according to Example 1.

[0228] The amorphous form of Compound A was characterized as received by XRPD, TGA, DSC, microscopy, DVS, LC, FT-IR, 'H-NMR,13C-NMR, and19F-NMR. An overview of the results is given in Table 6 below.Table 6

[0229] To measure the Log P, Log D, and pKa of Compound A, a reversed phase HPLC method with UV detection was used. A total of sixteen pH (pH 2-12) values were tested in USP buffers (USP <27>). First, a stock buffer was prepared by dissolving citric acid, boric acid and sodium chloride in 1.0 L milliQ water. Then, 37% HC1 and phosphoric acid were added. This stock buffer was divided for preparation of the 16 buffer solutions, and pH was adjusted using IM NaOH. For the determination of each pH value, 500 pl buffer, 10 pl of DMSO stock solution (100 mg compound in 5 mL DMSO) and 500 pl octanol was added. These samples were shaken for 24 hours.

[0230] The XRPD was measured using Bruker D8 Discover in Bragg-Brentano configuration according USP <491> with a scan range of 2-45° 20. The collected XRPD diffractogram is displayed in FIGURE 1. The compound shows no peaks which is characteristic for amorphous material. This was expected since the received material was concentration of a solution to dryness.

[0231] The DSC thermogram of the received compound is displayed in FIGURE 2. The DSC measurement was performed using Mettler Toledo DSC-3+ equipment, the sample was heated from 20°C to 350°C in an aluminum (pierced) cup. A heating rate of 10°C / min was applied. DSC measurements were performed to determine endothermic and exothermic events. Amorphous Form of Compound A showed a glass transition event at Tpeak=66.4°C. Then, a crystallization event occurs at TPeak=121.4oC, followed by a melting event at Tpeak=146.8oC.Cycle-DSC experiments are performed to get an understanding of this phase transition. The higher melting event is an indication of a more stable form present.

[0232] Based on the DSC-analysis, a crystallization event occurred. Therefore, a cycle-DSC measurement was performed. The DSC measurement was heated to 137°C (after the crystallization event), then cooled to 0°C and heated to 35O°C, all with a heating / cooling rate of 10°C / min. These DSC measurements are pictured in FIGURE 3.

[0233] The first heating curve (upper, black) showed the glass transition event at Tpeak=66°C, followed by the recrystallization event at Tpeak=121°C. The cooling cycle (middle, red) did not show any recrystallization and the second heating cycle (lower, blue) only showed the higher melting event at Tpeak=147°C. This resulted in the opportunity to isolate the higher melt event compound and to measure XRPD. The XRPD pattern is displayed in FIGURE 4 and is a crystalline pattern. This crystalline pattern is defined as Form 1. This Form 1 is an anhydrous form. A peak list of this form or Form 1 is depicted in FIGURE 8.

[0234] The TGA-DSC of the amorphous form of Compound A was measured using Mettler Toledo equipment. A heating rate of 10°C / min was applied. The sample showed a mass loss of 0.3% from 29 to 116 deg C; this could be an indication of residual solvent (FIGURE 5).EXAMPLE 8Characterizing solid forms of Compound A free base

[0235] X-ray powder diffraction (XRPD) and TGA. DSC analysis were used to analyze and compare the polymorphic forms and crystallinity of multiple samples of Compound A free base.X-Ray Powder Diffraction (XRPD) Analysis

[0236] Unless otherwise indicated, the XRPD was measured according to USP <941> in Bragg-Brentano configuration. The method used is “Default Reflection,” scan range 4-45 degree 2Theta, l.Os / step, o.oo5 degree / step; using a standard sample holder (0.1 mm cavity in silicon wafer).

[0237] Unless otherwise indicated, a Bruker AXS D8 Advance reflection (DRPX- 05) was used to perform XRPD analysis. Using a Cu anode at 40kV, 40mA; sample stage standard rotating. Slits 0.6 mm divergence slits, primary axial Soller slit 2.5 degrees, secondary axial Soller slit 2.5 degrees. The detector was a linear detector LYNXEYE withreceiving slit 3 degrees detector opening. Measurement conditions were: scan range 4-45 degree 2Thcta, sample rotation 15 rpm, Is / stcp, 0.005 dcgrcc / stcp, and all measuring conditions were logged in the instrument control file. The software used for data collection is Diffrac .Commander v.2.6.1. Data analysis was done using Diffrac.Eva v4.2.0. No background correction or smoothing was applied to the patterns. As system suitability, corundum sample A13-B77 (NIST standard) was checked for peak position, peak shape and intensity and linearity.

[0238] The results are summarized in Table 7. Peak lists are included in the Figures.Table 7

[0239] FIGURE 6 is an overlay of XRPD patterns of the Form 1 solid form prepared according to the method of Example 5 (Sample 1A) and (Sample IB) and Form 2 solid form prepared according to the method of Example 6 (Sample 2). FIGURE 9 is an overlay of XRPD patterns of Form 1 form (Sample IB) and Form 2. The XRPD pattern of sample 1A and sample IB show sharp peaks which are characteristic of good crystalline material. The contribution to the background due to amorphous content is low for both samples. The patterns show different peak positions than Sample 2, suggesting the samples do not conform to polymorphic solid form 2 of Compound A free base. Samples conform to Compound A free base solid Form 1. FIGURE 7 is an overlay of XRPD patterns of the Form1 solid form prepared according to the methods of Example 5 (Sample 1 A, Sample IB and Sample 1C).

[0240] FIGURE 13A is an XRPD pattern obtained from Sample 1A. FIGURE 13B is a XRPD peak list from the XRPD pattern shown in FIGURE 13A. FIGURE 14A is an XRPD pattern obtained from Sample IB. FIGURE 14B is a XRPD peak list form the XRPD pattern shown in FIGURE 14A.

[0241] The XRPD pattern of sample 2 shows sharp peaks which are characteristic of good crystalline material. The contribution to the background due to amorphous content is low. This sample is defined as comprising solid Form 2 of Compound A free base. FIGURE 15A is an XRPD pattern obtained from Sample 2. FIGURE 15B is a XRPD peak list from the XRPD pattern shown in FIGURE 15 A.TGA / DSC Analysis

[0242] The TGA / DSC analysis was performed according to USP <891>. The samples are prepared using Al crucibles (40 microliter). Enough material was used to cover the bottom of the pan that is then loaded into a pre-weighed Al crucible, which is closed and pierced. The method includes an equilibration at 20 deg C for 5 minutes, after which the crucible is heated at a rate of 10 deg C / min from 20 deg C to 350 deg C for 1 minute. A nitrogen purge of 40 ml / min was maintained over the sample. The DSC signal was indicative for the thermal behavior.

[0243] The TGA / DSC measurements were performed using a 34-position auto sampler. No corrections were applied to the thermograms. As a system suitability check, indium and zinc were measured. For calibration of the instrument benzophenone, indium, lead, tin and zinc were used as references.

[0244] FIGURE 10 is a graph obtained from a TGA / DSC analysis of Sample 1A. FIGURE 11 is a graph obtained from a TGA / DSC analysis of Sample IB. FIGURE 12 is a graph obtained from a TGA / DSC analysis of Sample 2.

[0245] The results are summarized in Table 8 below.Table 8

[0246] The melting event of Sample 1A was comparable to the melting event of Sample IB (approximately 150 deg C). The melting event of Sample 2 was higher (165.0 deg C) and therefore did not conform to the melting events of the Samples 1A and IB.

[0247] An overview of the characterization of Form 1 (Sample IB) and Form 2 is given in Table 9. Based on these results it can be concluded that Form 2 is a new polymorphic form, with a higher melting event and melting energy which is an indication of a more stable form. The morphology of the different forms shows that form 1 consists of slightly smaller particles than form 2. Form 2 is slightly less soluble in the tested solutions than Form 1.Table 9EXAMPLE 9AOral Dosage Form of Compound A

[0248] An oral dosage form of Compound A can be prepared by combining Compound A free base in solid Form 1, solid Form 2 or a combination of Solid Form 1 and Solid Form 2, as the active pharmaceutical ingredient (API) with pharmaceutically acceptable excipients to form a tablet. The intra granulation excipients can include microcrystalline cellulose (e.g., CEOLUS UF-711), crospovidone Type A (e.g., Polyplasdone XL), hydroxypropyl Cellulose HPC-SL, hydroxypropyl cellulose-Low Substituted L-HPC LH-21, and purified water. The extra granulation excipients can include Compound A and magnesium stearate (e.g., hyqual vegetable source).

[0249] Preferably, the formulation includes about 20% w / w of Compound A free base or salt in a solid form and pharmaceutically acceptable carriers. In some embodiments, the pharmaceutically acceptable carriers includes (e.g., about 60-65% w / w) microcrystalline cellulose having a Compactibility Index of about 150 and a Repose Angle of MCC of about 42 degrees, such as Microcrystalline Cellulose (CEOLUS™ UF-711). In some embodiments, the pharmaceutically acceptable carriers includes (e.g., about 5% w / w) of crospovidone Type A (coarser than about 50 micrometers). In some embodiments, the pharmaceu tic ally acceptable carriers includes (e.g., about 5% w / w) of a low-viscosity hydroxypropylcellulose (HPC) grade SL, or comparable cellulosic non-ionic polymer having a molecular weight of about 100,000 having a Tg of about -25~0 and a Tm of about 180-220 (degrees C). In some embodiments, the pharmaceutically acceptable carriers includes (e.g., about 5% w / w) of a low substituted hydroxy propylcellulose such as Hydroxypropyl Cellulose-Low Substituted, L- HPC LH-21.

[0250] In some embodiments, the formulation is prepared as an oral tablet. The oral tablet can comprise an intra granulation composition having about 20% w / w of the free base or a salt of Compound A in an amorphous form or a crystalline solid form, about 60-65% w / w of the mocrocrystalline cellulose, about 5% w / w of crospovidone Type A, about 5% w / w of the hydroxypropyl cellulose HPC-SL, about 5% w / w of the low-substituted hydroxypropylcellulose. The tablet can further comprise an extra granulation composition comprising about 99% % w / w of the Compound A granulate and about 1% of a lubricantsuitable for tablet compression processes (e.g., magnesium stearate). The tablet can optionally include a polyvinyl alcohol based coating (e.g., Opadry II White).

[0251] In some embodiments, the tablet comprises 120 mg or 160 mg of Compound A.

[0252] For example, a tablet dosage form is described in the Table 9 below. In some embodiments, the API in Table 10A is Compound A in solid Form 1. In some embodiments, the API in Table 10A is Compound A in solid Form 2.Table 10A. Compound A Formulation Composition.

[0253] In some embodiments, a tablet can include a coating, such as a polyvinyl alcohol-based coating (e.g., Opadry II White) as described in the Table 9B below. In some embodiments, the API in Table 10B is Compound A in solid Form 1. In some embodiments, the API in Table 10B is Compound A in solid Form 2.Table 10B. Formulation composition for 120 mg and 160 mg dose strengths coated withOpadry II White ©coating (polyvinyl alcohol-bascd coating)

[0254] In some embodiments, a tablet can include a coating, such as a hydroxypropyl methylcellulose-based coating (e.g., Opadry White) as described in the Table 9C below. In some embodiments, the API in Table 10C is Compound A in solid Form 1. In some embodiments, the API in Table 10C is Compound A in solid Form 2.Table 10C. Formulation composition for 120 mg and 160 mg dose strengths coated with Opadry White® coating (Hydroxylpropyl Methylcellulose-based coating)In some embodiments, Compound A free base solid Form 2 is present in formulated composition of Table 9B or Table 9C, identified by characteristic 2-theta XRPD peaks at 7.0, 9.2, 9.6, 13.4 and 16.4.

[0255] X-ray powder diffraction (XRPD) measurements shown in Figures 26-29 were conducted using a Bruker D2 Phaser equipped with a Lynxeye detector. The scan parameters were as follows: The radiation source was Cu-Ka with a wavelength of 1.54Angstrom. The device operated at a voltage of 30 kV and a current of 10 mA. The scan type used was coupled 20 / 0 with a continuous PDS fast scan mode. The scan speed was set at 2.0 seconds per step, with a step width of 0.0400 degrees, covering a range of 3.0000 to 40.0000 degrees. The primary and secondary seller angles were both 2.5 degrees, the divergence slit was set at 0.1 mm, and the receiving slit at 3 mm. Additionally, the rotation speed was 15 rpm and the wattage was 300 watts. The runtime for each scan was approximately 40 minutes. Samples were held in a front-loading zero background sample holder with air scattering set to 1 mm.EXAMPLE 9BOral Dosage Form of Compound A

[0256] An oral dosage form of Compound A can be prepared by combining Compound A as the active pharmaceutical ingredient (API) in a solid form disclosed herein with pharmaceutically acceptable excipients to form a tablet. The intra granulation excipients can include microcrystalline cellulose (e.g., CEOLUS™ UF-711), crospovidone Type A (e.g., Polyplasdone™ XL), hydroxypropyl Cellulose HPC-SL, hyroxypropyl cellulose-Low Substituted L-HPC LH-21, and purified water. The extra granulation excipients can include Compound A and magnesium stearate (e.g., hyqual vegetable source). For example, a tablet dosage form is described in the Tables 10D and 10E below.

[0257] In some embodiments, the API is Compound A in a solid form disclosed herein. In some aspects, the API comprises Compound A as a free base or pharmaceutically acceptable salt of Compound A.

[0258] In some aspects, the API is a free base of Compound A. In some aspects, the API is the free base of Compound A in Form 1 as disclosed herein. In some aspects, the API is the free base of Compound A in Form 2 as disclosed herein. In some aspects, the API is a mixture of the free base of Compound A in Form 1 and in Form 2 as disclosed herein. In some aspects, the API is a mixture of the free base of Compound A in an amorphous form and / or Compound A in Form 1 and / or in Form 2 as disclosed herein.

[0259] In some aspects, the API is a pharmaceutically acceptable salt of CompoundA. In some aspects, the API comprises Compound A in a salt form that comprises a counter ion selected from the group consisting of potassium, sodium, chloride, sulfate, bisulfate,aspartate, maleate, phosphate, glutamate, tartrate, fumarate, citrate, L-malate, hippurate, D- gluconatc, L-ascorbatc, succinate, acetate, naphthalene- 1,5-disulfonatc cthancsulfonatc, ethane- 1,2-sufonate, p-toluenesulfonate, methanesulfonate and benzoate.

[0260] In some aspects, the API is an aspartic acid salt for of Compound A in a crystalline, partially crystalline or amorphous form. In some aspects, the API is a maleic acid salt for of Compound A in a crystalline, partially crystalline or amorphous form. In some aspects, the API is an ascorbic acid salt for of Compound A in a crystalline, partially crystalline or amorphous form. In some aspects, the API is a hippuric acid salt for of Compound A in a crystalline, partially crystalline or amorphous form. In some aspects, the API is a glutamic acid salt for of Compound A in a crystalline, partially crystalline or amorphous form. In some aspects, the API is a galacteric acid salt for of Compound A in a cry stalline, partially cry stall inc or amorphous form. In some aspects, the API is a naphthalene- 1,5 -disulfonic acid salt for of Compound A in a crystalline, partially crystalline or amorphous form. In some aspects, the API is a dimethylcarbamate galactaric acid acid salt for of Compound A in a crystalline, partially crystalline or amorphous form.Table 10DTable 10EEXAMPLE 11Salt StudyF0261] Table 11 describes the solvents and counter ions selected for the salt study, which involved a total of 96 combinations of solvents and counter ions (4x24). The salt study on Form 1 was conducted using the following crystallization techniques; 1) slurry at 50°C for 2 hours; 2) cooling crystallization, 50°C-10°C; 3) evaporative crystallization; and 4) shake slurry at room temperature for 16 hours. These experiments were duplicated for each time point in the crystallization process, leading to a comprehensive total of 384 experiments.Table 11Salt Screen

[0262] A salt screen was conducted to determine candidate salts. First, the master plate was prepared: 20 mg of free base Form 1 was dispensed in each well. The solid acids (L- Aspartic acid, glutamic acid, fumaric acid, galactaric acid, hippuric acid, L-ascorbic acid, and succinic acid) were dispensed in the specified wells (molar ration FB:C1 1:1.1). The solvents (acetone, methanol, acetonitrile / water (9:1), and ethyl acetate) were dispensed in the specified wells (800 pl each well). The IM acid solutions (benzoic acid in MeOH, p-toluenesulfonic acid in H2O, ethane- 1 ,2-disulfonic acid in H2O, naphthalcncsulfonic acid in H2O) and 2M acid solutions (L-malic acid in H2O, citric acid in H2O, L-Tartaric acid in H2O, Maleic acid in H2O, sodium hydroxide in H2O, and potassium hydroxide in H2O) were dispensed in the specified wells.

[0263] Then the shake-slurry plate was prepared: 10 mg of Form 1 was dispensed in each well. The solid acids (L-Aspartic acid, glutamic acid, fumaric acid, galactaric acid, hippuric acid, L-ascorbic acid, and succinic acid) were dispensed in the specified wells (molar ration FB:C1 1:1.1). The solvents (acetone, methanol, acetonitrile / water (9:1), and ethyl acetate) were dispensed in the specified wells (800 pl each well). The IM acid solutions (benzoic acid in MeOH, p-toluenesulfonic acid in H2O, ethane- 1 ,2-disulfonic acid in H2O, naphthalene- 1,5 -sulfonic acid in H2O) and 2M acid solutions (L-malic acid in H2O, citric acid in H2O, L-Tartaric acid in H2O, Maleic acid in H2O, sodium hydroxide in H2O, and potassium hydroxide in H2O) were dispensed in the specified wells. The shakc / slurry plate was stored onthe shaker overnight at room temperature. The remaining liquid was absorbed using filter paper and then, the plate was stored in the vacuum oven until completely dry.

[0264] The master plate was then placed on a thermoshaker 50°C for two hours and the cooling plate and evaporation plate were prepared. 200 pl of the master plate was pipetted into the corresponding wells of the cooling plate and precipitation plate. The remaining liquid in the wells of the master plate was absorbed using filter paper and then, the plate was stored in the vacuum oven until completely dry as well. The evaporation plate was stored in a vacuum oven until completely dry. The cooling plate was cooled to 5 °C and stored at this temperature for approximately 16 hours. After that, remaining liquids in the cooling plate were absorbed by filter paper and the cooling plate was also placed in the vacuum oven until completely dry. The master plate, cooling plate, and evaporation plate were analyzed using XRPD. The XRPD patterns that were obtained were compared to the XRPD pattern of Form 1 (Table 12). In total, 15 new XRPD patterns were observed. FIGURES 16-22 show overlays of Form 1, counterion, and the observed new patterns. All new crystalline patterns were defined as candidate salts.Table 12

[0265] TGA-DSC measurements were performed on all new patterns found in the screen. The results of the measurements are summarized in Table 13. These salts were subsequently scaled up in order to fully characterize and confirm salt formation.Table 13

[0266] Based on the TGA-DSC and XRPD results, 9 promising salts were defined. The TGA / DSC analysis of New Pattern (NP) 2, 5, 6, 9, 10 and 12 showed a melting event equal to the melting event of the counter ion and were therefore no longer defined as candidate salts. The TGA / DSC analysis of NP 4, 7, 11, 13 and 14 showed a melting event of approximately 150°C. This melting event is similar to the melting event of Form 1 after recrystallization (146.8°C), but the XRPD pattern of these new patterns did not conform to the XRPD pattern of Form 1 and were therefore still identified as (anhydrous) candidate salts. For NP 7 and 13, the same counter ion (ascorbic acid) was used and the TGA / DSC analysis showed similar melting events, but the XRPD patterns were different. These patterns were identified as two different new patterns. TGA / DSC analysis of NP 8 showed a different melting event (136.8°C) than the melting event of the hippuric acid or the free molecule. The XRPD pattern was also different than the pattern of the counter ion and free molecule and was therefore identified as a candidate anhydrous salt. This candidate salt was an anhydrous form, because based on the TGA / DSC, there was no sign of solvent inclusion. NP 3, 15 and 16 were defined as candidate solvated salts. TGA / DSC analysis showed a desolvation event for all of the three identified candidate salts.EXAMPLE 12Salt Scale Up and Characterization

[0267] The results of the scale up experiments are summarized in the following paragraphs.Galactaric Candidate Salts

[0268] In the screen, one pattern was observed (NP14). The scale up experiment resulted in solid material after thermocycle. NP14 was not reproduced but a new pattern was found (NP17, Galacteric Solid). The scale up experiment is summarized in Table 14. FIGURE 23 shows an overlay of the XRPD pattern of Form 1, galactaric acid, the new pattern found in the screen (NP14) and experiment Galactaric Solid (NP17).Table 14

[0269] Table A is a list of 2-theta peaks and d-values peak from XRPD pattern obtained from the NP14 Compound A galactaric acid XRPD pattern.Table A. XRPD peak list of 107403 C5, NP14 (galactaric acid, NP14)Ascorbic Candidate Salts

[0270] In the screen, two different patterns were observed (NP7 and NP13). Experiment Ascorbic Temp 1 resulted in oily material and therefore no TGA / DSC and XRPD analysis were performed. NP13 was proven to be reproducible in ethyl acetate (slurry at 20°C, experiment Ascorbic Temp 2). The DSC thermogram showed a single melting event at 151.4°C, which was similar to the melting event found in the screen (146.9°C). ’ H-NMR confirmed salt formation. The potential salt was defined as anhydrous salt. The scale up experiments are summarized in Table 15. FIGURE 24 shows an overlay of the XRPD pattern of Form 1, ascorbic acid, the new pattern found in the screen (NP13), and experiment Ascorbic Temp 2 (NP13).Table 15

[0271] Table B is a list of 2-theta peaks and d-values peak from XRPD pattern obtained from the NP7 Compound A ascorbic acid XRPD pattern.Table B. XRPD peak list of 107400 H7, NP7 (L-ascorbic acid)

[0272] Table C is a list of 2-theta peaks and d-values peak from XRPD pattern obtained from the NP13 Compound A ascorbic acid XRPD pattern.Table C. XRPD peak list of 107401 H8, NP13 (L-ascorbic acid)

[0273] Naphthalene- 1,5-disulfonic Candidate Salts

[0274] In the screen, two new patterns were observed (NP15 and NP16). On scale up, NP15 was not reproduced, but a new candidate salt was found (NP18). This salt is defined as an anhydrous salt. 1H-NMR confirmed salt formation with a ratio of 1:0.5. The scale up experiment is summarized in Table 16. FIGURE 25 shows an overlay of the XRPD pattern of Form 1, naphthalene- 1,5-disulfonic acid, the new pattern found in the screen (NP15), and the experiment Naphthalene Solid (NP18).Table 16

[0275] Table D is a list of 2-theta peaks and d-values peak from XRPD pattern obtained from the NP15 Compound A naphthalene- 1,5-disulfonic acid XRPD pattern.Table D. XRPD peak list of 107403 C9, NP15 (Naphtalene- 1,5-disulfonic acid)

[0276] Table E is a list of 2-theta peaks and d- values peak from XRPD pattern obtained from the NP16 Compound A naphthalene- 1,5-disulfonic acid XRPD pattern.Table E. XRPD peak list of 107403 CH, NP16 (Naphtalene- 1,5-disulfonic acid)L-aspartic Acid Candidate Salts

[0277] Table F is a list of 2-theta peaks and d-values peak from XRPD pattern obtained from the NP3 Compound A L-aspartic acid XRPD pattern.Table F. XRPD peak list of 107400 E3, NP3 (L-aspartic acid, NP3).Maleic Acid Candidate Salts

[0278] Table G is a list of 2-theta peaks and d-values peak from XRPD pattern obtained from the NP4 Compound A maleic acid XRPD pattern.

[0279] Table G. XRPD peak list of 107400 Fl , NP4 (Maleic acid, NP4)Hippuric Acid Candidate Salts

[0280] Table H is a list of 2-theta peaks and d- values peak from XRPD pattern obtained from the NP8 Compound A hippuric acid XRPD pattern.Table H. XRPD peak list of 107401 F5, NP8 (Hippuric acid)Glutamic Acid Candidate Salts

[0281] Table I is a list of 2-theta peaks and d-values peak from XRPD pattern obtained from the NP11 Compound A glutamic acid XRPD pattern.Table I. XRPD peak list of 107401 H4, NP11 (Glutamic acid)Aqueous Solubility DeterminationF0282] The aqueous solubility of the potential salts was determined by HPLC analysis. The samples were prepared by adding a known amount of water (200 - 400 pl) and slurrying for 24 hours. All samples were not fully dissolved, as intended. All samples were filtered using syringe filters and diluted with acetonitrile. Experiment Aspartic Temp 1, Ascorbic Temp 2, and Aspartic Temp 2 crystallized after adding acetonitrile and were not diluted and measured in water. LC analysis of the samples was performed, and a calibration line was used for the determination of the solubilities.

[0283] All salt form samples were more soluble in water than free base Form 1. The sample with the highest solubility was Ascorbic Temp 2, with ascorbic acid as the counter ion. Based on 'H-NMR, salt formation did occur. Therefore, forming a salt did result in enhanced aqueous solubility. The results of the aqueous solubility study of the potential salts are summarized in Table 17.Table 17

[0284] Based on the aqueous solubility of these two promising salts, the salt formed using ascorbic acid, Experiment Ascorbic Temp 2, resulted in enhanced aqueous solubility (11.3 mg / ml).EXAMPLE 13Analysis of Compound A Oral Doage Form

[0285] Tablets comprising 160 mg dose strength of Compound A free base in solid Form A were prepared according to Table 18. FIGURE 26 is a XPRD pattern from a tablet formulation of Compound A free base in Table 18 in Example 13. The diffractogram of the oral dosage form composition of Table 18 for tablet manufacture contained characteristic XRPD 2-theta peaks at about 2-theta values of about 7.0, 9.2, 9.6, 13.4 and 16.4 (+ / - 0.2).Table 18. Formulation composition for 160 mg dose strengths coated with Opadry II White ® coating (polyvinyl alcohol-based coating)0286] * Note: APIO quantity is calculated based on its % potency on the as-is basis

[0287] ** Adjust the MCC quantity based on the calculated quantity of API

[0288] Referring to FIGURE 26, the XRPD 2-theta peaks in Table 19 were identified as characteristic of the tablet formulation in Table 18 including Compound A free base in Solid Form 2.Table 19.

[0289] FIGURE 27 is a XRPD pattern of a placebo formulation of Table 20 in Example 13. The diffractogram of the oral dosage form composition of Table 20 placebo did not contain any XRPD 2-theta peaks at about 2-theta values of about 7.0, 9.2, 9.6, 13.4 and 16.4 (+ / - 0.2).Table 20. Placebo formulation composition* Note: APIO quantity is calculated based on its % potency on the as-is basis** Adjust the MCC quantity based on the calculated quantity of API

[0290] FIGURE 28 is a XRPD pattern of Compound A free base in solid Form 2 reference standard in Example 13. Referring to FIGURE 28, the XRPD 2-theta peaks in Table 21 were identified as characteristic of a reference standard of Compound A free base in Solid Form 2.Table 21.

[0291] FIGURE 29 is an overlay of XRPD patterns of the reference standard of Compound A free base in solid Form 2 (FIGURE 28) (top XRPD pattern), the tablet formulation of Compound A free base in Table 18 (FIGURE 26) (middle XRPD pattern), and the placebo formulation of Table 19 (FIGURE 27) (bottom XRPD pattern).

[0292] There was no interference from the placebo compositions with the characteristic 2-thcta XRPD peaks at about 7.0, 9.2, 9.6, 13.4 and 16.4 (+ / - 0.2 2-thcta) from Compound A in solid Form 2.EXAMPLE 14Pharmacokinetic Study of Compound A following Administration of Compound A to Dogs

[0293] In this study, Compound A was administered to Beagle dogs as either a solution (40 mg / animal) or as an oral dosage core tablet formulation (Table 18, Example 13), both with and without pre-treatment with pentagastrin. Pentagastrin pre-treatment produces similar effects to gastrin in the stomach, increasing gastric acid production and lowering gastric pH. With pentagastrin pre-treatment, the dog stomach pH is a better representative of human fasted stomach, and this model is useful in evaluating the absorption of drug formulations in humans. Reference: Zane P, Guo Z, MacGerorge D, Vicat P, Ollier C. Use of the pentagastrin dog model to explore the food effects on formulations in early drug development. Eur J Pharm Sci. 2014 Jun 16;57:207-13. doi: 10.1016 / j.ejps.2013.09.018. Epub 2013 Oct 1. PMID: 24090732.

[0294] Compound A was administered in solution or as an oral tablet form to male Beagle dogs at 40 mg / animal. The tablet formulation was the core tablet formulation in Table 18 (Example 13). Treatiment via oral or tablet administration was well tolerated with no test article related clinical signs observed. A total of 6 beagle dogs were initially assigned to the study, and the same animal were used with a minimum 2 day washout period between dosing.

[0295] This study was to determine the pharmacokinetics of compound A following a crossover PO tablet or PO gavage administration in Beagle dogs (n = 6) at a dose of 40 mg / animal, pretreated with or without (intramuscular; IM) pentagastrin. Dogs were pretreated with intramuscular pentagastrin (6 ug / kg) to increase gastric acid secretion and lower stomach pH (representing fasted human gastric pH; Fancher, 2001). Blood samples were collected from each animal from a jugular vein into tubes containing K+EDTA pre-dose and at 0.25, 0.5, 1, 2, 4, 6, 8 and 24-hours post-dose. Plasma analysis was performed with a validated LC-MS / MS method, using a d6-analog of compound A as internal standard. PK parameters were calculated using non-compartmental (NCA) PK analysis in Phoenix® WinNonlin® (Certara USA, Inc., Princeton, NJ, USA).

[0296] Figure 30 shows profiles for blood plasma concentration versus time from 0 to 6 h measured in Beagle dogs for each formulation treatment (n = 6). Mean (+ / - SD) plasma concentrations (ng / mL) of compound A after an oral dose of 40 mg as either an acidified (pH 3.0) solution or tablet with water in Beagle dogs pretreated with or without (intramuscular; IM) pentagastrin to increase gastric acid secretion to lower stomach pH in dogs, which better aligns with pH of the human stomach. There were no meaningful differences in absorption between animals' pretreatment with or without pentagastrin after an oral dose of 40 mg compound A in an acidified (pH 3.0) solution (Figure 30; open diamonds vs. open squares). However, significant decreases in absorption were observed after an oral dose of 40 mg compound B in tablet form when given with water if the pH of the stomach was not first lowered by pentagastrin pretreatment (Figure 30; open triangles vs. open circles, respectively).

[0297] Referring to the data in Figures 30, 31 A and 3 IB, and Tables 21 A and 21B, there were no meaningful differences in absorption between animals' pretreatment with or without IM pentagastrin after an oral dose of 40 mg compound A in an acidified (pH 3.0) solution. There was a general decrease in absorption (as measured by AUCtlast and Cmax values) of compound A in tablet with water when comparing acidified to non-acidified conditions in Beagle dogs. The mean Cmax values were decreased by -67% (2270 vs. 746 ng / mL) when comparing acidified (IM pentagastrin pretreatment) to non-acidified stomach conditions (no IM pentagastrin pretreatment). Similarly, the mean AUCtlast values were also decreased by -60% (2197 vs. 883 ng*h / mL) when comparing acidified to non-acidified stomach conditions (note: AUCtlast are estimates. Values calculated using nominal time data).Table 21 A. AUC (ng*h / mL)Table 2 IB. Cmax (ng / mL)F0298] The oral dosage tablet of Compound A unexpectedly increased the Cmax and AUC of Compound A in dogs that were pre-treated with pentagastrin.

[0299] When Compound A was administered in a solution, there was no to little difference in absorption between animals' pretreatment with or without IM pentagastrin after an oral dose of 40 mg compound A in an acidified (pH 3.0) solution. Administering Compound A in solution to dogs that were pre-treated with pentagastrin increased the AUC by about 10% and increased the Cmax by about 6-7% compared to when the Compound A solution was administered to dogs that were not pre-treated with pentagastrin.

[0300] In contrast, there was a significant increase in absorption of Compound A in the oral dosage tablet for dogs that were pre-treated with pentagastrin compared to dogs that were not treated with pentagastrin. Administering Compound A in the oral dosage tablet to dogs that were pre-treated with pentagastrin increased the AUC by about 250% and increased the Cmax by about 300% compared to when the Compound A solution was administered to dogs that were not pre-treated with pentagastrin.

[0301] There was a general decrease in absorption (as measured by AUCtlast and Cmax values) of compound A in tablet with water when comparing acidified to non-acidified conditions in Beagle dogs. The mean Cmax values were decreased by -67% (2270 vs. 746 ng / mL) when comparing acidified (IM pentagastrin pretreatment) to non-acidified stomach conditions (no IM pentagastrin pretreatment). Similarly, the mean AUCtlast values were also decreased by -60% (2197 vs. 883 ng*h / mL) when comparing acidified to non-acidified stomach conditions (note: AUCtlast are estimates. Values calculated using nominal time data).

[0302] Accordingly, the solid tablet formulation of Compound A significantly increased both Cmax and AUC in pentagastrin pre-treated Beagle dogs compared to theadministration of Compound A in solution. These data demonstrate that stomach acidity is an important factor that contributes to compound A’s oral bioavailability.

[0303] Reference: Fancher, R.M.; Zhang, H.; Sleczka, B.; Derbin, G.; Rockar, R.; Marathe, P. Development of a canine model to enable the preclinical assessment of pH- dependent absorption of test compounds. J. Pharm. Sci. 2011, 100, 2979-2988.

[0304] While certain embodiments of the inventions have been described, such embodiments have been presented by way of example, and are not intended to limit the scope of the disclosure. Indeed, the compounds, compositions, processes, and methods described herein may be embodied in a variety of other forms. Furthermore, various omissions, substitutions and changes in the systems and methods described herein may be made without departing from the spirit of the disclosure. The accompanying claims and their equivalents are intended to cover such forms or modifications as would fall within the scope and spirit of the disclosure. Features, materials, characteristics, or groups described in conjunction with a particular aspect, embodiment, or example are to be understood to be applicable to any other aspect, embodiment or example described in this section or elsewhere in this specification unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The protection is not restricted to the details of any foregoing embodiments. The protection extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed. For purposes of this disclosure, certain aspects, advantages, and novel features are described herein. Not necessarily all such advantages may be achieved in accordance with any particular embodiment. Thus, for example, those skilled in the art will recognize that the disclosure may be embodied or carried out in a manner that achieves one advantage or a group of advantages as taught herein without necessarily achieving other advantages as may be taught or suggested herein. The scope of the present disclosure is not intended to be limited by the specific disclosures of preferred embodiments.

Claims

WHAT IS CLAIMED IS:

1. A composition comprising the free base of Compound A,Compound A, wherein, the composition is characterized by one or more of the following:(a) a solid form of the freebase of Compound A characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.8°, 15.6°, 15.8°, 16.3°, and 21.8° 20 (±0.2 20);(b) a solid form of the freebase of Compound A characterized by a TGA / DSC showing a melting event at Tpeak of about 150 °C and a decomposition event at Tonset of about 245-255 °C and a mass loss of about 35%;(c) a solid form of the free base of Compound A characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.0°, 9.2°, 9.6°, 13.4°, and 16.4° 20 (±0.220); and(d) a solid form of the free base of Compound A characterized by a TGA / DSC showing a melting event at Tpeak of about 165.0 °C and a decomposition event at Tonsetof about 260 °C and a mass loss of about 30%.

2. The composition of claim 1, wherein the solid form of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.8°, 12.6°, 15.6°, 15.8°, 16.3°, and 21.8° 20 (±0.2 20).

3. The composition of any one of claims 1-2, wherein the solid form of the freebase of Compound A is further characterized by a TGA / DSC showing a melting event at Tpeak of about 149.3-150.5 °C and a decomposition event at Tonset of about 245.6-255.7 °C and a mass loss of about 35.0-35.3%.

4. The composition of any one of claims 1-3, wherein the solid form of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 7, or substantially as shown in Figure 13A or substantially as shown in Figure 14 A.

5. The composition of any one of claims 1-4, wherein the solid form is the solid Form 1 of the free base of Compound A.

6. The composition of claim 1, wherein the solid form of the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.0°, 9.2°, 9.6°, 13.4°, and 16.4° 26 (±0.2 20).

7. The composition of any one of claims 1 or 6, wherein the solid form is characterized by a TGA / DSC showing a melting event at Tpeak of about 165 °C and a decomposition event at TOnset of about 260 °C and a mass loss of about 29.7%.

8. The composition of any one of claims 1 or 6-7, wherein the freebase of Compound A is characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 15 A.

9. The composition of any one of claims 1 or 6-8, wherein the solid form is the solid Form 2 of free base of Compound A.

10. A solid form of the free base of Compound A:(Compound A) wherein the solid form is characterized by an X-ray powder diffraction pattern comprising peaks at 15.8°, 16.3°, and 21.8° 20 (±0.2 20).

11. The solid form of the free base of Compound A of claim 10, exhibiting an X-ray powder diffraction pattern comprising peaks at 10.8°, 12.6°, 15.6°, 15.8°, 16.3°, and 21.8° 20 (±0.2 20).

12. The solid form of the free base of Compound A of claim 10 or 11, exhibiting an X- ray powder diffraction pattern comprising at 10.8°, 12.6°, 13.5°, 15.6°, 15.8°, 16.3°, 16.5°, 16.8°, 18.2°, 20.6°, 21.8° and 27.2° 20 (±0.220).

13. The solid form of the free base of Compound A of any one of claims 10 to 13, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 7, or Figure 8.

14. The solid form of the free base of Compound A of any one of claims 10 to 13, wherein the solid form of Compound A is further characterized by a TGA / DSC showing a melting event at Tpeak of about 150 °C and a decomposition event at Tonset of about 245-255 °C and a mass loss of about 35%.

15. The solid form of the free base of Compound A of any one of claims 10 to 13, wherein the solid form of Compound A is further characterized by a TGA / DSC showing a melting event at Tpeak of about 149.3-150.5 °C and a decomposition event at TonSet of about 245.6-255.7 °C and a mass loss of about 35.0-35.3%.

16. The solid form of the free base of Compound A of any one of claims 10 to 15, wherein the solid form is Solid Form 1.

17. A solid form of the free base of Compound A:(Compound A) wherein the solid form is characterized by an X-ray powder diffraction pattern comprising peaks at 7.0°, 9.2°, 9.6°, 13.4°, and 16.4° 29 (±0.2 20).

18. The solid form of claim 17, exhibiting an X-ray powder diffraction pattern comprising peaks at about of 7.0°, 9.1°, 9.5°, 13.4°, 16.4° and 17.8° 20 (±0.220).

19. The solid form of any one of claims 17-18, exhibiting an X-ray powder diffraction pattern comprising at least five peaks at about 7.1°, 9.1°, 9.5°, 13.3°, 16.4°, 17.8°, 19.3°, 20.7°, 21.3°, 21.5°, 22.4°, 23.7°, and 23.4° 29 (±0.2 20).

20. The solid form of the free base of Compound A of any one of claims 17 to 19, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 15A.

21. The solid form of the free base of Compound A of any one of claims 17 to 20 wherein the solid form is further characterized by a TGA / DSC showing a melting event at Tpeak of about 165.0 °C and a decomposition event at Tonset of about 260 °C and a mass loss of about22. The solid form of the free base of Compound A of any one of claims 17 to 21 further characterized by a TGA / DSC showing a melting event at Tpeak of 165 °C and a decomposition event at TonSetof 260 °C and a mass loss of 29.7%.

23. The solid form of the free base of Compound A of any one of claims 17 to 22, wherein the solid form is Solid Form 2.

24. A salt form of Compound A:(Compound A). wherein the salt form comprises a counter ion selected from the group consisting of potassium, sodium, chloride, sulfate, bisulfatc, aspartate, maleate, phosphate, glutamate, tartrate, fumarate, citrate, L-malate, hippurate, D-gluconate, L-ascorbate, succinate, acetate, naphthalene- 1,5 -disulfonate ethanesulfonate, ethane-l,2-sufonate, p-toluenesulfonate, methanesulfonate and benzoate.

25. The salt of Compound A of claim 24, selected from the group consisting of: a HC1 salt of Compound A, a sulfuric acid salt of Compound A, a phosphoric acid salt of Compound A, a citric acid salt of Compound A, a succinic acid salt of Compound A, an acetic acid salt of Compound A and a methanesulfonic acid salt of Compound A.

26. The salt of Compound A of claim 24, wherein(a) the salt is selected from the group consisting of:(i) a galacteric acid salt of Compound A characterized by melting point of about 220.0°C;(ii) a L-Aspartic acid salt of Compound A characterized by a melting point of about 264.1°C;(iii)a maleic acid salt of Compound A characterized by a melting point of about 130.5°C;(iv)a hippuric acid salt of Compound A characterized by a melting point of about 187.0°C;(v) a L-ascorbic acid salt of Compound A characterized by a melting point of about 190.0°C;(vi)a glutamic acid salt of Compound A characterized by a melting point of about 199.0°C; and a(vii) a naphthalene- 1 ,5-disulfonic acid salt of Compound A characterized by a melting point of about 242.5°C; or(b) the salt is selected from the group consisting of:(i) a galacteric acid salt of Compound A characterized by a TGA / DSC showing a melting event at Tpeak of about 221.4°C; or a galacteric acid salt of Compound A characterized by a TGA / DSC showing a melting event at Tpeak of about 149.6°C;(ii) a L-Aspartic acid salt of Compound A characterized by a TGA / DSC showing a desolvation event at about 69.9 °C and an exotherm at about 173.8 °C;(iii)a maleic acid salt of Compound A characterized by a TGA / DSC showing a melt event at about 151.3 °C;(iv)a hippuric acid salt of Compound A characterized by a TGA / DSC showing a melt event at about 186.5 °C; or a hippuric acid salt of Compound A characterized by a TGA / DSC showing a melt event at about 136.8 °C and an exotherm at about 165.2 °C;(v) a L-ascorbic acid salt of Compound A characterized by a TGA / DSC showing a melt / decomposition event at about 189.3 °C; or a L-ascorbic acid salt of Compound A characterized by a TGA / DSC showing a melt event at about 150.3 °C and a melt / decomposition event at about 186.8°C; or a L-ascorbic acid salt of Compound A characterized by a TGA / DSC showing a melt / decomposition event at about 188.1°C; or a L-ascorbic acid salt of Compound A characterized by a TGA / DSC showing a melt event at about 146.9 °C and a melt / decomposition event at about 188.6°C; and(vi)a glutamic acid salt of Compound A characterized by a TGA / DSC showing a melt / decomposition event at about 198.8°C; or a glutamic acid salt of Compound A characterized by a TGA / DSC showing a melt / decomposition event at about 196.9°C; or a glutamic acid salt of Compound A characterized by a TGA / DSC showing a melt event at about 150.9°C, and a melt / decomposition event at about 201.5°C; or(vii) a napthalene-1,5- disulfonic acid salt of Compound A characterized by a TGA / DSC showing desolvation event at about 92.6°C, a desolvation event at about 127.1°C, and a melt event at about 213.8°C; or a napthalene-1,5- disulfonic acid salt of Compound A characterized by a TGA / DSC showing desolvation event at about 119°C; or(c) the salt is selected from the group consisting of:(i) a galacteric acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP2; or a galacteric acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP14;(ii) a L-Aspartic acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP3;(iii)a maleic acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP4;(iv)a hippuric acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP5; or a hippuric acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP8;(v) a L-ascorbic acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP6; or a L-ascorbic acid salt of Compound A characterized by an X-ray powder diffraction(XRPD) pattern substantially as shown in NP7; or a L-ascorbic acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP12; or a L-ascorbic acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP13; and(vi)a glutamic acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP9; or a glutamic acid salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in NP10.(d) the salt is selected from the group consisting of:(i) a galactaric acid salt of Compound A characterized by a X-ray powder diffraction (XRPD) pattern comprising peaks at 13.5°, 15.6°, 15.8°, 16.5°, and 27.2° 26 (±0.2 20);(ii) a L-Aspartic acid salt of Compound A characterized by a X-ray powder diffraction (XRPD) pattern comprising peaks at 21.7°, 28.2°, and 31.1° 20 (±0.2 20);(iii)a maleic acid salt of Compound A characterized by a X-ray powder diffraction (XRPD) pattern comprising peaks at 21.6°, 28.2°, 31.1°, 32.2°, and 35.1° 20 (±0.2 20);(iv)a hippuric acid salt of Compound A characterized by a X-ray powder diffraction (XRPD) pattern comprising peaks at 21.8°, 21.9°, 22.2°, 28.0°, and 31.7° 20 (±0.2 20);(v) a L-ascorbic acid salt of Compound A characterized by a X-ray powder diffraction (XRPD) pattern comprising peaks at 19.9°, 28.0°, and 30.9° 20 (±0.2 20); or a L-ascorbic acid salt of Compound A characterized by a X- ray powder diffraction (XRPD) pattern comprising peaks at 30.0°, and 19.7° 20 (±0.2 20); and(vi)a glutamic acid salt of Compound A characterized by a X-ray powder diffraction (XRPD) pattern comprising peaks at 21.4°, 22.0°, and 25.6° 20 (±0.220).

27. A pharmaceutical composition comprising a salt or solid form of Compound A according to of any one of claims 1 to 26 and at least one pharmaceutically acceptable carrier.

28. The pharmaceutical composition of claim 27, comprising(a) 20% w / w of the salt or solid form of Compound A according to any one of claims 1 to 27;(b) 60-65% w / w of a microcrystalline cellulose having a Compactibility Index of about 150 and a Repose Angle of MCC of about 42 degrees;(c) about 5% w / w Type A Crospovidone;(d) about 5% w / w hydroxypropyl cellulose SL; and(e) about 5% w / w low substituted hydroxypropyl cellulose.

29. An oral dosage form tablet comprising a total of 120 mg or 160 mg and 20% w / w of Compound A free base characterized by an X-ray powder diffraction pattern comprising peaks at 7.0°, 9.2°, 9.6°, 13.4°, and 16.4° 20 (±0.2 20).

30. A method of treating a patient with a RAS-mutated or RAF-mutated cancer, comprising administering a therapeutically effective amount of the pharmaceutical composition of any one of claims 29 and 28 or the tablet of claim 29, wherein the Compound A is administered to the patient (a) in a dose amount that achieves a Cmax effective to inhibit pERK and pMEK and (b) with an interval between consecutive doses that is at least about seven times the plasma half-life of the dual-MEK inhibitor.

31. The method claim 30, wherein the patient is diagnosed with a cancer harboring a mutation in (a) KRAS optionally selected from G12C, G12S, G12D or G12V; (b) NRAS optionally selected from Q61L, Q61K, Q61R; (c) HRAS; or (d) BRAF optionally selected from V600E.

32. The method any one of claims 30 and 31, wherein the patient is diagnosed with a cancer selected from the group consisting of: pancreatic cancer, human lung adenocarcinoma, human malignant melanoma, human NSCLC and human colon carcinoma.

Images