HPK1 inhibitor formulations and methods of making the same

Abstract

The present invention relates to formulations and dosage forms of substituted isoindolin-1-ones that are useful as HPK1 inhibitors and methods of making the formulations and dosage forms. The invention also provides methods of treating disorders using the formulations and dosage forms.

Description

HPK1 INHIBITOR FORMULATIONS AND METHODS OF MAKING THE SAMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The application claims the benefit of priority to U.S. Provisional Application No. 63 / 680,489, filed August 7, 2024, the content of which is herein incorporated by reference.TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to formulations and dosage forms of substituted isoindolin-l-ones that are useful as HPK1 inhibitors and methods of making the formulations and dosage forms. The invention also provides methods of treating disorders using the formulations and dosage forms.BACKGROUND OF THE INVENTION

[0003] Hematopoietic progenitor kinase 1 (HPK1, also known as MAP4K1) is a member of the MAP4K family of protein serine / threonine kinases, involved in negatively regulating signal transduction cascades in cells of hematopoietic lineage. Inhibition of HPK1 has the potential to enhance and prime a patient’s immune system to recognize and eliminate tumor cells and also to augment immune checkpoint blockade (ICB) therapies on T cell responses (Sawasdikosol and Burakoff. "A perspective on HPK1 as a novel immuno-oncology drug target." Elife 9 (2020): e55122).

[0004] A need exists to develop formulations for HPK1 inhibitors for use in cancer therapy.SUMMARY OF THE INVENTION

[0005] In one aspect, the present invention provides pharmaceutical compositions, fonnulations, and unit dosage fonns comprising:(a) Compound A:33355712 1 Page 1 of 113 398110-93HPWO (217136)or a solvate or pharmaceutically acceptable salt thereof:(b) one or more filler (e.g., microcrystalline cellulose);(c) one or more anti-adherent (e.g., talc);(d) one or more disintegrant (e.g., croscarmellose sodium);(e) one or more glidant (e.g., colloidal silicon dioxide); and(f) one or more lubricant (e.g., sodium stearyl fumarate).

[0006] In another aspect, the present invention provides a method of preparing a unit dosage form comprising:(a) Compound A:or a solvate or pharmaceutically acceptable salt thereof;(b) one or more filler (e.g., microcrystalline cellulose);(c) one or more anti-adherent (e.g., talc);(d) one or more disintegrant (e.g., croscarmellose sodium);(e) one or more glidant (e.g., colloidal silicon dioxide); and(f) one or more lubricant (e.g., sodium stearyl fumarate).

[0007] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage form comprising:(a) 10-20 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) 50-70 mg of a filler such as microcrystallinc cellulose;(c) 10-15 mg of an anti -adherent such as talc;(d) 10-20 mg of a disintegrant such as croscarmellose sodium;(e) 1-2 mg of a glidant such as colloidal silicon dioxide; and(f) 2-3 mg of a lubricant such as sodium stearyl fumarate.33355712 1 Page 2 of 113 398110-93HPWO (217136)

[0008] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage form comprising:(a) 20-40 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) 120-150 mg of a filler such as microcrystalline cellulose;(c) 15-25 mg of an anti -adherent such as talc;(d) 20-40 mg of a disintegrant such as croscarmellose sodium;(e) 2-3 mg of a glidant such as colloidal silicon dioxide; and(f) 4-6 mg of a lubricant such as sodium stearyl fumarate.

[0009] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage fonn comprising:(a) 50-80 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) 30-50 mg of a filler such as microcrystalline cellulose;(c) 10-15 mg of an anti -adherent such as talc;(d) 10-30 mg of a disintegrant such as croscarmellose sodium;(e) 1-3 mg of a glidant such as colloidal silicon dioxide; and(f) 2-4 mg of a lubricant such as sodium stearyl fumarate.

[0010] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage form comprising:(a) 90-140 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof(b) 50-70 mg of a filler such as microcrystalline cellulose;(c) 15-35 mg of an anti -adherent such as talc;(d) 30-50 mg of a disintegrant such as croscannellose sodium;(e) 3-5 mg of a glidant such as colloidal silicon dioxide; and(f) 4-8 mg of a lubricant such as sodium stearyl fumarate.

[0011] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage form comprising:(a) 150-200 mg of Compound A or a solvate or pharmacally acceptable salt thereof;(b) 80-100 mg of a filler such as microciy stalline cellulose;(c) 30-50 mg of an anti -adherent such as talc;(d) 50-70 mg of a disintegrant such as croscarmellose sodium;(e) 4-7 mg of a glidant such as colloidal silicon dioxide; and(f) 6-10 mg of a lubricant such as sodium stearyl fumarate.33355712 1 Page 3 of 113 398110-93HPWO (217136)

[0012] These and other aspects of this disclosure will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information and procedures.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 shows an XRPD of Compound A malate hydrate with 2-theta (degrees) on the x-axis and intensity (counts per second) on the y-axis.

[0014] FIG. 2 shows the solubility of Compound A malate hydrate with different surfactants.

[0015] FIG. 3 shows non-sink dissolution results of Compound A malate hydrate in biorelevant media.

[0016] FIG. 4 shows prototype capsule fonnulation screening in a sink dissolution study at 100 mgA / 400 mgW strength. Error bars represent the data range (n = 2).

[0017] FIG. 5 shows impact of dose strength and API lot on dissolution in prototype capsules. Both lots are 150 mgA / 600 mgW. Error bars represent one standard deviation (n = 3).

[0018] FIG. 6 shows impact of strength and drug loading on sink dissolution in 0.01 N HC1 in prototype capsules.

[0019] FIG. 7 shows dissolution profdes of pre-pilot capsules stored at accelerated conditions. Data points are jitter-offset for visual aid.

[0020] FIG. 8 shows the manufacturing process flow diagram for 10. 20. 50, and 150 mgA capsules.

[0021] FIG. 9 shows histogram of the particle size distribution of pilot granulations.

[0022] FIG. 10 shows a cumulative particle size distribution plot of the pilot granulations.

[0023] FIG. 11 shows sink dissolution results of pilot capsules.DETAILED DESCRIPTION OF THE INVENTION1. General Description of Certain Embodiments of the Invention:

[0024] Compound A:33355712 1 Page 4 of 113 398110-93HPWO (217136)A is an HPK1 inhibitor previously disclosure by Applicant. See US 11,548,890. Compound A is a weak base with good solubility at low pH, with solubility decreasing with increasing pH. This higher pH insolubility may present barriers in formulating tire compound for patient administration or treatment of said patients because, e.g., insolubility at higher intestinal pH may affect bioavailability and therapeutic outcomes. Hie present disclosure satisfies the need for suitable formulations of Compound A and provides other related advantages.

[0025] Compound A is a novel small molecule inhibitor of HPK1 selected for clinical development based on HPK1 potency, its effects on T cell, B cell, and dendritic cell activation in vitro, and its ability to modulate immune responses and inhibit tumor growth in mouse tumor models. Compound A has high selectivity for HPK1 versus other kinases and has limited potential for other “off-target” effects at high multiples of the concentrations that inhibit HPK1 in vitro.

[0026] In the following disclosure, certain specific details are in the art will understand that the methods and uses described herein may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be constmed in an open, inclusive sense, that is. as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0027] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the tenn “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.2. Definitions

[0028] Formulations and methods described herein include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, tire following definitions shall apply unless otherwise indicated. For purposes of the present disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of33355712 1 Page 5 of 113 398110-93HPWO (217136)Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March’s Advanced Organic Chemistry. 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001 .

[0029] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmacally acceptable, nontoxic acid addition salts are salts of an amino group fonned with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate. lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0030] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (Ci 4alkyl) salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0031] As used herein, "‘about” or “approximately” in reference to a numerical value means that the stated numerical value may vary by up to 10% of the stated value. For example, “about 10” refers to a value of 9.9 to 10.1 (10 + / - 0.1).

[0032] ‘ 'Nominal particle size,” as used herein refers to a particle size representing the mass average of the particles.

[0033] ‘ ‘Loose bulk density,” as used herein, refers to the mass per unit volume of a loose powder.33355712 1 Page 6 of 113 398110-93HPWO (217136)

[0034] A '‘solubilizer,” as used herein, may refer to one or more compounds added to the formulation that increases solubility in any given solvent system, e.g., water, organic solvents, biological fluids, simulated biological fluids, and mixtures thereof.

[0035] A “binder,” as used herein, may refer to one or more compounds that promote cohesiveness among the other components in the formulation, tire binders, also called adhesives, help the other ingredients in a formulation to mix together. Binders may help turn powder to granules; this may be achieved during the process of granulation.

[0036] A “surfactant,” as used herein, may refer to one or more compounds that lower the surface tension between two liquids, between a gas and a liquid, or between a liquid and a solid. Surfactants may act as detergents, wetting agents, emulsifiers, foaming agents, or dispersants.

[0037] “Glidants.” as used herein, are additive substances that are used to enhance the flowability of a powder by reducing tire interparticle friction, surface charge, and cohesion, which in turn decreases the angle of repose. They are often incorporated as a dry powder just prior to direct compression.

[0038] ‘ ‘Granulation,” as used herein, refers to a process to produce larger or smaller granules or particles of a substance or mixture of substances. The process also may remove fine granules and improve flowability within the formulation. Both wet granulation and / or dry granulation may be employed. Dry granulation is achieved using only a combination of granules without the need for any liquid thereon. Slugging uses a tablet press to fonn large tablets that vary in weight due to the poor flowability of the formulation. The slugs created are then put through a granulator to be broken down into granules and then compressed once again for a final granulated product.

[0039] Tire process may include roller compaction wherein the formulation is fed through a roller compactor, the mixture is fed through a top hopper where two rollers would compact the powder to form a ribbon, this would then pass through a granulator where the powder is forced against a mesh which creates the granules of the desired size. In some embodiments, the granules have a mean particle diameter between about 0.01 mm and about 10 mm. Tn some embodiments, the granules have a mean particle diameter between about 0.2 mm and about 0.4 mm.

[0040] Wet granulation may be used to facilitate aggregation of particles. An adhesive usually called a binder may be incorporated in the fomi of a solution or suspension in a suitable liquid.

[0041] A fluid bed granulator may be used for wet granulation wherein hot air is fed into a bed lifting the granules whilst they are sprayed, granules bind together to form bridges between themselves. The initial phase of wet granulation may include the spraying of the granules, the spray rate may be varied. Wetting of the powder may then begin to form liquid bridges between the granules. The process is continued until the required size granule is fomred with solid bridges between the granules. Once complete granules may go to the drying process, the spraying process may be turned off and the hot air will continue to flow through33355712 1 Page 7 of 113 398110-93HPWO (217136)the bed drying the granules. The wet granulation may be performed in a high shear wet granulator, commercially available or known to those having ordinary skill in the art, e.g., a wet granulator as described in Liu et al., “A review of high shear wet granulation for better process understanding, control and product development,” Powder Technology, 381, March 2021, Pages 204-223. As to the drying process, such methods and apparatuses to perform the same will be known to those having ordinary skill in the art. Hie drying may be performed in a fluid bed dryer, e.g.. as described in Srivastava et al.. “Fluid Bed Technology: Overview and Parameters for Process Selection,” International Journal of Pharmaceutical Sciences and Drug Research 2010; 2(4): 236-246.

[0042] Screen milling of the process material may be used, e.g., for example after drying. Screen milling procedures and equipment are will known to those having ordinary skill in the art, e.g., as described in Kotamarthy. L.V.G., (2018). “Understanding the effect of granulation and mill process parameters on granule critical quality attributes,” [Master’s dissertation, Rutgers University]. Rutger’s Library.

[0043] “Blending,” as used herein, refers to techniques for blending solid material well known to those of ordinary7skill in the art. Such techniques and machinery for blending are described in the art, e.g., Mendez et al., “Evaluation of powder mixing operation during batch production: application to operational qualification procedure in the pharmaceutical industry.” Powder Technol.2009; 198:310-3. Hamby N. “An engineering view of pharmaceutical powder mixing.” Pharm Sci Technol Today. 2000;3:303-9. Remy B. et al., “Discrete element simulation of free flowing grains in a four-bladed mixer.” AIChE J. 2009;55:2035- 48; and StieB M. “Mechanische Verfahrenstechnik — Partikeltechnologie 1.” 3rd ed. Berlin: Springer; 2009.

[0044] Other methods of granulation are known to those having ordinary skill in the art, and are described in Miyazaki S et al. “Drug release from oral mucosal adhesive tablets of chitosan and sodium alginate.” Int J Phann 1995; 118: 257-263; Selmeczi B. “Hie influence of the compressional force on the physical properties of tablets made by different technological processes.” Arch Phann (Weinheim) 1974; 307(10): 755-760; and Beg et al.. 2021, “Handbook of Analytical Quality by Design.” Elsevier Inc.

[0045] ‘ ‘De-lumping,” as used herein, refers to a process by passing the powder formulation through a mesh screen. Screens used herein for processes, e.g., blending or de-lumping, may have a mesh size between about 1 to about 100 pm, about 100 to about 500 pm, about 500 to about 1,000 pm, about 1,000 to about 5,000 pm, about 5,000 pm to about 10,000 pm, about 10,000 to about 50,000 pm, or about 50,000 to about 100.000 pm.3. Description of Exemplary Pharmaceutical Compositions, Formulations, and Unit Dosage Forms

[0046] In one aspect, the present invention provides pharmaceutical compositions, formulations, and unit dosage forms comprising:(a) Compound A:33355712 1 Page 8 of 113 398110-93HPWO (217136)or a solvate or pharmaceutically acceptable salt thereof;(b) one or more filler;(c) one or more anti-adherent;(d) one or more disintegrant;(e) one or more glidant; and(f) one or more lubricant.

[0047] In some embodiments, Compound A is in the form of a solvate, e.g., a hydrate, or a pharmacally acceptable salt of such solvate. In some embodiments, Compound A is in the fonn of a free base. In some embodiments, Compound A is in the form of a crystalline solid. In some embodiments, the crystalline solid is Compound A L-malate monohydrate.

[0048] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 1 mg to about 500 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof In some embodiments, a pharmaceutical composition, formulation, or unit dosage fonn of the present invention comprises about 10 mg to about 150 mg of Compound A or a solvate or pharmacally acceptable salt thereof. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 10 mg to about 20 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 20 mg to about 40 mg of Compound A or a solvate or pharmacally acceptable salt thereof. In some embodiments, a pharmaceutical composition, fonnulation, or unit dosage form of the present invention comprises about 50 mg to about 80 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 100 mg to about 140 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutical composition, formulation, or unit dosage33355712 1 Page 9 of 113 398110-93HPWO (217136)form of the present invention comprises about 150 mg to about 200 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof.

[0049] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises Compound A or a solvate or pharmaceutically acceptable salt thereof in an amount of from about 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg. about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 100 mg to about 105 mg, about 105 mg to about 110 mg, about 110 mg to about 115 mg, about 11 mg to about 120 mg, about 120 mg to about 125 mg. about 125 mg to about 130 mg. about 130 mg to about 135 mg. about 135 mg to about 140 mg, about 140 mg to about 145 mg, about 145 mg to about 150 mg, about 150 mg to about 155 mg, about 155 mg to about 160 mg, about 160 mg to about 165 mg, about 165 mg to about 170 mg, about 170 mg to about 175 mg, about 175 mg to about 180 mg, about 180 mg to about 185 mg, about 185 mg to about 190 mg, about 190 mg to about 195 mg, or about 195 mg to about 200 mg.

[0050] In some embodiments, a pharmaceutical composition, fonnulation, or unit dosage form of the present invention comprises about 1 mg, about 5 mg. about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 95 mg to about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg. about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg. about 175 mg, about 180 mg. about 185 mg, about 190 mg, about 195 mg, or about 200 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 10 mg, about 20 mg, about 50 mg, about 100 mg, or about 150 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof.

[0051] In some embodiments, a pharmaceutical composition, fonnulation, or unit dosage form of the present invention comprises about 5 to about 60% (w / w) of Compound A or a solvate or pharmacally acceptable salt thereof. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 10 to about 50% (w / w) of Compound A or a solvate or pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 12% (w / w) of Compound A or a solvate or pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutical composition,33355712 1 Page 10 of 113 398110-93HPWO (217136)formulation, or unit dosage form of the present invention comprises about 50% (w / w) of Compound A or a solvate or pharmaceutically acceptable salt thereof.

[0052] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises a filler or diluent. In some embodiments, a filler comprises microcrystalline cellulose or any one or more of the fillers or diluents described herein. In some embodiments, a filler is microcrystalline cellulose.

[0053] Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as Avicel-PH-101 and Avicel-PH-102 (Dupont), and mixtures thereof.

[0054] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 10 mg to about 500 mg of a filler. In some embodiments, a pharmacal composition, fonnulation, or unit dosage fonn of the present invention comprises about 20 mg to about 150 mg of a filler. In some embodiments, a pharmaceutical composition, fonnulation, or unit dosage form of the present invention comprises about 50 mg to about 70 mg of a filler. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 120 mg to about 150 mg of a filler. In some embodiments, a pharmaceutical composition, fonnulation, or unit dosage fonn of the present invention comprises about 30 mg to about 50 mg of a filler. In some embodiments, a pharmaceutical composition, fonnulation, or unit dosage fomr of tire present invention comprises about 50 mg to about 70 mg of a filler. In some embodiments, a pharmacal composition, formulation, or unit dosage form of the present invention comprises about 80 mg to about 100 mg of a filler.

[0055] In some embodiments, a pharmaceutical composition, formulation, or unit dosage fonn of the present invention comprises an amount of filler from about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg. about 40 mg to about 45 mg. about 45 mg to about 50 mg. about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 100 mg to about 105 mg, about 105 mg to about 110 mg, about 110 mg to about 115 mg, about 115 mg to about 120 mg, about 120 mg to about 125 mg, about 125 mg to about 130 mg, about 130 mg to about 135 mg, about 135 mg to about 140 mg. about 140 mg to about 145 mg, or about 145 mg to about 150 mg.

[0056] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg,33355712 1 Page 11 of 113 398110-93HPWO (217136)about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg of a filler. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 31 mg, about 67 mg, about 93 mg, about 62 mg, or about 133 mg of a filler.

[0057] In some embodiments, a pharmaceutical composition, fonnulation, or unit dosage form of the present invention comprises about 10 to about 70% (w / w) of a filler. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 23 to about 60% (w / w) of a filler. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 23% (w / w) of a filler. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 60% (w / w) of a filler.

[0058] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises an anti-adherent or lubricant. In some embodiments, an anti-adherent comprises talc or any one or more of the anti-adherents or lubricants described herein. In some embodiments, an anti-adherent is talc

[0059] Suitable forms of talc include, but are not limited to, the materials sold as Parteck LUB Talc (EMD Millipore Corporation, Burlington, MA).

[0060] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 5 mg to about 50 mg of an anti-adherent. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 10 mg to about 45 mg of an anti -adherent. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 5 mg to about 15 mg of an anti -adherent. In some embodiments, a pharmaceutical composition, fonnulation, or unit dosage form of the present invention comprises about 10 mg to about 20 mg of an anti -adherent. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 15 mg to about 25 mg of an anti-adherent. In some embodiments, a pharmaceutical composition, formulation, or unit dosage fonn of the present invention comprises about 15 mg to about 35 mg of an anti -adherent. In some embodiments, a pharmacal composition, fonnulation, or unit dosage fonn of the present invention comprises about 30 mg to about 50 mg of an anti-adherent.

[0061] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises an anti -adherent from about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg.33355712 1 Page 12 of 113 398110-93HPWO (217136)

[0062] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg of an anti -adherent. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 11 mg, about 13 mg, about 22 mg, about 27 mg, or about 40 mg of an anti -adherent.

[0063] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 5 to about 20% (w / w) of an anti-adherent. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 10% (w / w) of an anti-adherent.

[0064] In some embodiments, a pharmaceutical composition, formulation, or unit dosage fonn of the present invention comprises a disintegrant. In some embodiments, a disintegrant comprises croscarmellose sodium or any one or more of the disintegrants described herein. In some embodiments, a disintegrant is croscarmellose sodium.

[0065] Suitable forms of croscarmellose sodium include, but are not limited to, the materials sold as Ac- Di-Sol (Dupont).

[0066] In some embodiments, a pharmaceutical composition, fonnulation, or unit dosage form of the present invention comprises about 5 mg to about 80 mg of a disintegrant. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 10 mg to about 70 mg of a disintegrant. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 10 mg to about 20 mg of a disintegrant. In some embodiments, a pharmacal composition, formulation, or unit dosage form of the present invention comprises about 20 mg to about 40 mg of a disintegrant. In some embodiments, a pharmacal composition, formulation, or unit dosage form of the present invention comprises about 10 mg to about 30 mg of a disintegrant. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 30 mg to about 50 mg of a disintegrant. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 50 mg to about 70 mg of a disintegrant.

[0067] In some embodiments, a pharmaceutical composition, fonnulation, or unit dosage form of the present invention comprises an amount of disintegrant from about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg. about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, or about 55 mg to about 60 mg.

[0068] In some embodiments, a pharmacal composition, formulation, or unit dosage fonn of the present invention comprises about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 3533355712 1 Page 13 of 113 398110-93HPWO (217136)mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg of a disintegrant. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 16 mg, about 19 mg, about 32 mg, about 38 mg, or about 57 mg of a disintegrant.

[0069] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 10 to about 20% (w / w) of a disintegrant. In some embodiments, a pharmaceutical composition, formulation, or unit dosage fonn of the present invention comprises about 14% (w / w) of a disintegrant.

[0070] In some embodiments, a pharmaceutical composition, formulation, or unit dosage fonn of the present invention comprises a glidant. In some embodiments, a glidant comprises colloidal silicon dioxide or any one or more of the glidants described herein. In some embodiments, a glidant is colloidal silicon dioxide.

[0071] Suitable forms of colloidal silicon dioxide include, but are not limited to, the materials sold as EMPROVE (EMD Millipore Corporation, Burlington, MA).

[0072] In some embodiments, a pharmaceutical composition, formulation, or unit dosage fonn of the present invention comprises about 1 mg to about 10 mg of a glidant. In some embodiments, a pharmaceutical composition, formulation, or unit dosage fonn of the present invention comprises about 1 mg to about 7 mg of a glidant. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 1 mg to about 3 mg of a glidant. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 1 mg to about 2 mg of a glidant. In some embodiments, a pharmaceutical composition, formulation, or unit dosage fomr of the present invention comprises about 2 mg to about 3 mg of a glidant. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 3 mg to about 5 mg of a glidant. In some embodiments, a pharmacal composition, formulation, or unit dosage form of the present invention comprises about 4 mg to about 7 mg of a glidant.

[0073] In some embodiments, a pharmaceutical composition, formulation, or unit dosage fonn of the present invention comprises an amount of glidant from about 0.5 mg to about 1.0 mg, about 1.0 mg to about 1.5 mg, about 1.5 mg to about 2.0 mg, about 2.0 mg to about 2.5 mg, about 2.5 mg to about 3.0 mg, about 3.0 mg to about 3.5 mg. about 3.5 mg to about 4.0 mg, about 4.0 mg to about 4.5 mg, about 4.5 mg to about 5.0 mg. about 5.0 mg to about 5.5 mg, or about 5.5 mg to about 6.0 mg.

[0074] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, or about 6.0 mg of a glidant.33355712 1 Page 14 of 113 398110-93HPWO (217136)In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 1.4 mg, about 1.7 mg, about 2.8 mg, about 3.4 mg, or about 5 mg of a glidant.

[0075] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 1 to about 3% (w / w) of a glidant. In some embodiments, a pharmacal composition, formulation, or unit dosage fonn of the present invention comprises about 1.3% (w / w) of aglidant.

[0076] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises a lubricant. In some embodiments, a lubricant comprises sodium stearyl fumarate or any one or more of the lubricants described herein. In some embodiments, a lubricant is sodium stearyl fumarate.

[0077] Suitable forms of sodium stearyl fumarate include, but are not limited to, the materials sold as PRUV (JRS Pharma).

[0078] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 1 mg to about 15 mg of a lubricant. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 2 mg to about 10 mg of a lubricant. In some embodiments, a pharmaceutical composition, fonnulation, or unit dosage fomr of the present invention comprises about 2 mg to about 3 mg of a lubricant. In some embodiments, a phamraceutical composition, formulation, or unit dosage form of the present invention comprises about 4 mg to about 6 mg of a lubricant. In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 2 mg to about 4 mg of a lubricant. In some embodiments, a pharmaceutical composition, formulation, or unit dosage fonn of the present invention comprises about 4 mg to about 8 mg of a lubricant. In some embodiments, a pharmacal composition, formulation, or unit dosage form of the present invention comprises about 6 mg to about 10 mg of a lubricant.

[0079] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises a lubricant in an amount from about 1.5 mg to about 2.0 mg, about 2.0 mg to about 2.5 mg, about 2.5 mg to about 3.0 mg, about 3.0 mg to about 3.5 mg, about 3.5 mg to about 4.0 mg, about 4.0 mg to about 4.5 mg. about 4.5 mg to about 5.0 mg, about 5.0 mg to about 5.5 mg, about 5.5 mg to about 6.0 mg, about 6.0 mg to about 6.5 mg. about 6.5 mg to about 7.0 mg, about 7.0 mg to about 7.5 mg, about 7.5 mg to about 8.0 mg. about 8.0 mg to about 8.5 mg, or about 8.5 mg to about 9.0 mg.

[0080] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 7.5 mg, about 8.0 mg. about 8.5 mg, or about 9.0 mg of a lubricant. In some embodiments, a pharmacal33355712 1 Page 15 of 113 398110-93HPWO (217136)composition, formulation, or unit dosage form of the present invention comprises about 2.2 mg, about 2.7 mg, about 4.4 mg, about 5.4 mg, or about 8 mg of a lubricant.

[0081] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of the present invention comprises about 1 to about 3% (w / w) of a lubricant. In some embodiments, a pharmacal composition, formulation, or unit dosage form of the present invention comprises about 2% (w / w) of a lubricant.

[0082] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage form comprising:(a) from about 5 mg to about 15 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) from about 25 mg to about 35 mg of filler such as microcrystalline cellulose;(c) from about 5 mg to about 15 mg of anti -adherent such as talc;(d) from about 10 mg to about 20 mg of disintegrant such as croscarmellose sodium;(e) from about 1.0 mg to about 2.0 mg of glidant such as colloidal silicon dioxide; and(f) from about 2.0 to about 3.0 mg of lubricant such as sodium stearyl fumarate.

[0083] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage form comprising:(a) from about 15 mg to about 25 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) from about 60 mg to about 75 mg of filler such as microcrystalline cellulose;(c) from about 10 mg to about 20 mg of anti-adherent such as talc;(d) from about 15 mg to about 25 mg of disintegrant such as croscarmellose sodium;(e) from about 1.0 mg to about 2.0 mg of glidant such as colloidal silicon dioxide; and(f) from about 2.5 to about 3.5 mg of lubricant such as sodium stearyl fumarate.

[0084] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage form comprising:(a) from about 45 mg to about 55 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) from about 60 mg to about 75 mg of filler such as microcrystalline cellulose;(c) from about 15 mg to about 25 mg of anti-adherent such as talc;(d) from about 25 mg to about 40 mg of disintegrant such as croscarmellose sodium;(e) from about 2.0 mg to about 3.5 mg of glidant such as colloidal silicon dioxide; and(f) from about 4.0 to about 5.0 mg of lubricant such as sodium stearyl fumarate.33355712 1 Page 16 of 113 398110-93HPWO (217136)

[0085] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage form comprising:(a) from about 90 mg to about 110 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) from about 50 mg to about 70 mg of a filler such as microcrystalline cellulose;(c) from about 15 mg to about 35 mg of an anti -adherent such as talc;(d) from about 30 mg to about 50 mg of a disintegrant such as croscarmellose sodium;(e) from about 3.0 mg to about 5.0 mg of a glidant such as colloidal silicon dioxide; and(f) from about 4.0 mg to about 8.0 mg of a lubricant such as sodium stearyl fumarate.

[0086] In some embodiments, the present invention provides a pharmaceutical composition, fonnulation, or unit dosage form comprising:(a) from about 140 mg to about 160 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) from about 125 mg to about 140 mg of filler such as microcrystal I inc cellulose;(c) from about 35 mg to about 45 mg of anti-adherent such as talc;(d) from about 45 mg to about 60 mg of disintegrant such as croscarmellose sodium;(e) from about 4.0 mg to about 5.0 mg of glidant such as colloidal silicon dioxide; and(f) from about 7.5 to about 8.5 mg of lubricant such as sodium stearyl fumarate.

[0087] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage form comprising:(a) about 11.9% (w / w) of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) about 60.5% (w / w) of filler such as microcrystalline cellulose;(c) about 10.0% (w / w) of anti-adherent such as talc;(d) about 14.3% (w / w) of disintegrant such as croscarmellose sodium;(e) about 1 .3% (w / w) of glidant such as colloidal silicon dioxide; and(f) about 2.0% (w / w) of lubricant such as sodium stearyl fumarate.

[0088] In some embodiments, the present invention provides a pharmaceutical composition, fonnulation, or unit dosage form comprising:(a) about 49.1% (w / w) of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) about 23.3% (w / w) of filler such as microcrystalline cellulose;(c) about 10.0% (w / w) of anti-adherent such as talc;(d) about 14.3% (w / w) of disintegrant such as croscarmellose sodium;(c) about 1.3% (w / w) of glidant such as colloidal silicon dioxide; and(f) about 2.0% (w / w) of lubricant such as sodium steary l fumarate.33355712 1 Page 17 of 113 398110-93HPWO (217136)

[0089] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage form comprising:(a) 10-20 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) 50-70 mg of a filler such as microcrystalline cellulose;(c) 10-15 mg of an anti -adherent such as talc;(c) 10-20 mg of a disintegrant such as croscarmellose sodium;(d) 1-2 mg of a glidant such as colloidal silicon dioxide; and(e) 2-3 mg of a lubricant such as sodium stearyl fumarate.

[0090] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage fonn comprising:(a) 20-40 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) 120-150 mg of a fdler such as microcrystalline cellulose;(c) 20-25 mg of an anti-adherent such as talc;(c) 20-40 mg of a disintegrant such as croscarmellose sodium;(d) 2-3 mg of a glidant such as colloidal silicon dioxide; and(e) 4-6 mg of a lubricant such as sodium stearyl fumarate.

[0091] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage form comprising:(a) 50-80 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) 30-50 mg of a filler such as microcrystalline cellulose;(c) 10-15 mg of an anti -adherent such as talc;(c) 10-30 mg of a disintegrant such as croscannellose sodium;(d) 1-3 mg of a glidant such as colloidal silicon dioxide; and(e) 2-4 mg of a lubricant such as sodium stearyl fumarate.

[0092] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage form comprising:(a) 90-140 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) 50-70 mg of a filler such as microcrystalline cellulose;(c) 15-35 mg of an anti -adherent such as talc;(d) 30-50 mg of a disintegrant such as croscarmellose sodium;(e) 3-5 mg of a glidant such as colloidal silicon dioxide; and(f) 4-8 mg of a lubricant such as sodium stearyl fumarate.

[0093] In some embodiments, the present invention provides a pharmaceutical composition, fonnulation, or unit dosage form comprising:33355712 1 Page 18 of 113 398110-93HPWO (217136)(a) 150-200 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof:(b) 80-100 mg of a filler such as microcrystallinc cellulose;(c) 30-50 mg of an anti -adherent such as talc;(c) 50-70 mg of a disintegrant such as croscarmellose sodium;(d) 4-7 mg of a glidant such as colloidal silicon dioxide; and(e) 6-10 mg of a lubricant such as sodium stearyl fumarate.

[0094] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage form comprising: i) intragranularly: about 11.9% (w / w) Compound A L-malate monohydrate, about 50.5% (w / w) microcrystalline cellulose, about 10.0% (w / w) talc, about 12.0% (w / w) croscarmellose sodium, about 0.8% (w / w) colloidal silicon dioxide, and about 1.5% (w / w) sodium stearyl fumarate; and ii) extragranularly: about 10.0% (w / w) microcrystalline cellulose, about 2.3% (w / w) croscarmellose sodium, about 0.5% (w / w) colloidal silicon dioxide, and about 0.5% (w / w) sodium stearyl fumarate.

[0095] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage form comprising: i) intragranularly: about 49.1% (w / w) Compound A L-malate monohydrate, about 13.3% (w / w) microcrystalline cellulose, about 10.0% (w / w) talc, about 12.0% (w / w) croscarmellose sodium, about 0.8% (w / w) colloidal silicon dioxide, and about 1.5% (w / w) sodium stearyl fumarate; and ii) extragranularly: about 10.0% (w / w) microcrystallinc cellulose, about 2.3% (w / w) croscarmellose sodium, about 0.5% (w / w) colloidal silicon dioxide, and about 0.5% (w / w) sodium stearyl fumarate.

[0096] In some embodiments, the present invention provides a dosage fomi comprising:33355712 1 Page 19 of 113 398110-93 HPWO (217136)

[0097] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage form comprising: i) intragranularly: about 13.1 mg Compound A L-malate monohydrate, about 55.6 mg microcrystalline cellulose, about 11.0 mg talc, about 13.2 mg croscannellose sodium, about 0.8 mg colloidal silicon dioxide, and about 1.7 mg sodium stearyl fumarate: and ii) extragranularly: about 11.0 mg microcrystalline cellulose, about 2.6 mg croscannellose sodium, about 0.6 mg colloidal silicon dioxide, and about 0.6 mg sodium stearyl fumarate.

[0098] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage fonn comprising: i) intragranularly: about 26.2 mg Compound A L-malate monohydrate, about 111.1 mg microcrystalline cellulose, about 22.0 mg talc, about 26.4 mg croscannellose sodium, about 1.7 mg colloidal silicon dioxide, and about 3.3 mg sodium stearyl fumarate: and ii) extragranularly: about 22.0 mg microcrystalline cellulose, about 5.1 mg croscannellose sodium, about 1.1 mg colloidal silicon dioxide, and about 1.1 mg sodium stearyl fumarate.

[0099] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage form comprising: i) intragranularly: about 65.5 mg Compound A L-malate monohydrate, about 17.7 mg microcrystalline cellulose, about 13.3 mg talc, about 16.0 mg croscannellose sodium, about 1.0 mg colloidal silicon dioxide, and about 2.0 mg sodium stearyl fumarate; and ii) extragranularly: about 13.3 mg microcrystalline cellulose, about 3.1 mg croscannellose sodium, about 0.7 mg colloidal silicon dioxide, and about 0.7 mg sodium stearyl fumarate.

[0100] In some embodiments, the present invention provides a pharmaceutical composition, formulation, or unit dosage form comprising: i) intragranularly: about 196.6 mg Compound A L-malate monohydrate, about 53.1 mg microcrystalline cellulose, about 40.0 mg talc, about 48.0 mg croscannellose sodium, about 3.0 mg colloidal silicon dioxide, and about 6.0 mg sodium stearyl fumarate; and ii) extragranularly: about 40.0 mg microcrystalline cellulose, about 9.3 mg croscannellose sodium, about 2.0 mg colloidal silicon dioxide, and about 2.0 mg sodium stearyl fumarate.

[0101] In some embodiments, the present invention provides a dosage form comprising:33355712 1 Page 20 of 113 398110-93HPWO (217136)4. General Description of Exemplary Pharmaceutical Compositions, Formulations, and Unit Dosage Forms

[0102] The compositions described herein are administered using any amount and any route of administration effective for treating or lessening the severity of a disease described above. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compound A is preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage fonn” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions described herein will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism (e.g., and feline, canine, bovine, equine, porcine, or aves) will depend upon a variety of factors including the disorder being treated and the severity of the disorder: the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.33355712 1 Page 21 of 113 398110-93HPWO (217136)

[0103] Pharmaceutically acceptable compositions described herein can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intrathecally, transdermally, transmucosally, opthalmically, via inhalation, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, intranasally, as an oral or nasal spray, or the like, depending on the severity of the disease being treated. In certain embodiments, the compounds described herein are administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and for example from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0104] A unit dosage form described herein can be formulated for oral administration. Pharmaceutical compositions / formulations that are suitable for oral administration can be provided as discrete dosage forms, such as, but not limited to. tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum. bulk powders, effervescent or non- effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In some embodiments, such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy known to those skilled in the art. See generally, Remington’s Pharmacal Sciences, 18thcd., Mack Publishing, Easton Pa. (1990). As used herein, oral administration also includes buccal, lingual, and sublingual administration.

[0105] In some embodiments, the fonnulation further comprises one or more pharmaceutically acceptable excipients or carriers.

[0106] A person of ordinary skill would recognize that pharmaceutical formulation ingredients may serve multiple purposes within a formulation. Accordingly, a person of ordinary skill would recognize that certain fonnulation components may be classified according to multiple functions (e.g., a component may be both a filler and a binder).

[0107] In some embodiments, a unit dosage form provided herein are prepared by combining the active ingredients in an intimate admixture with one or more pharmaceutically acceptable excipients or carriers, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide, according to conventional pharmaceutical compounding techniques. Excipients or carriers can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients or carriers suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients or carriers suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and33355712 1 Page 22 of 113 398110-93HPWO (217136)caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.

[0108] In some embodiments, the pharmaceutically acceptable excipients and carriers are selected from fillers, anti -adherents, disintegrants, glidants and lubricants.

[0109] In some embodiments, a capsule can include a provided pharmacal composition in the form of a solid dosage form. In some embodiments, the solid dosage form can be a capsule.

[0110] In certain embodiments, the dosage form is a capsule, wherein the capsules may be manufactured using standard, art-recognized capsule processing procedures and equipment. In certain embodiments, soft gelatin capsules may be prepared in which the capsules contain a mixture comprising a solid form provided herein and vegetable oil or non-aqueous, water miscible materials, such as, for example, polyethylene glycol and the like. In certain embodiments, hard gelatin capsules may be prepared containing granules of solid forms provided herein in combination with a solid pulverulent carrier, such as, for example, lactose, saccharose, sorbitol, mannitol, potato starch, com starch, amylopectin, cellulose derivatives, or gelatin. In certain embodiments, a hard gelatin capsule shell may be prepared from a capsule composition comprising gelatin and a small amount of plasticizer such as glycerol. In certain embodiments, as an alternative to gelatin, the capsule shell may be made of a carbohydrate material. In certain embodiments, the capsule composition may additionally include polymers, colorings, flavorings and opacifiers as required. In certain embodiments, the capsule comprises HPMC.

[0111] In some embodiments, the pharmaceutical composition comprises one or more fillers. In certain embodiments, the filler is selected from ammonium aliginate, calcium carbonate, calcium lactate, calcium phosphate, calcium silicate, calcium sulfate, cellulose acetate, compressible sugar (e.g., lactose, glucose, and sucrose), com starch, dextrates, erythritol, ethyl cellulose, glyceryl palmitostearate, isomalt, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, medium-chain triglycerides, microcrystalline cellulose, pre-gelatinized starch, polydextrose, polymethacrylates, silicic acid, simethicone, sodium alginate, sodium chloride, sorbitol, starch, sugar spheres, sulfobutylether P-cyclodextrin, talc, tragacanth, trehalose, and xylitol, or a combination thereof.

[0112] In some embodiments, the filler is selected from talc, calcium carbonate (e.g., granules or powder), microcry stalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0113] In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the filler is lactose. In some embodiments, the filler is starch. In some embodiments, the filler is a combination of starch and lactose. In some embodiments, the filler is a combination of lactose and microcry stalline cellulose. In some embodiments, the filler is a combination of two or three components recited above. In some embodiments, the filler comprises at least microcrystalline cellulose, lactose, and mannitol.33355712 1 Page 23 of 113 398110-93HPWO (217136)

[0114] In some embodiments, the microcrystalline cellulose is selected from Avicel PH-101 or Avicel PH- 102. In some embodiment the microcrystalline cellulose can have a nominal particle size between about 10 mm to about 20 mm, about 20 mm to about 30 mm, about 30 mm to about 40 mm, about 40 mm to about 50 mm, about 50 mm to about 60 mm, about 60 mm to about 70 mm, or about 70 mm to about 80 mm. In some embodiments, the microcry stalline cellulose can have a nominal particle size of about 50 mm. In some embodiments, the microcrystalline cellulose can have a moisture content between about 0.5% (w / w) to about 1% (w / w), about 1% (w / w) to about 1.5% (w / w), about 1.5% (w / w) to about 2% (w / w), about 2% (w / w) to about 2.5% (w / w), about 2.5% (w / w) to about 3% (w / w), about 3.5% (w / w) to about 4% (w / w), about 4% (w / w) to about 4.5% (w / w), or about 4.5% (w / w) to about 5% (w / w). In some embodiments, the microcrystalline cellulose can have a moisture content between about 3% (w / w) to about 5% (w / w). In some embodiments, the microcrystalline cellulose can have a loose bulk density between about 0.1 g / cm3to about 0.15 g / cm3. about 0.15 g / cm3to about 0.2 g / cm3. about 0.2 g / cm3to about 0.25 g / cm3, about 0.25 g / cm3to about 0.3 g / cm3, about 0.3 g / cm3to about 0.35 g / cm3, about 0.35 g / cm3to about 0.4 g / cm3, about 0.4 g / cm3to about 0.45 g / cm3, or about 0.45 g / cm3to about 0.5 g / cm3. In some embodiments, the microcrystalline cellulose can have a loose bulk density’ between about 0.26 g / cm3to about 0.31 g / cm3.

[0115] In certain embodiments, dosage fonns provided herein comprise one or more diluents. Diluents may be used, e.g., to increase bulk so that a practical size capsule is ultimately provided. Suitable diluents include dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry' starch, microcrystalline cellulose (e.g., Avicel), microfme cellulose, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g.. EUDRAGIT), potassium chloride, sodium chloride, sorbitol and talc, among others. Diluents also include, e g., ammonium alginate, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, compressible sugar, confectioner’s sugar, dextrates. dextrin, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glycery l palmitostearate, isomalt, kaolin, lacitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-chain triglycerides, microcrystalline cellulose, microcrystalline silicified cellulose, powered cellulose, polydextrose, polymethylacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, sulfobutylether-[3-cyclodextrin, talc, tragacanth, trehalose, and xylitol.

[0116] In some embodiments, the pharmaceutical composition comprises one or more binders. Binders may be used, e g., to impart cohesive qualities to a capsule, and thus ensure that the formulation remains intact after compression. In some embodiments, the binder is selected from acacia gum, agar, alginic acid, calcium carbonate, calcium lactate, carbomcrs (e.g., acrylic acid polymer, carboxy polymcthylcnc, polyacrylic acid, carboxyvinyl polymer), carboxy methylcellulose sodium, carrageenan, cellulose acetate33355712 1 Page 24 of 113 398110-93HPWO (217136)phthalate, ceratonia, chitosan, copovidone, com starch, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydrogenated vegetable oil type I, hydroxyethylcellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose, inulin, lactose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, microcrystalline cellulose, pectin, poloxamer, polycarbohil. polydextrose, polyethylene oxide, polymetharylates, polyvinylpyrrolidone, pre-gelatinized starch, povidone, sodium alginate, starch, stearic acid, sucrose, tricaprylin, vitamin E polyethylene glycol succinate, and zein.

[0117] Suitable binders include, but are not limited to, starch (including potato starch, com starch, and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, propylene glycol, waxes, and natural and synthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone (PVP), cellulosic polymers (including hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), methyl cellulose, ethyl cellulose, hydroxyethyl cellulose (HEC), carboxymethyl cellulose and the like), veegum, carbomer (e.g., carbopol), sodium, dextrin, guar gum, hydrogenated vegetable oil, magnesium aluminum silicate, maltodextrin, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), microcrystalline cellulose, among others. Binding agents also include, e.g., acacia, agar, alginic acid, cabomers, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, confectioner’s sugar, copovidone, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum. hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, inulin, lactose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethylacrylates, povidone, sodium alginate, sodium carboxymethylcellulose, starch, pregelatinized starch, stearic acid, sucrose, and zein.

[0118] Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as Avicel-PH-101. Avicel-PH-102. Avicel-PH-103 Avicel RC-581, Avicel-PH-105. and mixtures thereof. In some embodiment, a specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as Avicel RC-581 . Suitable anhydrous or low moisture excipients or additives include Avicel- PH-103 and Starch 1500 LM.

[0119] In some embodiments, the pharmacal composition comprises one or more disintegrants. In certain embodiments, the disintegrant is selected from alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, cellulose, chitosan, colloidal silicon dioxide, com starch, croscarmellose sodium, crospovidone, docusate sodium, glycine, guar gum, hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, inicrocrystallinc cellulose, pre- gclatinizcd starch, polacrilin potassium, povidone, silicates, sodium aliginatc, sodium carbonate, and sodium starch glycolate.33355712 1 Page 25 of 113 398110-93HPWO (217136)

[0120] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose sodium (Ac-Di-Sol); cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as com starch, potato starch, tapioca starch, and pre- gelatinized starch; clays; aligns; and mixtures thereof.

[0121] In some embodiments, the pharmaceutical composition comprises one or more surfactants. In some embodiments, the surfactant is selected from polyoxyethylene (20) sorbitan monolaurate (e.g., Tween-20), polyoxyethylene (20) sorbitan monooleate (e.g., Tween-80), sodium lauryl sulfate, and sodium dodecyl sulfate.

[0122] In some embodiments, the pharmaceutical composition comprises one or more pore formers. In some embodiments, the pore former is selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethyleneglycol, poloaxamer 188, povidone (e.g., Kollidon K25 / K30), or sugar (e.g., glucose, mannose, fructose, and sucrose).

[0123] In some embodiments, the pharmacal composition comprises one or more glidants. In some embodiments, the glidant is selected from calcium phosphate, cellulose, colloidal silicon dioxide, fumed silica, magnesium oxide, magnesium silicate, magnesium stearate, magnesium trisilicate, and talc. Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O-SIL™ (Cabot Co. of Boston, MA), and asbestos-free talc.

[0124] In some embodiments, the pharmacal composition comprises one or more lubricants. In some embodiments, the lubricant is selected from calcium stearate, glycerin monosterate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil. hydrogenated vegetable oil, light mineral oil, myristic acid, poloxamer, polyethy lene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, solid polyethylene glycols, stearic acid, and talc.

[0125] Lubricants that can be used in pharmaceutical compositions and dosage fonns include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil. cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.), and mixtures thereof.33355712 1 Page 26 of 113 398110-93HPWO (217136)

[0126] Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof. A color lake is tire combination by adsorption of a water- soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye.

[0127] Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate.

[0128] Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame.

[0129] Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (Tween-20), polyoxyethylene sorbitan monooleate 80 (Tween-80), and triethanolamine oleate.

[0130] Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, magnesium aluminum silicate (Veegum®), acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.

[0131] Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol.

[0132] A therapeutically effective dose of Compound A. may vary from 0.15 mg / kg to 20 mg / kg patient body weight per day, more particularly 0.015 to 1.0 mg / kg, which can be administered in single or multiple doses per day. For oral administration, the drug can be delivered in the form of capsules containing 1 mg to 100 mg of the active ingredient specifically, 1 mg, 5 mg, 10 mg, 20 mg, 50 mg, or 100 mg, or in the fonns of capsules containing at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50% (w / w) of the active ingredient. For example, a capsule may contain 50 mg of Compound A, or 5-10% (w / w) of the active ingredient. For example, a capsule may contain 100 mg of Compound A, or 20-50% (w / w) of the active ingredient. For example, a capsule may contain, in addition to Compound A, a disintegrant or emollient (e.g., croscarmellose or its sodium salt and methyl cellulose), a diluent (e.g., microcrystallinc cellulose), and a lubricant (e.g., sodium stearate and magnesium stearate). The drug can be administered on a daily basis either once, twice or more per day.

[0133] In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered once, twice, thrice, or four times per day. In some embodiments, the compound or pharmacally acceptable salt thereof is administered once per day. In some embodiments, the dose of the compound or pharmaceutically acceptable salt thereof is between about 5 mg QD (i.e., once per day) to about 200 mg QD.33355712 1 Page 27 of 113 398110-93HPWO (217136)

[0134] In some embodiments, the pharmaceutical composition is administered daily in one or more divided doses. In some embodiments, the composition is administered once per day (qua diem; QD). In some embodiments, the composition is administered twice per day (bis in die; BID).

[0135] In some embodiments, the solid form of Compound A is substantially amorphous or crystalline, or is a mixture thereof. In some embodiments, the solid fonn is substantially free of impurities.

[0136] In certain embodiments, Compound A is a crystalline solid. In some embodiments. Compound A is a crystalline solid substantially free of amorphous Compound A. In some embodiments, Compound A L-malate monohydrate is crystalline comprising an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles substantially as shown in FIG.l.

[0137] As used herein, the term “substantially free of amorphous Compound A" means that the compound contains no significant amount of amorphous Compound A. In some embodiments, at least about 95% by weight of crystalline Compound A is present. In still other embodiments described herein, at least about 99% by weight of crystalline Compound A is present.4. Methods of Producing the Exemplary Pharmaceutical Compositions, Formulations, and Unit Dosage Forms

[0138] In one aspect, the present disclosure provides a method of producing a pharmaceutical composition, formulation, or unit dosage form, the method comprising dry granulating a mixture comprising:(a) Compound A:or a solvate or a pharmaceutically acceptable salt thereof;(b) one or more filler such as microcrystalline cellulose;(c) one or more anti-adherent such as talc;(c) one or more disintegrant such as croscarmellose sodium;(d) one or more glidant such as colloidal silicon dioxide; and33355712 1 Page 28 of 113 398110-93HPWO (217136)(e) one or more lubricant such as sodium stearyl fumarate.

[0139] In some embodiments, the dry granulation comprises a roller compactor. In some embodiments, the dry granulation mixture is an intragranular mixture. In some embodiments, the dry granulation is as described in Example 4, below.

[0140] In some embodiments, method can include the step of: (1) blending one or more filler such as microcrystalline cellulose with Compound A or a solvate or a pharmaceutically acceptable salt thereof, one or more anti-adherent such as talc, one or more disintegrant such as croscarmellose sodium, and one or more glidant such as colloidal silicon dioxide prior to dry granulation. In some embodiments, the blending step (1) is as described in Example 4, below.

[0141] In some embodiments, the method can include the step of: (2) de-lumping the blend of step (1) prior to dry granulation. In some embodiments, the de-lumping step (2) comprises passing the blend of ( 1) through a cone mill for dispersive mixing and deagglomeration. In some embodiments, the de-lumping step (2) is as described in Example 4, below.

[0142] In some embodiments, the method can include the step of: (3) further blending the de-lumped the blend of step (2) prior to dry granulation. In some embodiments, the blending step (3) is as described in Example 4, below.

[0143] In some embodiments, the method can include the step of: (4) blending the mixture of step (3) with one or more lubricant such as sodium stearyl fumarate prior to dry granulation. In some embodiments, the blending step (4) is as described in Example 4, below.

[0144] In some embodiments, the dry granulation mixture is an intragranular mixture which is then blended with an extragranular mixture. In some embodiments, the method further comprises blending the dry granulation mixture with a mixture comprising:(a) one or more filler such as microcrystalline cellulose;(b) one or more disintegrant such as croscarmellose sodium;(c) one or more glidant such as colloidal silicon dioxide; and(d) optionally one or more lubricant such as sodium stearyl fumarate.

[0145] In some embodiments, the blending of the dry granulation mixture comprises a first step of blending with a mixture comprising:(a) one or more filler such as microcrystalline cellulose;(b) one or more disintegrant such as croscarmellose sodium; and(c) one or more glidant such as colloidal silicon dioxide; followed by a second step of blending the mixture of the first step with one or more lubricant such as sodium stearyl fumarate.

[0146] In some embodiments, the method further comprises encapsulating the blended mixture.33355712 1 Page 29 of 113 398110-93HPWO (217136)

[0147] In some embodiments, the method comprises Compound A L-malate monohydrate.

[0148] In some embodiments of the method, the filler comprises microcrystalline cellulose; the antiadherent comprises talc; the disintegrant comprises croscarmellose sodium; the glidant comprises colloidal silicon dioxide; and the lubricant comprises sodium stearyl fumarate.

[0149] In some embodiments of the method, a pharmaceutical composition, fonnulation, or unit dosage form comprises about 11.9% (w / w) of Compound A or a solvate or pharmaceutically acceptable salt thereof; about 60.5% (w / w) microcrystalline cellulose; about 10.0% (w / w) of talc; about 14.3% (w / w) of croscarmellose sodium; about 1.3% (w / w) of colloidal silicon dioxide; and about 2.0% (w / w) of sodium stearyl fumarate.

[0150] In some embodiments of tire method, a pharmacal composition, formulation, or unit dosage form comprises about 49.1% (w / w) of Compound A or a solvate or pharmaceutically acceptable salt thereof; about 23.3% (w / w) microcrystalline cellulose; about 10.0% (w / w) of talc; about 14.3% (w / w) of croscarmellose sodium; about 1.3% (w / w) of colloidal silicon dioxide; and about 2.0% (w / w) of sodium stearyl fumarate.

[0151] In some embodiments, a method of producing a pharmacal composition, formulation, or unit dosage fonn of present invention is as depicted in Example 4, below.5. Uses of Formulations

[0152] The pharmaceutical compositions, formulations, or unit dosage forms comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof described herein are generally useful for the inhibition of kinase activity of one or more enzymes. In some embodiments the kinase inhibited by the pharmaceutical compositions, fonnulations, or unit dosage forms of the invention comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof is HPK1.

[0153] The presently disclosed pharmaceutical compositions, formulations, or unit dosage fonns comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof find use in inhibiting the activity of the enzyme HPK1. HPK1 is a member of the germinal center kinase subfamily of Ste20- related serine / threonine kinases. HPK1 functions as a MAP4K by phosphorylating and activating MAP3K proteins, including MEKK1, MLK3 and TAK1, leading to the activation of the MAPK Jnk.

[0154] According to one embodiment, the invention relates to a method of inhibiting HPK1. or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of this invention. In certain embodiments, the invention relates to a method of irreversibly inhibiting HPK1, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a pharmacal composition, formulation, or unit33355712 1 Page 30 of 113 398110-93HPWO (217136)dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of this invention.

[0155] Tire term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0156] Inhibition of HPK1 (or a mutant thereof) activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

[0157] According to another embodiment, the invention relates to a method of inhibiting activity of HPK 1 , or a mutant thereof, in a patient comprising the step of administering to said patient a pharmaceutical composition, fonnulation, or unit dosage fonn comprising Compound A or a solvate or a pharmacally acceptable salt thereof of the present invention. According to certain embodiments, the invention relates to a method of reversibly or irreversibly inhibiting one or more of HPK1, or a mutant thereof, activity in a patient comprising the step of administering to said patient a pharmaceutical composition, formulation, or unit dosage fomr comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the present invention. In other embodiments, the present invention provides a method for treating a disorder mediated by HPK1, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the present invention. Such disorders are described in detail herein.

[0158] In certain embodiments, the subject matter disclosed herein is directed to a method for enhancing an immune response in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a pharmaceutical composition, formulation, or unit dosage fonn comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the present invention. In certain aspects of this embodiment, the T cells in the subject have at least one of enhanced priming, enhanced activation, enhanced migration, enhanced proliferation, enhanced survival, and enhanced cytolytic activity relative to prior to the administration of a pharmaceutical composition, formulation, or unit dosage fomr comprising Compound A or a solvate or a pharmacally acceptable salt thereof of the present invention. In certain aspects of this embodiment, the T cell activation is characterized by an elevated frequency of y- IFN+ CD8 T cells or enhanced levels of IL-2 or granzyme B production by T cells relative to prior to administration of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the present invention. In certain aspects of this embodiment, the number of T cells is elevated relative to prior to administration a pharmaceutical composition, formulation, or unit dosage fonn comprising Compound A or a solvate or a pharmacally33355712 1 Page 31 of 113 398110-93HPWO (217136)acceptable salt thereof of the present invention. In certain aspects of this embodiment, the T cell is an antigen-specific CD8 T cell. In certain aspects ofthis embodiment, the antigen presenting cells in the subject have enhanced maturation and activation relative prior to the administration of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the present invention. In certain aspects of this embodiment, the antigen presenting cells are dendritic cells. In certain aspects of this embodiment, the maturation of the antigen presenting cells is characterized by increased frequency of CD83+ dendritic cells. In certain aspects of this embodiment, the activation of the antigen presenting cells is characterized by elevated expression of CD80 and CD86 on dendritic cells.

[0159] The presently disclosed compounds bind directly to HPK1 and inhibit its kinase activity. In some embodiments, the presently disclosed pharmaceutical compositions, formulations, and unit dosage forms comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the present invention reduce, inhibit, or otherwise diminish the HPK1 -mediated phosphorylation of SLP76 and / or Gads.

[0160] The presently disclosed pharmaceutical compositions, formulations, or unit dosage forms comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof are specific HPK1 antagonists. A specific HPK1 antagonist reduces the biological activity of HPK1 by an amount that is statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other serine / threonine kinases). In certain embodiments, the presently disclosed compounds specifically inhibit the serine / threonine kinase activity of HPK1. In some of these embodiments, the IC50 of the HPK1 antagonist for HPK1 is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001%, or less of the IC50 of the HPK1 antagonist for another serine / threonine kinase or other type of kinase (e.g., tyrosine kinase).

[0161] The presently disclosed pharmaceutical compositions, formulations, or unit dosage forms comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof can be used in a method for inhibiting HPK1. Such methods comprise contacting HPK 1 with an effective amount of a presently disclosed pharmaceutical compositions, formulations, or unit dosage forms comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof. By "contact" is intended bringing the compound within close enough proximity to an isolated HPK1 enzyme or a cell expressing HPK1 (e.g., T cell, B cell, dendritic cell) such that the compound is able to bind to and inhibit the activity of HPK1. The pharmaceutical compositions, formulations, or unit dosage forms comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof can be contacted with HPK1 in vitro or in vivo via administration of the pharmaceutical compositions, formulations, or unit dosage forms comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof to a subject.33355712 1 Page 32 of 113 398110-93HPWO (217136)

[0162] Any method known in the art to measure the kinase activity of HPK1 may be used to determine if HPK1 has been inhibited, including in vitro kinase assays, immunoblots with antibodies specific for phosphorylated targets of HPK1, such as SLP76 and Gads, or the measurement of a downstream biological effect of HPK1 kinase activity, such as the recruitment of 14-3-3 proteins to phosphory lated SLP7 and Gads, release of tire SLP76-Gads- 14-3-3 complex from LAT-containing microclusters, or T or B cell activation.

[0163] The presently disclosed pharmaceutical compositions, formulations, or unit dosage forms comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof can be used to treat a HPK1 -dependent disorder. As used herein, a "HPK1 -dependent disorder" is a pathological condition in which HPK1 activity is necessary for tire genesis or maintenance of the pathological condition. In some embodiments, the HPK1 -dependent disorder is cancer.

[0164] The presently disclosed pharmaceutical compositions, formulations, or unit dosage forms comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof also find use in enhancing an immune response in a subject in need thereof. Such methods comprise administering an effective amount of a pharmaceutical composition, formulation, or unit dosage fonn comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the invention.

[0165] As used herein, "enhancing an immune response" refers to an improvement in any immunogenic response to an antigen. Non-limiting examples of improvements in an immunogenic response to an antigen include enhanced maturation or migration of dendritic cells, enhanced activation of T cells (e.g., CD4 T cells, CD8 T cells), enhanced T cell (e.g., CD4 T cell, CD8 T cell) proliferation, enhanced B cell proliferation, increased survival of T cells and / or B cells, improved antigen presentation by antigen presenting cells (e.g., dendritic cells), improved antigen clearance, increase in production of cytokines by T cells (e.g., interleukin-2), increased resistance to prostaglandin E2-induced immune suppression, and enhanced priming and / or cytolytic activity of CD8 T cells.

[0166] In some embodiments, the CD8 T cells in the subject have enhanced priming, activation, proliferation and / or cytolytic activity relative to prior to the administration of a pharmaceutical compositions, formulations, or unit dosage forms comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof. In some embodiments, the CD8 T cell priming is characterized by elevated CD44 expression and / or enhanced cytolytic activity in CD8 T cells. In some embodiments, the CD8 T cell activation is characterized by an elevated frequency of y-IFN CD8 T cells. In some embodiments, the CD8 T cell is an antigen-specific T-cell.

[0167] In some embodiments, the antigen presenting cells in the subject have enhanced maturation and activation relative to prior to the administration of pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the invention33355712 1 Page 33 of 113 398110-93HPWO (217136)or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. In some embodiments, the antigen presenting cells are dendritic cells. In some embodiments, the maturation of the antigen presenting cells is characterized by an increased frequency of CD83+dendritic cells. In some embodiments, the activation of the antigen presenting cells is characterized by elevated expression of CD80 and CD86 on dendritic cells.

[0168] In some embodiments, the serum levels of cytokine IL-10 and / or chemokine IL-8, a human homolog of murine KC, in the subject are reduced relative to prior to the administration of pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof.

[0169] Engagement of the TCR leads to HPK1 activation, which functions as a negative regulator of TCR- induced AP-1 response pathway. It is believed that HPK1 negatively regulates T cell activation by reducing the persistence of signaling microclusters by phosphorylating SLP76 at Ser376 (Di Bartolo et al. (2007) JEM 204:681-691) and Gads at Thr254, which leads to the recruitment of 14-3-3 proteins that bind to the phosphorylated SLP76 and Gads, releasing the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, which leads to T cell dysfunction, including anergy and exhaustion (Lasserre et al. (2011) J Cell Biol 195(5):839-853).

[0170] In some embodiments, administration of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof to a subject results in an enhancement of T cell function.

[0171] Accordingly, the presently disclosed pharmaceutical compositions, formulations, or unit dosage fomrs comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the invention are useful in treating T cell dysfunctional disorders. A "T cell dysfunctional disorder" is a disorder or condition of T cells characterized by decreased responsiveness to antigenic stimulation. In a particular embodiment, a T cell dysfunctional disorder is a disorder that is specifically associated with increased kinase activity of HPK1. In another embodiment, a T cell dysfunctional disorder is one in which T cells are anergic or have decreased ability to secrete cytokines, proliferate, or execute cytolytic activity. In a specific aspect, the decreased responsiveness results in ineffective control of a pathogen or tumor expressing an immunogen. Examples of T cell dysfunctional disorders characterized by T-cell dysfunction include unresolved acute infection, chronic infection and tumor immunity.

[0172] Thus, the presently disclosed pharmaceutical compositions, formulations, or unit dosage fonns comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof can be used in treating conditions where enhanced immunogenicity is desired, such as increasing tumor immunogenicity for the treatment of cancer.33355712 1 Page 34 of 113 398110-93HPWO (217136)

[0173] The term "dysfunction" in the context of immune dysfunction, refers to a state of reduced immune responsiveness to antigenic stimulation. The term includes the common elements of both exhaustion and / or anergy in which antigen recognition may occur, but the ensuing immune response is ineffective to control infection or tumor growth.

[0174] The term "dysfunctional", as used herein, also includes refractory or unresponsive to antigen recognition, specifically, impaired capacity to translate antigen recognition into downstream T-cell effector functions, such as proliferation, cytokine production (e.g., IL-2, y-IFN) and / or target cell killing.

[0175] Tire term "anergy" refers to the state of unresponsiveness to antigen stimulation resulting from incomplete or insufficient signals delivered through the T-cell receptor (e.g. increase in intracellular Ca+2in the absence of ras-activation). T cell anergy can also result upon stimulation with antigen in the absence of co-stimulation, resulting in the cell becoming refractory to subsequent activation by the antigen even in the context of costimulation. The unresponsive state can often be overridden by the presence of Interleukin - 2. Anergic T-cells do not undergo clonal expansion and / or acquire effector functions.

[0176] Tire term "exhaustion" refers to T cell exhaustion as a state of T cell dysfunction that arises from sustained TCR signaling that occurs during many chronic infections and cancer. It is distinguished from anergy in that it arises not through incomplete or deficient signaling, but from sustained signaling. It is defined by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. Exhaustion can result from both extrinsic negative regulatory' pathways (e.g., immunoregulatory cy okines) as well as cell intrinsic negative regulatory' (costimulatory) pathways (PD-1, B7-H3, B7-H4, etc.).

[0177] "Immunogenecity" refers to the ability of a particular substance to provoke an immune response. Tumors are immunogenic and enhancing tumor immunogenicity aids in the clearance of the tumor cells by the immune response.

[0178] “Enhancing T cell function" means to induce, cause or stimulate a T cell to have a sustained or amplified biological function, or renew or reactivate exhausted or inactive T cells. Examples of enhancing T cell function include: increased secretion of cytokines (e.g., y-interferon, IL-2, IL-12, and TNFoc), increased proliferation, increased antigen responsiveness (e.g.. viral, pathogen, or tumor clearance) relative to such levels before the intervention, and increased effector granule production by CD8 T cells, such as granzyme B. In one embodiment, the level of enhancement is as least 50%, alternatively 60%, 70%, 80%, 90%, 100%, 120%, 150%, 200%. Tire manner of measuring this enhancement is known to one of ordinary' skill in the art.

[0179] "Tumor immunity" refers to the process in which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is "treated" when such evasion is attenuated, and the tumors33355712 1 Page 35 of 113 398110-93HPWO (217136)are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage and tumor clearance.

[0180] Tire present disclosure provides methods of modulating (e.g., inhibiting) HPK1 activity, said method comprising administering to a patient a pharmacal composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the invention.

[0181] In some embodiments, a solid or salt form of this invention is for use in medicine.

[0182] In one aspect, provided herein is a method for treating of cancer in a subject in need thereof comprising administering to the subject an effective amount of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the invention.

[0183] In the methods described herein, pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the invention is administered to a subject that has cancer. In some embodiments, a patient has a relapsed and / or refractory cancer. In some embodiments, a patient has a relapsed and / or refractory tumor. In some embodiments, a patient has a relapsed and / or refractory' solid tumor. In some embodiments, a patient has a relapsed and / or refractory liquid tumor. In some embodiments, the patient has received at least one prior therapy. In some embodiments, the patient has received at least two prior therapies. In some embodiments, the patient has received at least three prior therapies. In some embodiments, the patient has received at least four prior therapies. In some embodiments, the patient has received at least five prior therapies. In some embodiments, the patient has received at least six prior therapies.

[0184] In certain embodiments, the subject matter disclosed herein is directed to a method for treating a HPK1 -dependent disorder, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the invention. In certain aspects of this embodiment, the HPK1 -dependent disorder is a cancer. In certain aspects of this embodiment, the cancer comprises at least one cancer selected from the group consisting of colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, a hematological malignancy, and a renal cell carcinoma. In certain aspects of this embodiment, tire cancer has elevated levels of T-cell infiltration. In certain aspects of this embodiment, the cancer cells in the subject selectively have elevated expression of MHC class I antigen expression relative to prior to the administration of the compound or composition.

[0185] In some embodiments, the subject matter disclosed herein is directed to a method for treatment of chronic viral infections. In some embodiments, the subject matter disclosed herein is directed to tire use of an HPK1 inhibitor as an adjuvant treatment for increasing the efficacy of vaccination.33355712 1 Page 36 of 113 398110-93HPWO (217136)

[0186] In certain aspects, the invention provides a method of treating cell proliferation disorders, including cancers, benign papillomatosis, gestational trophoblastic diseases, and benign neoplastic diseases, such as skin papilloma (warts) and genital papilloma.

[0187] In one aspect, the invention provides a method of treating a cell proliferation disorder in a subject, comprising administering a therapeutically effective amount of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmacally acceptable salt thereof of the invention, to the subject.

[0188] In certain embodiments, the cell proliferation disorder is cancer.

[0189] Examples of cancers that are treatable using the compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or urethra, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T -cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers.

[0190] In some embodiments, cancers that are treatable using the pharmacal compositions, formulations, or unit dosage forms comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer, etc.), liquid tumors such as hematological cancers (e.g.. lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma or multiple myeloma) and combinations of said cancers.33355712 1 Page 37 of 113 398110-93HPWO (217136)

[0191] In some embodiments, the present invention provides a method of treating a lymphoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof.

[0192] In some embodiments, the present invention provides a method of treating prostate cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0193] In some embodiments, the present invention provides a method of treating colon cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmacally acceptable salt thereof.

[0194] In some embodiments, the present invention provides a method of treating esophageal cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments, the present invention provides a method of treating endometrial cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, the present invention provides a method of treating cervical cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmacal composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmacally acceptable salt thereof.

[0197] In some embodiments, the present invention provides a method of treating ovarian cancer in a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments, the present invention provides a method of treating uterine cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmacal composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof.

[0199] In some embodiments, the present invention provides a method of treating urothelial cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmacally acceptable salt thereof.33355712 1 Page 38 of 113 398110-93HPWO (217136)

[0200] In some embodiments, the present invention provides a method of treating renal cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments, the present invention provides a method of treating kidney cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, the present invention provides a method of treating liver cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmacal composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, the present invention provides a method of treating pancreatic cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmacally acceptable salt thereof.

[0204] In some embodiments, the present invention provides a method of treating gastric cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, the present invention provides a method of treating breast cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmacal composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, the present invention provides a method of treating lung cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmacally acceptable salt thereof.

[0207] In some embodiments, the present invention provides a method of treating skin cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, the present invention provides a method of treating cancers of the head and neck in a patient in need thereof, comprising administering to the patient a therapeutically effective amount33355712 1 Page 39 of 113 398110-93HPWO (217136)of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments, the present invention provides a method of treating thyroid cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmacal composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, tire present invention provides a method of treating glioblastoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments, the present invention provides a method of treating sarcoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmacal composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, the present invention provides a method of treating bladder cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmacal composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof.

[0213] In certain embodiments, the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma. In another embodiment the cancer is selected from the group consisting of glioma, glioblastoma multifonne, paraganglioma, supratentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, melanoma, breast, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.

[0214] In certain embodiments, the cancer is selected from brain and spinal cancers, cancers of the head and neck, leukemia and cancers of the blood, skin cancers, cancers of the reproductive system, cancers of the gastrointestinal system, liver and bile duct cancers, kidney and bladder cancers, bone cancers, lung cancers, malignant mesothelioma, sarcomas, lymphomas, glandular cancers, thyroid cancers, heart tumors, germ cell tumors, malignant neuroendocrine (carcinoid) tumors, midline tract cancers, and cancers of unknown primary (cancers in which a metastasized cancer is found but the original cancer site is not known). In particular embodiments, tire cancer is present in an adult patient; in additional embodiments, the cancer is present in a pediatric patient. In particular embodiments, the cancer is AIDS-related.

[0215] In a further embodiment, the cancer is selected from brain and spinal cancers. In particular embodiments, the cancer is selected from the group consisting of anaplastic astrocytomas, glioblastomas,33355712 1 Page 40 of 113 398110-93HPWO (217136)astrocytomas, and estheosion euroblastomas (olfactory blastomas). In particular embodiments, the brain cancer is selected from the group consisting of astrocytic tumor (e.g., pilocytic astrocyto a, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma. anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma), oligodendroglial tumor (e.g., oligodendroglioma, and anaplastic oligodendroglioma), oligoastrocytic tumor (e.g., oligoastrocytoma, and anaplastic oligoastrocytoma), ependymoma (e.g., myxopapillary ependymoma, and anaplastic ependymoma): medulloblastoma, primitive neuroectodermal tumor, schwannoma, meningioma, atypical meningioma, anaplastic meningioma, pituitary' adenoma, brain stem glioma, cerebellar astrocytoma, cerebral astorcytoma / malignant glioma, visual pathway and hypothalamic glioma, and primary central nervous system lymphoma. In specific instances of these embodiments, the brain cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, and supratentorial primordial neuroectodermal tumors (sPNET).

[0216] In specific embodiments, the cancer is selected from cancers of the head and neck, including nasopharyngeal cancers, nasal cavity and paranasal sinus cancers, hypopharyngeal cancers, oral cavity cancers (e.g., squamous cell carcinomas, lymphomas, and sarcomas), lip cancers, oropharyngeal cancers, salivary gland tumors, cancers of the larynx (e.g., laryngeal squamous cell carcinomas, rhabdomyosarcomas), and cancers of the eye or ocular cancers. In particular embodiments, the ocular cancer is selected from the group consisting of intraocular melanoma and retinoblastoma.

[0217] In specific embodiments, the cancer is selected from leukemia and cancers of the blood. In particular embodiments, the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasm (MPN). post-MPN AML. post-MDS AML, del(5q)-associated high risk MDS or AML. blastphase chronic myelogenous leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerans cell histiocytosis, hairy cell leukemia, and plasma cell neoplasms including plasmacytomas and multiple myelomas. Leukemias referenced herein may be acute or chronic.

[0218] In specific embodiments, the cancer is selected from skin cancers. In particular embodiments, the skin cancer is selected from the group consisting of melanoma, squamous cell cancers, and basal cell cancers.

[0219] In specific embodiments, the cancer is selected from cancers of the reproductive system. In particular embodiments, the cancer is selected from the group consisting of breast cancers, cervical cancers, vaginal cancers, ovarian cancers, prostate cancers, penile cancers, and testicular cancers. In specific instances of these embodiments, the cancer is a breast cancer selected from the group consisting of ductal33355712 1 Page 41 of 113 398110-93HPWO (217136)carcinomas and phyllodes tumors. In specific instances of these embodiments, the breast cancer may be male breast cancer or female breast cancer. In specific instances of these embodiments, the cancer is a cervical cancer selected from the group consisting of squamous cell carcinomas and adenocarcinomas. In specific instances of these embodiments, the cancer is an ovarian cancer selected from the group consisting of epithelial cancers.

[0220] In specific embodiments, the cancer is selected from cancers of the gastrointestinal system. In particular embodiments, the cancer is selected from the group consisting of esophageal cancers, gastric cancers (also known as stomach cancers), gastrointestinal carcinoid tumors, pancreatic cancers, gallbladder cancers, colorectal cancers, and anal cancer. In instances of these embodiments, the cancer is selected from the group consisting of esophageal squamous cell carcinomas, esophageal adenocarcinomas, gastric adenocarcinomas, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gastric lymphomas, gastrointestinal lymphomas, solid pseudopapillary tumors of the pancreas, pancreatoblastoma, islet cell tumors, pancreatic carcinomas including acinar cell carcinomas and ductal adenocarcinomas, gallbladder adenocarcinomas, colorectal adenocarcinomas, and anal squamous cell carcinomas.

[0221] In specific embodiments, tire cancer is selected from liver and bile duct cancers. In particular embodiments, the cancer is liver cancer (hepatocellular carcinoma). In particular embodiments, the cancer is bile duct cancer (cholangiocarcinoma); in instances of these embodiments, the bile duct cancer is selected from tire group consisting of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.

[0222] In specific embodiments, the cancer is selected from kidney and bladder cancers. In particular embodiments, the cancer is a kidney cancer selected from the group consisting of renal cell cancer, Wilms tumors, and transitional cell cancers. In particular embodiments, the cancer is a bladder cancer selected from the group consisting of urethelial carcinoma (a transitional cell carcinoma), squamous cell carcinomas, and adenocarcinomas.

[0223] In specific embodiments, the cancer is selected from bone cancers. In particular embodiments, the bone cancer is selected from the group consisting of osteosarcoma, malignant fibrous histiocytoma of bone, Ewing sarcoma, and chordoma.

[0224] In specific embodiments, the cancer is selected from lung cancers. In particular embodiments, the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancers, bronchial tumors, and pleuropulmonary blastomas.

[0225] In specific embodiments, the cancer is selected from malignant mesothelioma. In particular embodiments, the cancer is selected from the group consisting of epithelial mesothelioma and sarcomatoids.33355712 1 Page 42 of 113 398110-93HPWO (217136)

[0226] In specific embodiments, the cancer is selected from sarcomas. In particular embodiments, the sarcoma is selected from the group consisting of central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, clear cell sarcoma of tendon sheaths, and Kaposi's sarcoma.

[0227] In specific embodiments, the cancer is selected from lymphomas. In particular embodiments, the cancer is selected from the group consisting of Hodgkin lymphoma (e g., Reed-Stemberg cells), nonHodgkin lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoides, Sezary syndrome, primary central nervous system lymphoma), cutaneous T-cell lymphomas, and primary central nervous system lymphomas.

[0228] In specific embodiments, the cancer is selected from glandular cancers. In particular embodiments, the cancer is selected from the group consisting of adrenocortical cancer, pheochromocytomas, paragangliomas, pituitary tumors, thymoma, and thymic carcinomas.

[0229] In specific embodiments, the cancer is selected from thyroid cancers. In particular embodiments, the thyroid cancer is selected from the group consisting of medullary thyroid carcinomas, papillary thyroid carcinomas, and follicular thyroid carcinomas.

[0230] In specific embodiments, the cancer is selected from germ cell tumors. In particular embodiments, the cancer is selected from the group consisting of malignant extracranial germ cell tumors and malignant extragonadal germ cell tumors. In specific instances of these embodiments, the malignant extragonadal germ cell tumors are selected from the group consisting of nonseminomas and seminomas.

[0231] In specific embodiments, the cancer is selected from heart tumors. In particular embodiments, the heart tumor is selected from the group consisting of malignant teratoma, lymphoma, rhabdomyosarcoma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.

[0232] In specific embodiments, the cell-proliferation disorder is selected from benign papillomatosis, benign neoplastic diseases and gestational trophoblastic diseases. In particular embodiments, the benign neoplastic disease is selected from skin papilloma (warts) and genital papilloma. In particular embodiments, the gestational trophoblastic disease is selected from the group consisting of hydatidiform moles, and gestational trophoblastic neoplasia (e.g., invasive moles, choriocarcinomas, placental-site trophoblastic tumors, and epithelioid trophoblastic tumors).

[0233] In some embodiments, the subject has melanoma. The melanoma may be at early stage or at late stage. In some embodiments, the subject has colorectal cancer. The colorectal cancer may be at early stage or at late stage. In some embodiments, the subject has non-small cell lung cancer. The non-small cell lung cancer may be at early stage or at late stage. In some embodiments, the subject has pancreatic cancer. The pancreatic cancer may be at early stage or late state . In some embodiments, the subj ect has a hematological malignancy. The hematological malignancy may be at early stage or late stage. In some embodiments, the subject has ovarian cancer. The ovarian cancer may be at early stage or at late stage. In some embodiments,33355712 1 Page 43 of 113 398110-93HPWO (217136)the subj ect has breast cancer. The breast cancer may be at early stage or at late stage . In some embodiments, the subject has renal cell carcinoma. The renal cell carcinoma may be at early stage or at late stage. In some embodiments, the cancer has elevated levels of T-cell infiltration.

[0234] In some embodiments, cancers treatable with compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma), renal cancer (e g. clear cell carcinoma), prostate cancer (e.g. hormone refractory prostate adenocarcinoma), breast cancer, triple-negative breast cancer, colon cancer and lung cancer (e.g. non-small cell lung cancer and small cell lung cancer). Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure.

[0235] In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0236] Exemplary hematological cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL). mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular). Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglubulinemia, hairy cell ly mphoma, chronic myelogenic lymphoma and Burkitt's lymphoma.

[0237] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, and teratoma.

[0238] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.

[0239] Exemplary gastrointestinal cancers include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.33355712 1 Page 44 of 113 398110-93HPWO (217136)

[0240] Exemplary genitourinary tract cancers include cancers of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).

[0241] Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0242] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma ( osteocartilaginous exostoses ), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors

[0243] Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, meduoblastoma, glioma, ependymoma, genninoma (pinealoma), glioblastoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

[0244] Exemplary gynecological cancers include cancers of the uterus (endometrial carcinoma), cervix (cervical carcinoma, pre -tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).

[0245] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple-negative breast cancer (TNBC), myelodysplastic syndromes, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma.

[0246] Exemplary head and neck cancers include glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas, adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer, nasal and paranasal cancers, thyroid and parathyroid cancers.33355712 1 Page 45 of 113 398110-93HPWO (217136)

[0247] In some embodiments, HPK1 inhibitors may be used to treat tumors producing PGE2 (e.g. Cox-2 overexpressing tumors) and / or adenosine (CD73 and CD39 over-expressing tumors). Overexpression ofCox-2 has been detected in a number of tumors, such as colorectal, breast, pancreatic and lung cancers, where it correlates with a poor prognosis. Overexpression of COX-2 has been reported in hematological cancer models such as RAJI (Burkitt's lymphoma) and U937 (acute promonocytic leukemia) as well as in patient's blast cells. CD73 is up-regulated in various human carcinomas including those of colon, lung, pancreas and ovary. Importantly, higher expression levels of CD73 are associated with tumor neovascularization, invasiveness, and metastasis and with shorter patient survival time in breast cancer.

[0248] In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.

[0249] The presently disclosed compounds may be administered in any suitable manner known in the art. In some embodiments, the compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdennally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, intratumorally, or intranasally.

[0250] In some embodiments, the HPK1 antagonist is administered continuously. In other embodiments, the HPK1 antagonist is administered intermittently. Moreover, treatment of a subject with an effective amount of a HPK1 antagonist can include a single treatment or can include a series of treatments.

[0251] It is understood that appropriate doses of the active compound depends upon a number of factors within the knowledge of the ordinarily skilled physician or veterinarian. The dose(s) of the active compound will vary, for example, depending upon the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, and any drug combination.

[0252] It will also be appreciated that the effective dosage of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the invention used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent from the results of diagnostic assays.

[0253] In some embodiments, the HPK1 antagonist is administered to the subject at a dose of between about 0.001 pg / kg and about 1000 mg / kg, including but not limited to about 0.001 pg / kg, 0.01 pg / kg, 0.05 pg / kg, 0.1 pg / kg, 0.5 pg / kg, 1 pg / kg, 10 pg / kg, 25 pg / kg, 50 pg / kg, 100 pg / kg, 250 pg / kg, 500 pg / kg, 1 mg / kg, 5 mg / kg. 10 mg / kg, 25 mg / kg, 50 mg / kg, 100 mg / kg, and 200 mg / kg.33355712 1 Page 46 of 113 398110-93HPWO (217136)

[0254] In the methods described herein, the method can further comprise administering a chemotherapeutic agent to the subject. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject simultaneously with the compound or the composition. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject prior to administration of the compound or the composition. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject after administration of the compound or the composition.

[0255] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g.. in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0256] The term "administration" or "administering" includes routes of introducing the compound(s) to a subject to perform their intended function. Examples of routes of administration which can be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), topical, oral, inhalation, rectal and transdennal.

[0257] The term "effective amount" includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result. An effective amount of compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.

[0258] The phrases "systemic administration," "administered systemically", "peripheral administration" and "administered peripherally" as used herein mean the administration of a compound(s), drug or other material, such that it enters the patient's system and, thus, is subject to metabolism and other like processes.

[0259] The phrase "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and / or relieve to some extent one or more of the symptoms associated with the cancer. To the extent the drug may prevent growth and / or kill existing cancer cells, it may be cytostatic33355712 1 Page 47 of 113 398110-93HPWO (217136)and / or cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0260] Tire term "subject" refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human.Combination Therapies

[0261] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.”

[0262] In certain embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent.

[0263] Examples of agents the combinations of this invention may also be combined with include, without limitation: treatments for Alzheimer’s Disease such as Aricept® and Excelon®; treatments for HIV such as ritonavir; treatments for Parkinson’s Disease such as L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide. trihexephendyl, and amantadine: agents for treating Multiple Sclerosis (MS) such as beta interferon (e g., Avonex® and Rebif®), Copaxone®, and mitoxantrone: treatments for asthma such as albuterol and Singulair®; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide. azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and antiParkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors: agents that prolong or improve pharmacokinetics such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e g., ketokenozole and ritonavir), and agents for treating immunodeficiency disorders such as gamma globulin.33355712 1 Page 48 of 113 398110-93HPWO (217136)

[0264] In certain embodiments, combination therapies of the present invention, or a pharmaceutically acceptable composition thereof, are administered in combination with a monoclonal antibody or an siRNA therapeutic.

[0265] Those additional agents may be administered separately from a provided combination therapy, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage fomr, mixed together with a pharmacal composition, fonnulation, or unit dosage fonn comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the invention. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

[0266] As used herein, tire temr “combination," “combined,” and related tenns refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the current invention, an additional therapeutic agent, and a pharmacally acceptable carrier, adjuvant, or vehicle.

[0267] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0268] In one embodiment, the present invention provides a composition comprising a solid or salt fonn described herein and one or more additional therapeutic agents. The therapeutic agent and solid or salt form may be administered together, or may be administered prior to or following administration of a solid or salt form. Suitable therapeutic agents are described in further detail below. In certain embodiments, a solid or salt form described herein may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, a solid or salt form described herein may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes. 1 hour. 2 hours, 3 hours. 4 hours, 5, hours. 6 hours, 7 hours. 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.

[0269] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder or condition by administering to a patient in need thereof a solid or salt fonn described33355712 1 Page 49 of 113 398110-93HPWO (217136)herein and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biologic agents and include, for example, acetaminophen, non-steroidal antiinflammatory drugs (N SAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®). methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofm (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and "anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti -IL- 1” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Haris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), “anti -T-cell” agents such as abatacept (Orencia®), “anti-IL-6” agents such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®). laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HF A), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and fonnoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®). triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®). abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®). lamivudine / zidovudine (Combivir®). stavudine (Zerit®). and zalcitabine (Hivid®), nonnucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tcnofovir (Viread®), protease inhibitors such as amprenavir (Agcncrasc®), atazanavir (Rcyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®),33355712 1 Page 50 of 113 398110-93HPWO (217136)nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®). and dexamethasone (Decadron ®) in combination with lenalidomide (Revlimid ®), or any combination(s) thereof.

[0270] In another embodiment, the present invention provides a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofm (Ridaura®), D- penicillamine (Depen®1or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such as abatacept (Orencia®) and “anti -IL-6” agents such as tocilizumab (Actemra®).

[0271] In some embodiments, the present invention provides a method of treating osteoarthritis comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drags (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonal antibodies such as tanezumab.

[0272] In some embodiments, the present invention provides a method of treating cutaneous lupus erythematosus or systemic lupus erythematosus comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drags (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[0273] In some embodiments, the present invention provides a method of treating Crohn’s disesase, ulcerative colitis, or inflammatory’ bowel disease comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from mesalamine33355712 1 Page 51 of 113 398110-93HPWO (217136)(Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics or antispasmodics such as dicyclomine (Bentyl®). anti-TNF therapies, steroids, and antibiotics such as Flagyl or ciprofloxacin.

[0274] In some embodiments, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such as omalizumab (Xolair®).

[0275] In some embodiments, the present invention provides a method of treating COPD comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®)), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo- Dur®. Theolair®. Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®1, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort ®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®,

[0276] In another embodiment, the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®). vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0277] In another embodiment, the present invention provides a method of treating a solid tumor comprising administering to a patient in need thereof a solid or salt form described herein and one or more33355712 1 Page 52 of 113 398110-93HPWO (217136)additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0278] In another embodiment, the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a solid or salt form described herein and a Hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al ‘'Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma” Leuk. Res. (2012), published online July 17).

[0279] In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL) comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[0280] In another embodiment, the present invention provides a method of treating multiple myeloma comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).

[0281] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a solid or salt form described herein and a BTK inhibitor, wherein the disease is selected from inflammatory bowel disease, arthritis, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP). rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still’s disease, juvenile arthritis, diabetes, myasthenia gravis. Hashimoto’s thyroiditis, Ord’s thyroiditis. Graves’ disease, autoimmune thyroiditis, Sjogren’s syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison’s disease, opsoclonusmyoclonus syndrome, ankylosing spondylosis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary- cirrhosis, Reiter’s syndrome. Takayasu’s arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener’s granulomatosis, psoriasis, alopecia universalis, Behcet’s disease, chronic fatigue, dysautonomia, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, ncuromyotonia, sclcrodcnna, vulvodynia, a hypcrprolifcrativc disease, rejection of transplanted organs or tissues, Acquired Immunodeficiency Syndrome (AIDS, also known as HIV), type 133355712 1 Page 53 of 113 398110-93HPWO (217136)diabetes, graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis. Crohn’s disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorder, e.g., diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin’s lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer, or cancer of the mast cells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, diseases of the bone and joints including, without limitation, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter’s disease), Behcet’s disease, Sjogren’s syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastasis, a thromboembolic disorder, (e.g., myocardial infarct, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, deep venous thrombosis), inflammatory' pelvic disease, urethritis, skin sunbum, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy, Crohn’s disease, irritable bowel syndrome, ulcerative colitis, Sjogren’s disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic33355712 1 Page 54 of 113 398110-93HPWO (217136)states. Goodpasture’s syndrome, atherosclerosis, Addison’s disease, Parkinson’s disease, Alzheimer’s disease, diabetes, septic shock, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto’s thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome. Behcet’s disease, sclerodenna, mycosis fungoides, acute inflammatory responses (such as acute respiratory' distress syndrome and ischemia / reperfusion injury), and Graves’ disease.

[0282] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a solid or salt form described herein and a PI3K inhibitor, wherein the disease is selected from a cancer, a neurodegenerative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin- induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, and a CNS disorder.

[0283] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a solid or salt form described herein and a PI3K inhibitor, wherein the disease is selected from benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or a tumor of the neck and head, an epidennal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas, (including, for example, nonHodgkin’s Lymphoma (NHL) and Hodgkin's ly mphoma (also termed Hodgkin’s or Hodgkin’s disease)), a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or a leukemia, diseases include Cowden syndrome. Lhennitte-Dudos disease and Bannayan- Zonana syndrome, or diseases in which the PI3K / PKB pathway is aberrantly activated, asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection, acute lung injury (ALI), adult / acutc respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD),33355712 1 Page 55 of 113 398110-93HPWO (217136)including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy, bronchitis of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis, pneumoconiosis (an inflammatory , commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis. anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis, Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multifonna, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, sclerodenna, Wegener granulomatosis, dennatomyositis. chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy, restenosis, cardiomegaly. atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative disease caused by traumatic injury , glutamate neurotoxicity and hypoxia.

[0284] In some embodiments the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a solid or salt fomr described herein and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. In some embodiments, the disorder is a proliferative disorder, lupus, or lupus nephritis. In some embodiments, the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-ccll lymphoma, Hodgkin’s33355712 1 Page 56 of 113 398110-93HPWO (217136)disease, small-cell lung cancer, non-small-cell lung cancer, myelodysplastic syndrome, lymphoma, a hematological neoplasm, or solid tumor.

[0285] In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. In some embodiments the JH2 binding compound is a solid or salt fonn described herein . Other suitable JH2 domain binding compounds include those described in W02014074660A1, WO201407466IAI, WO2015089143A1. Suitable JH1 domain binding compounds include those described in WO2015131080A1.

[0286] A compound of the current invention may also be used to advantage in combination with other therapeutic compounds. In some embodiments, tire other therapeutic compounds are antiproliferative compounds. Such antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors: compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting / decreasing a protein or lipid kinase activity and further anti- angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors: matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms: telomerase inhibitors; proteasome inhibitors: compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17- DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin. NSC707545), IPI-504, CNF1010, CNF2024. CNF1010 from Conforma Therapeutics; temozolomide (Temodal®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY 142886 from Array BioPharma, AZD6244 from AstraZeneca, PD 181461 from Pfizer and leucovorin. The term "aromatase inhibitor" as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. Hie term includes, but is not limited to steroids, especially atamestane. exemestane and formestane and. in particular, non-steroids, especially aminoglutethimide, roglethimide. pyridoglutethimide, trilostane, testolactone, ketokonazole. vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Fadrozole is marketed under the trade name Afcma™. Anastrozole is marketed under the trade name Arimidcx™. Letrozole is marketed under the trade names Femara™ or Femar™. Aminoglutethimide is marketed under the trade name Orimeten™. A33355712 1 Page 57 of 113 398110-93HPWO (217136)combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.

[0287] Tire term "antiestrogen" as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level. Tire term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. A combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.

[0288] Tire term "anti -androgen" as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic honnones and includes, but is not limited to, bicalutamide (Casodex™). The temr "gonadorelin agonist" as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.

[0289] The term "topoisomerase I inhibitor" as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, e.g. in tire fonn as it is marketed, e.g. under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

[0290] The tenn "topoisomerase II inhibitor" as used herein includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as Caelyx™), daunorubicin, epimbicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide is marketed under the trade name Etopophos™. Teniposide is marketed under the trade name VM 26-Bristol Doxorubicin is marketed under the trade name Acriblastin ™ or Adriamycin™. Epimbicin is marketed under the trade name Fannorubicin™. Idarubicin is marketed, under the trade name Zavedos™. Mitoxantrone is marketed under the trade name Novantron.

[0291] The term "microtubule active agent" relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodemiolides; cochicine and epothilones and derivatives thereof. Paclitaxel is marketed under the trade name Taxol™. Docetaxel is marketed under the trade name Taxotere™. Vinblastine sulfate is marketed under the trade name Vinblastin R.P™. Vincristine sulfate is marketed under the trade name Farmistin™.

[0292] The tenn "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamidc, mclphalan or nitrosourea (BCNU or Gliadcl). Cyclophosphamide is marketed under the trade name Cyclostin™. Ifosfamide is marketed under the trade name Holoxan™.33355712 1 Page 58 of 113 398110-93HPWO (217136)

[0293] The term "histone deacetylase inhibitors" or "HD AC inhibitors" relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[0294] Tire term "antineoplastic antimetabolite" includes, but is not limited to, 5 -fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5 -azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name Xeloda™. Gemcitabine is marketed under the trade name Gemzar™.

[0295] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e g. under the trademark Eloxatin™.

[0296] The term "compounds targeting / decreasing a protein or lipid kinase activity: or a protein or lipid phosphatase activity: or further anti -angiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB-111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as compounds which target, decrease or inhibit the activity of IGF-IR, especially compounds which inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors; d) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors: e) compounds targeting, decreasing or inhibiting the activity of the Axl receptor tyrosine kinase family: f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting tire activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, such as imatinib; i) compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase) and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N- phcnyl-2-pyrimidinc-aminc derivative, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or33355712 1 Page 59 of 113 398110-93HPWO (217136)inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine / threonine kinases, members of the MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, BTK and TEC family, and / or members of the cyclin-dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; examples of further compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1. Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; isochinoline compounds: FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (Gleevec™) or tyrphostin such as Tyrphostin A23 / RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5- dihydroxyphenyl)methyl] amino (-benzoic acid adamantyl ester: NSC 680410, adaphostin): 1) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFRi ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, CP 358774. ZD 1839, ZM 105180: trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033. EKB- 569, GW-2016, El l, E2.4, E2.5, E6.2, E6.4, E2. l l, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit tire activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF, n) compounds targeting, decreasing or inhibiting the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds targeting, decreasing or inhibiting the kinase activity of PI3 kinase (PI3K) including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF- 4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and: and q) compounds targeting, decreasing or inhibiting the signaling effects of hedgehog protein (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib. itraconazole, erismodegib. and IPI-926 (saridegib).

[0297] The term “PI3K inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3 -kinase family, including, but not limited to PI3Ka, PI3Ky, PI3K5, PI3K0, PI3K-C2a, PI3K-C20, PI3K-C2y, Vps34, pl lO-a, pl 10-p,33355712 1 Page 60 of 113 398110-93HPWO (217136)pl lO-y, pl 10-5, p85-a, p85-|3, p55-y, pl50, plOl, and p87. Examples of PI3K inhibitors useful in this invention include but are not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK- 474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0298] Tire tenn “BTK inhibitor” as used herein includes, but is not limited to, compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.

[0299] The term “SYK inhibitor” as used herein includes, but is not limited to, compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0300] Tire tenn “Bcl-2 inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT- 199. ABT- 731. ABT-737, apogossypol, Ascenta’s pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl- 2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA 14-1 (and analogs thereof; see W02008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see W02004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ, of Michigan), and venetoclax. In some embodiments the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments the Bcl-2 inhibitor is a peptidomimetic.

[0301] Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in W02008039218 and WO2011090760.

[0302] Further examples of SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in W02003063794, W02005007623, and W02006078846.

[0303] Further examples of PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in W02004019973, W02004089925, W02007016176, US8138347, W02002088112, W02007084786, W02007I29I61, W02006122806, W02005113554, and W02007044729.

[0304] Further examples of JAK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in W02009114512. W02008109943, W02007053452, W02000142246, and W02007070514.

[0305] Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (Thalomid™) and TNP-470.33355712 1 Page 61 of 113 398110-93HPWO (217136)

[0306] Examples of proteasome inhibitors useful for use in combination with compounds of the invention include, but are not limited to bortezomib, disulfiram, epigallocatechin-3 -gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP- 18770, and MLN9708.

[0307] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25. such as okadaic acid or a derivative thereof.

[0308] Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, a- y- or 8- tocopherol or a- y- or 8-tocotrienol.

[0309] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5 -methyl - 2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.

[0310] The term "bisphosphonates" as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. Etridonic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the trade name Bonefos™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name Aredia™. Alendronic acid is marketed under the trade name Fosamax™. Ibandronic acid is marketed under the trade name Bondranat™. Risedronic acid is marketed under the trade name Actonel™. Zoledronic acid is marketed under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0311] Tire term "heparanase inhibitor" as used herein refers to compounds which target, decrease or inhibit heparin sulfate degradation. Tire term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to a lymphokine or interferons.

[0312] The temr "inhibitor of Ras oncogenic isoforms", such as H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a "famesyl transferase inhibitor" such as L-744832, DK8G557 or R115777 (Zamestra™). The term "telomerase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telome statin.

[0313] The term "methionine aminopeptidase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase. Compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.33355712 1 Page 62 of 113 398110-93HPWO (217136)

[0314] The term "proteasome inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of the proteasome. Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (Velcade™) and MLN 341.

[0315] Tire term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB- 2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

[0316] Tire term "compounds used in the treatment of hematologic malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-p-D- arabinofuransylcytosine (ara-c) and bisulfan; ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase, and Bcl-2 inhibitors.

[0317] Compounds which target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative. SU11248 and MLN518.

[0318] The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity ofHSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.

[0319] The term "antiproliferative antibodies" as used herein includes, but is not limited to. trastuzumab (Herceptin™), Trastuzumab-DMl, erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and 2C4 Antibody. By antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies fonned from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.

[0320] For the treatment of acute myeloid leukemia (AML), compounds of the current invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, compounds of the current invention can be administered in combination with, for example, famesyl transferase inhibitors and / or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Tcniposidc, Mitoxantronc, Idarubicin, Carboplatinum and PKC412. In some embodiments, the present invention provides a method of treating33355712 1 Page 63 of 113 398110-93HPWO (217136)AML associated with an ITD and / or D835Y mutation, comprising administering a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the present invention together with a one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitors are selected from quizartinib (AC220), a staurosporine derivative (e g. midostaurin or lestaurtinib), sorafenib, tandutinib, LY -2401401. LS-104, EB-10, famitinib, NOV-110302, NMS-P948, AST-487. G-749. SB-1317. S-209, SC- 110219, AKN-028, fedratimb. tozasertib, and sumtmib. In some embodiments, the FLT3 inhibitors are selected from quizartinib, midostaurin, lestaurtinib, sorafenib, and sunitinib.

[0321] Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2 - alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds which target, decrease or inhibit activity of histone deacetylase (HDAC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3-yl)- ethyl]- amino]methyl]phenyl]-2E-2-propenamide. or a pharmaceutically acceptable salt thereof and N- hydroxy-3-[4-[(2-hydroxyethyl){2-(lH-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt. Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230. Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4thEdition, Vol. 1, pp. 248-275 (1993).

[0322] Also included are EDG binders and ribonucleotide reductase inhibitors. The term “EDG binders” as used herein refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720. The temi ‘‘ribonucleotide reductase inhibitors” refers to pyrimidine or purine nucleoside analogs including, but not limited to. fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5 -fluorouracil, cladribine. 6-mercaptopurine (especially in combination with ara-C against ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are especially? hydroxyurea or 2-hydroxy-lH-isoindole-l ,3-dione derivatives.

[0323] Also included arc in particular those compounds, proteins or monoclonal antibodies of VEGF such as l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmacally acceptable salt thereof, l-(4-33355712 1 Page 64 of 113 398110-93HPWO (217136)chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate: Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

[0324] Photodynamic therapy as used herein refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as Visudyne™ and porfimer sodium.

[0325] Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11 -a-epihydrocotisol, cortexolone, 17a- hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.

[0326] Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.

[0327] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.

[0328] The compounds of the invention are also useful as co-therapeutic compounds for use in combination with other drug substances such as anti-inflammatory, bronchodilatory or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such dmgs or as a means of reducing required dosaging or potential side effects of such drugs. A compound of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance. Accordingly, the invention includes a combination of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the invention as hereinbefore described with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drag substance, said compound of the invention and said drag substance being in the same or different pharmaceutical composition.

[0329] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide ormometasone furoate; nonsteroidal glucocorticoid receptor agonists; LTB4 antagonists such LY293111. CGS025019C. CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-l 1294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering- Plough), Arofyllinc (Almirall Prodcsfarma), PD 189659 / PD168787 (Parke-Davis), AWD-12- 281 (Asta Medica), CDC-801 (Celgene), SelCID(TM) CC-1000433355712 1 Page 65 of 113 398110-93HPWO (217136)(Celgene), VM554 / UM565 (Vemalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and beta-2 adrenoceptor agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol fenoterol, procaterol, and especially, formoterol and pharmaceutically acceptable salts thereof. Suitable bronchodilatory drugs include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.

[0330] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.

[0331] Other useful combinations of compounds of the invention with anti-inflammatory drugs are those with antagonists of chemokine receptors, e g. CCR-1, CCR-2, CCR-3. CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10. CXCR1, CXCR2, CXCR3. CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH- 55700 and SCH-D, and Takeda antagonists such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]- methyl]tetrahydro-N,N-dimethyl-2H-pyran-4- aminium chloride (TAK-770).

[0332] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "Hie Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications).

[0333] Exemplary Immuno-Oncology agents

[0334] In some embodiments, one or more other therapeutic agent is an immuno-oncology agent. As used herein, the term “an immuno-oncology agent” refers to an agent which is effective to enhance, stimulate, and / or up-regulate immune responses in a subject. In some embodiments, the administration of an immuno- oncology agent with a pharmaceutical composition, formulation, or unit dosage fonn comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the invention has a synergic effect in treating a cancer.

[0335] An immuno-oncology agent can be, for example, a small molecule drug, an antibody, or a biologic or small molecule. Examples of biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, an antibody is a monoclonal antibody. In some embodiments, a monoclonal antibody is humanized or human.

[0336] In some embodiments, an immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co-inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses.

[0337] Certain of the stimulatory and inhibitory molecules arc members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-33355712 1 Page 66 of 113 398110-93HPWO (217136)inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fnl4, TWEAK, BAFFR, ED AR, XEDAR, TACI. APRIL, BCMA, LTpR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDAI, XEDAR, EDA2, TNFR1, Lymphotoxin a / TNFp, TNFR2, TNFa, LT0R, Lymphotoxin al|32, FAS, FASL, RELT, DR6, TROY, NGFR.

[0338] In some embodiments, an immuno-oncology agent is a cytokine that inhibits T cell activation (e.g. , IL-6, IL- 10, TGF-J3. VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation, for stimulating an immune response.

[0339] In some embodiments, a combination of a pharmaceutical composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the invention and an immuno-oncology agent can stimulate T cell responses. In some embodiments, an immuno- oncology agent is: (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-L PD-LL PD-L2, LAG-3, TIM-3. Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA. 2B4, CD48, GARP, PD1H. LAIR1. TIM-1, and TIMA; or (11) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4- 1BBL, ICOS, ICOS-L, 0X40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.

[0340] In some embodiments, an immuno-oncology agent is an antagonist of inhibitory' receptors on NK cells or an agonists of activating receptors on NK cells. In some embodiments, an immuno-oncology agent is an antagonist of KIR, such as lirilumab.

[0341] In some embodiments, an immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0342] In some embodiments, an immuno-oncology agent is selected from agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g. , PD-L 1 / PD- 1 interactions), deplete or inhibit Tregs (e.g. , using an anti- CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic33355712 1 Page 67 of 113 398110-93HPWO (217136)enzymes such as IDO, or reverse / prevent T cell energy or exhaustion) and agents that trigger innate immune activation and / or inflammation at tumor sites.

[0343] In some embodiments, an immuno-oncology agent is a CTLA-4 antagonist. In some embodiments, a CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some embodiments, an antagonistic CTLA- 4 antibody is YERVOY (ipilimumab) or tremelimumab.

[0344] In some embodiments, an immuno-oncology agent is a PD-1 antagonist. In some embodiments, a PD-1 antagonist is administered by infusion. In some embodiments, an immuno-oncology agent is an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death- 1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, a PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), LIBTAYO (cemiplimab), TYVYT (sintilimab), TEVIMBRA (tislelizumab), or MEDI- 0680 (AMP-514: WO2012 / 145493). In some embodiments, an immuno-oncology agent may be pidilizumab (CT-011). In some embodiments, an immuno-oncology agent is a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl, called AMP-224.

[0345] In some embodiments, an immuno-oncology agent is a PD-L1 antagonist. In some embodiments, a PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, a PD-L1 antibody is MPDL3280A (RG7446: W02010 / 077634). durvalumab (MEDI4736), BMS-936559 (W02007 / 00 874), and MSB0010718C (WO2013 / 79174).

[0346] In some embodiments, an immuno-oncology agent is a LAG-3 antagonist. In some embodiments, a LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, a LAG3 antibody is BMS- 986016 (W010 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (W008 / 132601, WO009 / 44273).

[0347] In some embodiments, an immuno-oncology agent is a CD 137 (4- IBB) agonist. In some embodiments, a CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, a CD137 antibody is urelumab or PF-05082566 (WO 12 / 32433).

[0348] In some embodiments, an immuno-oncology agent is a GITR agonist. In some embodiments, a GITR agonist is an agonistic GITR antibody. In some embodiments, a GITR antibody is BMS-986153, BMS-986156, TRX-518 (W0006 / 105021, W0009 / 009116), or MK-4166 (WO 11 / 028683).

[0349] In some embodiments, an immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, an IDO antagonist is selected from epacadostat (INCB024360. Incyte); indoximod (NLG-8189. NewLink Genetics Corporation): capmanitib (INC280, Novartis): GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Ph toccutica): an enzyme that breaks down kynurenine (Kynase, Ikena Oncology, formerly known as Kyn Therapeutics); and NLG-919 (W009 / 73620, WO009 / 1156652, WO11 / 56652, WO12 / 142237).33355712 1 Page 68 of 113 398110-93HPWO (217136)

[0350] In some embodiments, an immuno-oncology agent is an 0X40 agonist. In some embodiments, an 0X40 agonist is an agonistic 0X40 antibody. In some embodiments, an 0X40 antibody is MEDI-6383 or MEDI-6469.

[0351] In some embodiments, an immuno-oncology agent is an OX40L antagonist. In some embodiments, an OX40L antagonist is an antagonistic 0X40 antibody. In some embodiments, an OX40L antagonist is RG-7888 (WO06 / 029879).

[0352] In some embodiments, an immuno-oncology agent is a CD40 agonist. In some embodiments, a CD40 agonist is an agonistic CD40 antibody. In some embodiments, an immuno-oncology agent is a CD40 antagonist. In some embodiments, a CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, a CD40 antibody is lucatumumab or dacetuzumab.

[0353] In some embodiments, an immuno-oncology agent is a CD27 agonist. In some embodiments, a CD27 agonist is an agonistic CD27 antibody. In some embodiments, a CD27 antibody is varlilumab.

[0354] In some embodiments, an immuno-oncology agent is MGA271 (to B7H3) (WO11 / 109400).

[0355] In some embodiments, an immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab. durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED 14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab. olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

[0356] In some embodiments, an immuno-oncology agent is an immunostimulatory agent. For example, antibodies blocking the PD-1 and PD-L1 inhibitory axis can unleash activated tumor-reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in increasing numbers of tumor histologies, including some tumor types that conventionally have not been considered immunotherapy sensitive. See, e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14. 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (OPDIVO®, Bristol -Myners Squibb, also known as ONO-4538, MDX1106 and BMS-936558), has shown potential to improve the overall survival in patients with RCC who had experienced disease progression during or after prior anti-angiogenic therapy .

[0357] In some embodiments, the immunomodulatory therapeutic specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutics which may be used in the present invention include pomalidomide (POMALYST®, Celgene); lenalidomide (REVLIMID®. Celgene); ingenol mebutate (PICATO®, LEO Pharma)

[0358] In some embodiments, an immuno-oncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipulcuccl-T (PROVENGE®, Dcndrcon / Valcant Pharmaceuticals), which has been approved for treatment of asymptomatic, or minimally symptomatic metastatic castrate-resistant33355712 1 Page 69 of 113 398110-93HPWO (217136)(hormone-refractory) prostate cancer; and talimogene laherparepvec (IMLYGIC®, BioVex / Amgen, previously known as T-VEC), a genetically modified oncolytic viral therapy approved for treatment of unresectable cutaneous, subcutaneous and nodal lesions in melanoma. In some embodiments, an immunooncology agent is selected from an oncolytic viral therapy such as pexastimogene devacirepvec (PexaVec / JX-594. SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (REOLYSIN®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) which does not replicate in cells that are not RAS -activated, in numerous cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly known as ColoAdl), an adenovirus engineered to express a full length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors such as in colorectal cancer, bladder cancer, head and neck squamous cell carcinoma and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax / fonnerly Oncos), an adenovirus engineered to express GM-CSF, in melanoma (NCT03003676); and peritoneal disease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1 (GLV-lh68 / GLV-lhl53, Genelux GmbH), vaccinia viruses engineered to express betagalactosidase (beta-gal) / beta-glucoronidase or beta-gal / human sodium iodide symporter (hNIS), respectively, were studied in peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF, in bladder cancer (NCT02365818).

[0359] In some embodiments, an immuno-oncology agent is selected from JX-929 (SillaJen / formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which is able to convert the prodrug 5-fluorocytosine to the cytotoxic drug 5- fluorouracil; TG01 and TG02 (Targovax / fonnerly Oncos), peptide-based immunotherapy agents targeted for difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated: Ad5 / 3-E2F-delta24-hTNFa-IRES-hIL20; and VSV-GP (ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of ly mphocy tic choriomeningitis virus (LCMV), which can be further engineered to express antigens designed to raise an antigen-specific CD8 T cell response.

[0360] In some embodiments, an immuno-oncology agent is a T-cell engineered to express a chimeric antigen receptor, or CAR. The T-cells engineered to express such chimeric antigen receptor are referred to as a CAR-T cells.33355712 1 Page 70 of 113 398110-93HPWO (217136)

[0361] CARs have been constructed that consist of binding domains, which may be derived from natural ligands, single chain variable fragments (scFv) derived from monoclonal antibodies specific for cell-surface antigens, fused to endodomains that are the functional end of the T-cell receptor (TCR), such as the CD3- zeta signaling domain from TCRs, which is capable of generating an activation signal in T lymphocytes. Upon antigen binding, such CARs link to endogenous signaling pathways in the effector cell and generate activating signals similar to those initiated by the TCR complex.

[0362] For example, in some embodiments the CAR-T cell is one of those described in U.S. Patent 8,906,682 (June etal.), which discloses CAR-T cells engineered to comprise an extracellular domain having an antigen binding domain (such as a domain that binds to CD 19), fused to an intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3 zeta). When expressed in the T cell, the CAR is able to redirect antigen recognition based on the antigen binding specificity. In the case of CD 19, the antigen is expressed on malignant B cells. Over 200 clinical trials are currently in progress employing CAR-T in a wide range of indications.[https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=l].

[0363] In some embodiments, an immunostimulatory agent is an activator of retinoic acid receptor-related orphan receptor y (RORyt). RORyt is a transcription factor with key roles in the differentiation and maintenance of Type 17 effector subsets of CD4+ (Thl7) and CD8+ (Tcl7) T cells, as well as the differentiation of IL-17 expressing innate immune cell subpopulations such as NK cells. In some embodiments, an activator of RORyt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[0364] In some embodiments, an immunostimulatory agent is an agonist or activator of a toll-like receptor (TLR). Suitable activators of TLRs include an agonist or activator of TLR9 such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG which is being studied for B-cell, follicular and other lymphomas (NCT02254772). Agonists or activators of TLR8 which may be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamous cell cancer of the head and neck (NCT02124850) and ovarian cancer (NCT02431559).

[0365] Other immuno-oncology agents that can be used in the present invention include urelumab (BMS- 663513. Bristol-Myers Squibb), an anti-CD137 monoclonal antibody: varlilumab (CDX-1127. Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti- KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.33355712 1 Page 71 of 113 398110-93HPWO (217136)

[0366] In some embodiments, an immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of RORyt.

[0367] In some embodiments, an immunostimulatory therapeutic is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemias (NCT02689453). In some embodiments, an immunostimulatory agent is recombinant human interleukin 12 (rhIL-12). In some embodiments, an IL- 15 based immunotherapeutic is heterodimeric IL-15 (hetIL-15, Novartis / Admune), a fusion complex composed of a synthetic form of endogenous IL- 15 complexed to the soluble IL- 15 binding protein IL- 15 receptor alpha chain (IL15:sIL-15RA), which has been tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, a recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

[0368] In some embodiments, an immuno-oncology agent is selected from those descripted in Jerry L. Adams et al., “Big opportunities for small molecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages 603-622. In some embodiments, an immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams et al. In some embodiments, an immuno-oncology agent is a small molecule targeting an immuno-oncology target selected from those listed in Table 2 of Jerry L. Adams et al. In some embodiments, an immuno-oncology agent is a small molecule agent selected from those listed in Table 2 of Jerry L. Adams et al.

[0369] In some embodiments, an immuno-oncology agent is selected from the small molecule immuno- oncology agents described in Peter L. Toogood, “Small molecule immuno-oncology therapeutic agents,” Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pages 319-329. In some embodiments, an immuno-oncology agent is an agent targeting the pathways as described in Peter L. Toogood.

[0370] In some embodiments, an immune-oncology agent is a T Cell Engager (TCE). In some embodiments, the TCE is a bi-specific antibody, tri-specific antibody, or a BITE small molecule, such as teclistamab or talquetamab. In some embodiments, an immuno-oncology agent is selected from those described in Sandra L. Ross et al., “Bispecific T cell engager (BITE®) antibody constructs can mediate bystander tumor cell killing”, PLoS ONE 12(8): e0183390. In some embodiments, an immuno-oncology agent is a bispecific T cell engager (BITE®) antibody construct. In some embodiments, a bispecific T cell engager (BITE®) antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, a bispecific T cell engager (BITE®) antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, a bispecific T cell engager (BITE®) antibody construct activates T cells. In some embodiments, a bispecific T cell engager (BITE®) antibody construct activates T cells, which release cytokines inducing upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander33355712 1 Page 72 of 113 398110-93HPWO (217136)cells. In some embodiments, a bispecific T cell engager (BITE®) antibody construct activates T cells which result in induced bystander cell lysis. In some embodiments, the bystander cells are in solid tumors. In some embodiments, tire bystander cells being lysed are in proximity to the BITE®-activated T cells. In some embodiment, the bystander cells comprises tumor-associated antigen (TAA) negative cancer cells. In some embodiment, the bystander cells comprise EGFR-negative cancer cells. In some embodiments, an immuno-oncology agent is an antibody which blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, an immuno-oncology agent is an ex vivo expanded tumor-infiltrating T cell. In some embodiments, an immuno-oncology agent is a bispecific antibody construct or chimeric antigen receptors (CARs) that directly connect T cells with tumor-associated surface antigens (TAAs).Exemplary Immune Checkpoint Inhibitors

[0371] In some embodiments, an immuno-oncology agent is an immune checkpoint inhibitor as described herein.

[0372] The term “checkpoint inhibitor” as used herein relates to agents useful in preventing cancer cells from avoiding the immune system of the patient. One of the major mechanisms of anti -tumor immunity subversion is known as “T-cell exhaustion,” which results from chronic exposure to antigens that has led to up-regulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints in order to prevent uncontrolled immune reactions.

[0373] PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cell Immunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3 (Lag-3; CD223), and others are often referred to as a checkpoint regulators. They act as molecular “gatekeepers” that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed.

[0374] In some embodiments, an immune checkpoint inhibitor is an antibody to PD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1 ) to prevent the receptor from binding to the inhibitory ligand PDL- 1, thus overriding the ability of tumors to suppress the host anti-tumor immune response.

[0375] In some embodiments, the checkpoint inhibitor is a biologic therapeutic or a small molecule. In some embodiments, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein or a combination thereof. In some embodiments, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4. PDL1, PDL2. PD1, B7-H3, B7-H4. BTLA. HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof. In some embodiments, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR. B-7 family ligands or a33355712 1 Page 73 of 113 398110-93HPWO (217136)combination thereof. In some embodiments, the checkpoint inhibitor is an immunostimulatory agent, a T cell growth factor, an interleukin, an antibody, a vaccine or a combination thereof. In some embodiments, the interleukin is IL-7 or IL-15. In some embodiments, the interleukin is glycosylated IL-7. In an additional aspect, the vaccine is a dendritic cell (DC) vaccine.

[0376] Checkpoint inhibitors include any agent that blocks or inhibits in a statistically significant manner, the inhibitory pathways of the immune system. Such inhibitors can include small molecule inhibitors or can include antibodies, or antigen binding fragments thereof, that bind to and block or inhibit immune checkpoint receptors or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Illustrative checkpoint molecules that can be targeted for blocking or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, y8, and memory’ CD8+(a[3) T cells), CD160 (also referred to as BY55). CGEN-15049, CHK 1 and CHK2 kinases. A2aR, and various B-7 family ligands. B7 family ligands include, but are not limited to, B7- 1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies, or antigen binding fragments thereof, other binding proteins, biologic therapeutics, or small molecules, that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9. LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immune checkpoint inhibitors include, but are not limited to. Tremelimumab (CTLA-4 blocking antibody). anti-OX40. PD-L1 monoclonal Antibody (Anti-B7-Hl; MEDI4736), MK-3475 (PD-1 blocker), Nivolumab (anti-PDl antibody), CT-011 (anti-PDl antibody), BY55 monoclonal antibody, AMP224 (anti-PDLl antibody), BMS- 936559 (anti-PDLl antibody), MPLDL3280A (anti-PDLl antibody), MSB0010718C (anti-PDLl antibody ), and ipilimumab (anti-CTLA- 4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.

[0377] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD- L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (OPDIVO®), ipilimumab (YERVOY®), and pembrolizumab (KEYTRUDA®). In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti -PD-1 antibody, OPDIVO®, Bristol-Myers Squibb): pembrolizumab (anti-PD-1 antibody, KEYTRUDA®, Merck); ipilimumab (anti-CTLA-4 antibody, YERVOY®, Bristol-Myers Squibb); durvalumab (anti-PDLl antibody. IMFINZI®, AstraZeneca); and atezolizumab (anti-PD-Ll antibody, TECENTRIQ®, Genentech).

[0378] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105,33355712 1 Page 74 of 113 398110-93HPWO (217136)MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH210L pembrolizumab (KEYTRUDA®), and tremelimumab.

[0379] In some embodiments, an immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011. an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (BAVENCIO®, Pfizer / Merck KGaA), also known as MSB0010718C), a fully human IgGl anti-PD-Ll antibody, in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis), an inhibitory antibody that binds to PD-1, in clinical trials for non-small cell lung cancer, melanoma, triple negative breast cancer and advanced or metastatic solid tumors. Tremelimumab (CP-675.206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been in studied in clinical trials for a number of indications, including: mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell cancer of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN- 1884 (Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822).

[0380] In some embodiments, a checkpoint inhibitor is an inhibitor of T-cell immunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors that may be used in the present invention include TSR- 022. LY3321367 and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody which is being studied in advanced malignancies (NCT02608268).

[0381] In some embodiments, a checkpoint inhibitor is an inhibitor of T cell immunoreceptor w ith Ig and ITIM domains, or TIGIT, an immune receptor on certain T cells and NK cells. TIGIT inhibitors that may be used in the present invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

[0382] In some embodiments, a checkpoint inhibitor is an inhibitor of Lymphocyte Activation Gene-3 (LAG-3). LAG-3 inhibitors that may be used in the present invention include BMS-986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied33355712 1 Page 75 of 113 398110-93HPWO (217136)in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron), is also an anti-LAG-3 antibody, and is being studied in malignancies (NCT03005782). IMP321 (Immutep S.A.) is an LAG-3-Ig fusion protein, being studied in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).

[0383] Checkpoint inhibitors that can be used in the present invention include 0X40 agonists. 0X40 agonists that are being studied in clinical trials include PF-04518600 / PF-8600 (Pfizer), an agonistic anti- 0X40 antibody, in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562 (Medimmune / AstraZeneca), an agonistic anti-OX40 antibody, in advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonistic anti-OX40 antibody (Medimmune / AstraZeneca), in patients with colorectal cancer (NCT02559024). breast cancer (NCT01862900), head and neck cancer (NCT02274155) and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb) an agonistic anti-OX40 antibody, in advanced cancers (NCT02737475).

[0384] Checkpoint inhibitors that can be used in the present invention include CD137 (also called 4-1BB) agonists. CD 137 agonists that are being studied in clinical trials include utomilumab (PF-05082566, Pfizer) an agonistic anti-CD137 antibody, in diffuse large B-cell lymphoma (NCT02951156) and in advanced cancers and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-CD137 antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981); and CTX-471 (Compass Therapeutics), an agonistic anti- CD137 antibody in metastatic or locally advanced malignancies (NCT03881488).

[0385] Checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists that are being studied in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics) an agonistic anti-CD27 antibody, in squamous cell head and neck cancer, ovarian carcinoma, colorectal cancer, renal cell cancer, and glioblastoma (NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma (NCT02924038).

[0386] Checkpoint inhibitors that can be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists that are being studied in clinical trials include TRX518 (Leap Therapeutics), an agonistic anti -GITR antibody, in malignant melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors and lymphoma (NCT 02740270); INCAGNO 1876 (Incyte / Agenus), an agonistic anti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors (NCT02132754) and MEDI187333355712 1 Page 76 of 113 398110-93HPWO (217136)(Medimmune / AstraZeneca), an agonistic hexameric GITR-ligand molecule with a human IgGl Fc domain, in advanced solid tumors (NCT02583165).

[0387] Checkpoint inhibitors that can be used in the present invention include inducible T-cell costimulator (ICOS, also known as CD278) agonists. ICOS agonists that are being studied in clinical trials include MEDI-570 (Medimmune), an agonistic anti-ICOS antibody, in lymphomas (NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, in Phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody, in Phase 1 (NCT02904226).

[0388] Checkpoint inhibitors that can be used in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors that are being studied in clinical trials include lirilumab (IPH2102 / BMS- 986015, Innate Pharma / Bristol-Myers Squibb), an anti-KIR antibody, in leukemias (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma) in myeloma (NCT01222286 and NCT01217203): and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

[0389] Checkpoint inhibitors that can be used in the present invention include CD47 inhibitors of interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47 / SIRPa inhibitors that are being studied in clinical trials include ALX-148 (Alexo Therapeutics), an antagonistic variant of (SIRPa) that binds to CD47 and prevents CD47 / SIRPa-mediated signaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein created by linking the N-terminal CD47-binding domain of SIRPa with the Fc domain of human IgGl, acts by binding human CD47, and preventing it from delivering its “do not eat” signal to macrophages, is in clinical trials in Phase 1 (NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47 antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.), in colorectal neoplasms and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338) and lymphoma (NCT02953509).

[0390] Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors that are being studied in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody, in solid tumors (NCT02754141).

[0391] Checkpoint inhibitors that can be used in the present invention include agonists of stimulator of interferon genes protein (STING, also known as transmembrane protein 173, or TMEM173). Agonists of STING that are being studied in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech / Novartis), an agonistic synthetic cyclic dinuclcotidc, in Phase 1 (NCT02675439 and NCT03172936).33355712 1 Page 77 of 113 398110-93HPWO (217136)

[0392] Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF 1R inhibitors that are being studied in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF 1R small molecule inhibitor, in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710) and melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly), an anti-CSF-lR antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254). and solid tumors (NCT02718911): and BLZ945 (4-[2((lR2R)-2-hydroxycyclohexylamino)-benzothiazol-6- yloxyl]-pyridine-2 -carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid tumors (NCT02829723).

[0393] Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors that are being studied in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0394] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, pidilizumab, cemiplimab, sintilimab, or tislelizumab.

[0395] A compound of the current invention may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.

[0396] A compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a pharmacal composition, formulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the current invention can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-tenn therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.

[0397] Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a pharmacal composition, fonnulation, or unit dosage form33355712 1 Page 78 of 113 398110-93HPWO (217136)comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

[0398] The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage fomr will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of an inventive compound can be administered.

[0399] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, tire amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01-1,000 ug / kg body weight / day of the additional therapeutic agent can be administered.

[0400] Tire amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably tire amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0401] Tire pharmaceutical composition, fonnulation, or unit dosage form comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of this invention, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (renarrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a pharmacal composition, fonnulation, or unit dosage fomr comprising Compound A or a solvate or a pharmaceutically acceptable salt thereof of this invention are another embodiment of the present invention.

[0402] The following examples are provided for illustrative purposes only and are not to be construed as limiting this invention in any manner.33355712 1 Page 79 of 113 398110-93HPWO (217136)EXEMPLIFICATION

[0403] Compound A can be prepared by methods known to one of ordinary skill in the art, for example, as described in US 11,548,890.

[0404] AbbreviationsAPI Active Pharmaceutical IngredientBLQ Below Limit of QuantificationCTM Clinical Trial MaterialFaSSIF Fasted State Simulated Intestinal FluidGMP Good Manufacturing PracticeHPMC HydroxypropyhnethylcelluloseHPMCAS Hydroxypropylmethylcellulose Acetate SuccinateIG IntragramilarEG ExtragranularMCC Microcrystalline Cellulose mgA Milligrams Active mgW Capsule fill weight in milligramsND None DetectedLC Label ClaimRSD Relative Standard DeviationRT Retention TimeRRT Relative Retention TimeSD Standard DeviationSLS Sodium Lauryl SulfateTPGS D-a-Tocopherol Polyethylene Glycol 1000 SuccinateSummary

[0405] Compound A is a weak base with a strong pH-dependent solubility between pH 2 and pH 6.5, the physiologically relevant range for oral drug delivery. Based on pre-clinical development, the monohydrate fonn of the L-malate salt of Compound A was selected as the preferred form for enhanced bioavailability and acceptable pharmaceutical properties.

[0406] The pre-formulation assessment of Compound A focused on solubility assessments and excipient compatibility to guide formulation approaches. Based on the pre-formulation work, prototype capsule formulations were identified for evaluation. Prototype capsules were prepared at the bench scale using a material-sparing approach and evaluated in vitro and in vivo to help determine the optimal compositions. Once identified, a kg-scale manufacturing process was developed based on understanding material33355712 1 Page 80 of 113 398110-93HPWO (217136)properties and critical quality attributes identified during prototype development. A single, common dry granulation was used for 50 mg A and 150 mgA strengths, and a separate, low strength granulation was used for the 10 mgA and 20 mgA formulations. Encapsulation was conducted using a continuous motion MG2 capsule machine, model LABBY. A pre-pilot assessment was completed for each strength to determine the target processing parameters and to confirm material sticking to process equipment was not prohibitive. Pilot scale 10. 20. 50. and 150 mgA capsule batches were manufactured representative of the nominated CTM product. The formulations and processes were then formally transferred to GMP operations, where four strengths of capsules were successfully manufactured.

[0407] Tire following examples show the pre-formulation assessments, prototype capsule development, scaleup to kg-scale manufacturing processes, and pilot scale blending / dry-granulation / encapsulation manufacture and testing of 10 mgA. 20 mgA, 50 mgA, and 150 mgA strength capsules. GMP CTM manufacturing was successful for all four strengths.Example 1. Pre-Formulation and API assessmentSolid State Characterization

[0408] FIG. 1 represents an XRPD diffractogram of Compound A malate hydrate characteristic of crystalline material. XRPD was measured on a Rigaku MiniFlex 600 diffractometer with the following collection parameters:Aqueous Solubility

[0409] Equilibrium solubility of Compound A malate hydrate was evaluated in aqueous media across the pH range from pH 1 - pH 6.5 and in biorelevant media. Compound A was added to the media, and samples were mixed overnight in a water bath at ambient temperature to form a saturated solution. The pH of the suspension was measured, and samples were collected, centrifuged, and supernatant was diluted into 4: 1 ACN:H2O for Compound A quantitation via HPLC. Table 1 summarizes the results for two different lots33355712 1 Page 81 of 113 398110-93HPWO (217136)of API. It should be noted that the buffering capacity of media was insufficient in some samples to achieve the target pH; the measured pH is reported.Table 1. Compound A malate hydrate pH-dependent Equilibrium Solubility.* Outside demonstrated linear range of calibration curve ** Data point appears to be an outlier as a function of pH and was not included.

[0410] The apparent solubility of Compound A malate hydrate decreased in the presence of bile salts at intestinal pH, and only a slight increase in solubility as a function of bile salt concentration was observed. Typically, if API has the propensity to partition into bile salt micelles, an increase in apparent solubility will be observed as the concentration of bile salts is increased at a given pH. If API does not have the propensity to partition into bile salt micelles, a negligible increase in apparent solubility will be observed. The decrease in solubility and negligible dependence on bile salt concentration is atypical and not well explained. Although bile salt micelles are typically too small to be filtered or pelleted during centrifugation, the bile salt micelles containing Compound A malate hydrate may be larger than typical bile salt micelles and removed during sample preparation. Additional studies are needed to better understand this phenomenon and to confirm this hypothesis. It was determined at the time of pre-fonnulation assessment that the impact of bile salts on apparent solubility had negligible impact on the formulation strategy and would therefore not be evaluated further.

[0411] The addition of surfactants to formulations can form drug-rich micellular species that increase diffusion through the unstirred epithelial boundary layer and improve bioavailability or reduce food-effect. To better understand the partitioning of Compound A into surfactant micelles, the impact of surfactant on solubility was evaluated. Only room-temperature solid surfactants relevant to solid dosage form were evaluated. Excipients were evaluated at levels relevant to incorporation into a solid dosage form: 1: 1 - 1:533355712 1 Page 82 of 113 398110-93HPWO (217136)mass ratio with Compound A malate hydrate. All samples were evaluated in ‘’blank” FaSSIF - a media equivalent to FaSSIF at pH 6.5 with 0% bile salts. FIG. 2 and Table 2 illustrates a significant increase in the solubility of Compound A in the presence of surfactants but shows a minimal increase in solubility as a function of surfactant concentration. Poloxamer 407 and TPGS had a more significant effect than SLS.Table 2. Impact of Surfactant on Equilibrium Solubility in 0.1M phosphate and pH 6.8

[0412] While surfactants had an obvious impact on increasing the apparent solubility of Compound A malate salt, it should be noted that based on the observed solubility at physiological pH without surfactant, pre-clinical PK studies, and the anticipated target dose range for the Phase I study, solubility enhancement was not deemed necessary. Therefore, Poloxamer 407 was selected as the preferred surfactant in excipient compatibility studies but was not incorporated into prototype capsule formulations for further evaluation.Non-sink Dissolution in Biorelevant Media

[0413] To evaluate tire potential effect of variability in gastric pH on Compound A malate hydrate dissolution in biorelevant media, a two stage non-sink dissolution test was conducted at two different concentrations of API in gastric media, 5 mg / mL and 0.5 mg / mL, approximately corresponding to doses of 125 mg and 1.25 g, assuming a gastric volume of 250 mL. At each concentration, the test was conducted in gastric media at two different pH values, pH 2.0 and pH 4.0, representing a normal fasted state (pH 2.0) and an elevated pH (pH 4.0). Additionally, a sample at high concentration (5 mg / mL) and low pH (pH 2.0) containing HPMCAS-H as a precipitation inhibitor was included to evaluate the impact of a precipitation inhibitor on sustaining supersaturation after transfer from the gastric media in which the API is fully soluble, to the simulated intestinal fluid where it is not. To test this, in the first stage of the experiment, HPMCAS- H was added as a physical mixture with the API in a 1: 1 mass ratio with Compound A malate salt.

[0414] API was added to the specified gastric media at the target concentration, vortexed briefly to fully wet tire API, and then mixed using a magnetic stir bar. After 30 minutes in the specified gastric media at33355712 1 Page 83 of 113 398110-93HPWO (217136)pH 2.0 or pH 4.0, the suspension was diluted 3x to target a final FaSSIF media at pH 6.5. At each time point, samples were collected, filtered through a 0.22 urn cellulose acetate filter, and analyzed via HPLC to quantify Compound A concentration. Tire dissolution profiles are presented in FIG. 3.

[0415] For both high and low concentrations, at pH 2.0 and pH 4.0, Compound A malate hydrate reached near full dissolution in gastric media. After transfer to FaSSIF, the high concentration samples rapidly precipitated to approximately 30% dissolved (approximately 0.5 mg / mL). but the low concentration samples remained fully dissolved. There was no apparent effect of gastric pH or precipitation inhibitor. The data suggests that at high doses, a pH effect might be observed due to solubility limitations at higher pH. The data also suggests that the addition of HPMCAS-H as a precipitation inhibitor in the higher pH is not effective at mitigating the potential pH effect at high doses. Therefore, addition of a precipitation inhibitor to the capsule formulation was not considered further.Excipient Compatibility

[0416] An excipient compatibility study using excipient compacts (1 / 4” round, 100 mg, IkN compression force) stored under open accelerated conditions (40 °C / ambient humidity and 40 °C / 75% RH) was completed. A matrix study design was used in which compacts comprised of up to 4 excipients plus Compound A malate-hydrate were prepared; the overlap of excipients within the compacts allows for an independent assessment of each excipient. Table 3 describes the composition of each compact evaluated in the study. In addition to the compacts, an API control was also stored under the specified storage conditions for comparison. API content in each compact was limited to 10 wt% due to material limitations.Table 3. Excipient Compatibility Study Design33355712 1 Page 84 of 113 398110-93HPWO (217136)

[0417] Total impurities were evaluated after 2 weeks and 4 weeks of storage. However, due to poor chromatography observed as a split main peak, the 2-week data was discarded. Additional method characterization was completed between the 2 week and 4 week time points, but the observed split in the main peak could not be reproduced. Tire 4 week chromatography appeared as expected, and the data is presented below in Table 4.Table 4. Selected Peaks from Impurity Analysis of Excipient Compatibility Study after 4 weeks.

[0418] While no excipient compacts showed significant impurity growth relative to the API control, significant variability across the data set was observed. Tire excipient compatibility study was completed using a low-purity lot of API. It was determined that chromatography of the later, purer, lots of API w as improved, leading to less variability. While no obvious incompatibility was observed between excipient and API in this study, additional prototype and pilot stability data for lead formulations conducted with the higher purity API lot and consistent analytical methods were used to confirm stability.33355712 1 Page 85 of 113 398110-93HPWO (217136)Example 2. Prototype Capsule Development

[0419] Prototype Compound A capsules were manufactured in a screening study to evaluate drug loading, fdl density, and the use of starch as an alternate ductile fdlerto microcrystalline cellulose with high swelling potential. Table 5 summarizes information about tire capsules manufactured to support dissolution testing. The prototype formulation screening, manufacture process, and dissolution are discussed in the following sections.Table 5. Summary of Capsule Filling Studies to Produce Additional Capsules and Strengths*Compositions of blend A, B, and C are detailed in Table 6; Blend D in Table 12. * * Salt-hydrate factor = 0.763. *** Blend A and C arc the same formulations. Blend C was manufactured to provide more blend for additional dose strengths and capsules for testing. Bulk density = 0.524 g / cc, tapped density = 0.704 g / cc.Prototype Capsule Formulation Screening

[0420] Prototype capsules were prepared using Compound A malate (anhydrous, 0.37% moisture per CoA) was converted to the monohydrate by RH equilibration and confirmed to have 2.8 wt% moisture after conversion. Initially, two formulations, one comprised of MCC as filler and the other a combination of MCC and prc-gclatinizcd starch, were evaluated at a 100 mgA dose strength in both size #0 and #00 HPMC capsules. Dry granulated blends were prepared and filled into capsules using a single station Torpac ProFunnel unit. Tire prototype capsule manufacturing process is detailed below. Tire formulations in the initial capsule formulation screening are detailed in Table 6.Table 6. Capsule Formulations used in the Prototype Capsule Formulation Screening33355712 1 Page 86 of 113 398110-93HPWO (217136)* Compound A malate-hydrate conversion to free base equivalent: 0.763

[0421] After the intragranular blend step (Turbula T2F, 49 rpm, 15 min), the compression stress required to achieve a slug tensile strength of 0.75 ± 0.15 MPa was determined for each blend using a Natoli RD 10A single station press with 3 / 4” flat-face tooling. The compression stress required was determined to be 10 kN / 35.1 MPa and 16 kN / 56.1 MPa for blends A and B, respectively. The higher stress required for the starch formulations is consistent with its known poor compactability.Table 7. Physical Characterization of Slugs Produced during Prototype Capsule Formulation Screening33355712 1 Page 87 of 113 398110-93HPWO (217136)

[0422] After compaction, slugs were gently broken up into large pieces with a mortar and pestle and passed through a Vector rotary mill with a 1 mm screen. Following granulation, the extragranular components were added for the final blend step (Turbula T2F, 49 rpm, 15 min). Capsules were individually filled with the final blends using a Torpac ProFunnel. For each blend, six size #0 and six size #00 capsules were filled with approximately 400 mg of either A or B final blend (Table 5) for dissolution testing.Prototype Capsule Stability

[0423] An accelerated prototype capsule stability study was conducted to determine the relative effect of temperature and moisture on chemical stability of Compound A malate monohydrate capsule formulations. Tire fonuulations described in Table 6, A and B, were evaluated. Capsules were stored in open containers at 40 °C / ambient and 40 °C / 75% RH for 4 weeks. At the study start and after 2 and 4 weeks, samples were removed from storage and analyzed via HPLC for impurities. Impurity profiles are summarized in Table 8.

[0424] Method variability for repeat-standard injections within a sequence was 0.05% for total impurities. No significant increase in total impurities was observed after 4 weeks in either capsule formulation at either storage condition (Table 8); also, no significant increase or trends in impurity growth for individual impurities as a function of time was observed. It was concluded from this data that either formulation w as suitable for further development.Table 8: Prototype Accelerated Stability Summary of Impurities. Results from 0 and 2 weeks were separated from results from 4 weeks due to method change resulting in different retention times. The impurity observed at RT 12.14 highlighted at 4 weeks for Formulation B at 40 °C / 75% RH was hypothesized to be an outlier. BLQ = 0.05%. ND = < 0.02%.33355712 1 Page 88 of 113 398110-93HPWO (217136)* Impurities at RRT of 0.46 and 0.50 account for remainder of total impurities, with 0.25% and 0.20% peak area, respectively. These peaks were not detected in any of the stability samples, so were left out of the table as a visual aid.Prototype Capsule Dissolution

[0425] To evaluate the impact of formulation and fill density on dissolution, prototype 100 mgA capsules were evaluated in a sink dissolution study using a Type II apparatus at 75 rpm speed. The media selected for this initial screen was 100 mM sodium phosphate pH 6.8, which, based on initial solubility screening, was expected to provide approximately lOx sink conditions for the 100 mgA dose in a 900 mL volume. The high buffer concentration was selected for initial screening to ensure that pH did not change upon33355712 1 Page 89 of 113 398110-93HPWO (217136)dissolution of the API or formulation excipients. Dissolution profiles are shown in FIG. 4 and tabulated inTable 9.Table 9. Tabulated Dissolution Profiles from FIG. 4 for Prototype Capsules

[0426] While the starch containing formulations appear to dissolve slightly faster, the variability was such that no significant differences were observed between formulations for a given capsule size and fill density. However, faster dissolution was observed for the smaller capsule and higher fill density for both formulations. Based on these results, the microcrystallinc cellulose (MCC) based formulation targeting up to 100 mgA and 150 mgA dose strengths in size #0 and #00 HPMC capsules, respectively, was selected for further development.

[0427] In the further evaluation of the lead formulation, capsules were prepared using the pilot lot of API at 150 mgA strengths. These formulations were identical to the formulations A and B, respectively, described in Table 6 other than the API lot used.

[0428] These prototype capsules were also evaluated in a sink dissolution test whereby the sodium phosphate buffer strength was reduced from 100 mM to 10 mM and the pH was kept at 6.8. All other dissolution method parameters remained the same, including 75 rpm stirring speed.

[0429] Full dissolution was not observed for all dose strengths tested, as shown in FIG. 5 and tabulated in Table 10. This result could not be explained by solubility, differences in API lot, or pH changes during dissolution testing. It was later determined that the incomplete dissolution was attributable to croscarmcllosc sodium excipient-binding to Compound A, an effect mitigated at higher ionic strength or by using lower pH simulated gastric fluid.Table 10. Tabulated Dissolution Profiles from FIG. 5 for Prototype Capsules33355712 1 Page 90 of 113 398110-93HPWO (217136)

[0430] Additionally, dissolution of 100 mgA and 150 mgA capsules using the MCC lead formulation also were compared in 0.01N HC1 at 75 rpm speed (FIG. 6, Table 11). Hie 25 mgA dose strength was not evaluated in this study.

[0431] Compared to the 100 mM phosphate buffer dissolution results (FIG. 4, “MCC, #0 Cap”), the dissolution profiles are faster, i.e., 94% vs. 74% in 10 minutes. As discussed in the section below, a higher, 49%, drug loading formulation (Table 5 and Table 12), was also manufactured whereby 150 mgA / 400 mgW filled into #0 capsules had modestly slower dissolution than the 33% drug load formulation in size #00 capsules. This is discussed further in the next section.Table 11. Tabulated Dissolution Profiles from FIG. 6 for Prototype CapsulesDrug Loading Assessment

[0432] Based on the results of the prototype formulation screening, the formulation comprised of MCC as filler was selected as the lead formulation. To support the full range of desired capsule strengths and to minimize capsule size for tire high strength, additional studies were conducted to evaluate the impact of drug loading on dissolution. Three capsule formulations were compared; two comprised a common granulation containing 33% Compound A malate hydrate and one containing 49% Compound A malate hydrate. The 49% capsule formulation was manufactured at 30 g scale using the same equipment and procedures. 12 kN / 42 MPa compression stress was required to obtain 0.70-0.75 MPa tensile strength slugs. The formulations, fill weights, and capsule sizes are described in Table 12.Table 12. Capsule Formulations used for Evaluation of Drug Loading33355712 1 Page 91 of 113 398110-93HPWO (217136)

[0433] All three formulations were compared in sink dissolution studies to determine the impact of drug loading, fill density, and dose strength on dissolution. As described above, due to inconsistency seen in sink dissolution studies as a function of buffer strength in phosphate media at pH 6.8, these studies were conducted using 0.01 N HC1. While the use of 0.01 N HC1 for sink dissolution is more biorelevant for the disintegration and dissolution of immediate release oral solid dosage forms, the sink conditions for even the maximum dose strength (150 mgA) of Compound A at pH 2.0 are high (> lOOx sink) and may result in a less sensitive in vitro test. Nevertheless, the impact of drug loading on dissolution rate was apparent, as shown in FIG. 6, whereby higher drug loading (but smaller capsule size) had slower dissolution.Example 3. Pre- Pilot Manufacturing Assessment33355712 1 Page 92 of 113 398110-93HPWO (217136)

[0434] The manufacturability of Compound A was assessed before the manufacture of pilot batches due to previous issues with modest punch stickiness observed during slugging. Additionally, lower strength formulations were developed to support 10 mgA, 20 mgA, and 50 mgA capsule strengths. In total, three formulations containing 12%, 33%, and 49% drug loading were developed and produced for pre-pilot process assessments. The 49% formulation was designed for 50 mgA / 133.3 mgW and 150 mgA / 400 mgW strengths, the 33% formulation for 100 mgA / 400 mgW, and the 12% formulation for 10 mgA / 110 mgW and 20 mgA / 220 mgW capsule strengths. These are detailed below in Table 13, Table 14, and Table 15, respectively.Granulation

[0435] Each of the three batches was evaluated at 150 g scale by preblending IG components in a bottle, screening through a #40 mesh screen, blending in a Turbula T2F blender (49 rpm, 15 min), dry granulating using a Vector TFC-Micro roller compactor and Vector Oscillating Rotary Mill with a 1 mm screen, and final blending with extragramilar excipients in a Turbula T2F blender (49 rpm, 15 min). The granulation parameters and measured throughput values are detailed in Table 16.

[0436] In summai}', all three formulations process without any roll sticking or accumulation. The differences in throughput, lowest for the 12% formulation, are attributed to the observed better flow and associated less ‘draw-in" to the roller compactor nip region with the low strength granulation (i.e., a portion of the material slipped past the auger screw gaps in the nip region rather than being processed through the rolls). This is due to the TFC-Micros’s single tapered auger and non-gap and feed auger controls which ultimately led to thinner ribbons (at the same roll force). Related, 40 rpm is the maximum auger speed, so it could not be increased in attempt to maintain ribbon thickness and throughput. Lower roll speeds were not attempted since the primary goal was to observe ribbon quality and sticking potential. Since all kg-scale process was to be conducted using Gerteis roller compactors, which have gap control (i.e., ribbon thickness, force, and throughput), the lower throughput and thinner ribbon thickness limitations were not considered an issue for the future pilot batches. As discussed later, roll gap was maintained for all pilot batches on Gerteis equipment.Table 13. 49% High Drug Loading Formulation for Pre-Pilot Assessment33355712 1 Page 93 of 113 398110-93HPWO (217136)Table 14. 33% Drug Loading Formulation for Pre-Pilot AssessmentTable 15. 12% Drug Loading Formulation for Pre-Pilot Assessment33355712 1 Page 94 of 113 398110-93HPWO (217136)Capsules

[0437] 10 mgA (size #3 HPMC) and 150 mgA (size #0 HPMC) capsules were manufactured using the 12% and 49% formulations, respectively, using pre-pilot final blends and a single -station Torpac ProFunnel. This was conducted to confirm acceptable fill density and to provide capsules for analytical method development. No tamping was required for the 10 mgA capsules and minimal tamping was required for the 150 mgA capsules. Details are summarized in Table 16.Table 16. 10 mgA and 150 mgA Capsules Manufactured to Support Analytical Development* Qualicaps Quali-V HMPC capsulesStability

[0438] The pre-pilot 10 mgA and 150 mgA capsules were put up on stability to observe changes in impurity profde and dissolution at accelerated conditions. Capsules were stored at 40 °C / ambient closed and 40 °C / 75% RH open conditions. Capsules were analyzed after two and four weeks.

[0439] A summary of results from impurities and related substance analysis is reported in Table 17. In conclusion, no significant impurity growth was observed at the accelerated conditions.Table 17. Selected Peaks from Impurities and Related Substances HPLC Analysis33355712 1 Page 95 of 113 398110-93HPWO (217136)

[0440] Dissolution of the capsules stored at accelerated conditions for four weeks is shown in FIG. 7 and tabulated in Table 18 and Table 19. The lower strength capsules, 10 mgA, reached > 90% dissolution by 30 min for all samples. Dissolution appears to be slightly faster for the capsules tested after four weeks, with a plateau value of > 100% reached after 10 min. All 10 mgA capsules reached a plateau value > 96%.

[0441] The higher strength capsules, 150 mgA, were generally slower to dissolve than the 10 mgA capsules, likely due to the higher drug loading. The capsules tested after two weeks reached > 90% dissolution by 45 min and 60 min for storage in closed (40 °C / ambient) and open (40 °C / 75% RH) conditions, respectively. The capsules tested after four weeks dissolved slightly more quickly, with > 90% dissolution reached by 45 min and 30 min for storage in closed (40 °C / ambient) and open (40 °C / 75% RH) conditions, respectively. All 150 mgA capsules reached a plateau value of > 97%. Overall, the dissolution rates decreased slightly with longer storage time, but the plateau dissolution values were not affected by storage at accelerated conditions.Table 18. Tabulated Dissolution Profiles for Pre-Pilot 10 mgA Capsules over Four Weeks at Accelerated Conditions33355712 1 Page 96 of 113 398110-93HPWO (217136)Table 19. Tabulated Dissolution Profiles for Pre-Pilot 150 mgA Capsules over Four Weeks at Accelerated ConditionsExample 4. Pilot Manufacture and Characterization

[0442] The dose strengths needed for clinical manufacture were 10, 20. 50, and 150 mgA. These required two of the three granulations. 12% and 49% drug loading, identified during the prototype and pre-pilot development work. While prototype and pre-pilot capsules were manufactured manually using a Torpac Profiller ProFunnel one at a time, pilot batches required automated encapsulation equipment.12 Pilot confirmation batches were manufactured to confirm blending, dry granulation, and encapsulation process parameters for all four strengths. The following sections detail the manufacture of the capsule pilot batches and subsequent characterization.Pilot Capsule Compositions and Manufacture ProcessesCapsule Compositions

[0443] The final formulations for the pilot capsules are reported below in Table 20. The final blends are identical to pre-pilot batches A (49% drug loading; 50 mgA and 150 mgA capsules) and B (12% drug loading; 10 mgA and 20 mgA), respectively. However, the hypromellose capsules were switched from Qualicaps Quali-V to Capsugel VCaps Plus due to challenges with capsule opening and closing of Quali- V capsules on the MG2 Labby capsule machine.Table 20. Pilot Capsule Formulations33355712 1 Page 97 of 113 398110-93HPWO (217136)* Malate -monohydrate free base conversion factor (theory): 0.76314. ** Numbers in parenthesis represent the average empty capsule weight and not included in the fill weight total. *** Capsule body volumes (body'): 0.30, 0.37, 0.50, 0.68 cc for sizes #3, #2, #1, #0, respectivelyManufacturing Process Train

[0444] Pilot kg-scale batches were manufactured with batch sizes representative of the planned GMP campaigns. The manufacturing process is shown as a flow diagram in FIG. 8. Hie batch sizes and final yields for each strength are listed below in Table 21.Table 21. Pilot Capsule Batch Sizes33355712 1 Page 98 of 113 398110-93HPWO (217136)Intragranular Blend, Granulation, and Final Blend Process Details

[0445] The intragranular blends for each granulation were prepared using a blend-mill-blend process. This was selected as a conservative step to delump the materials and to provide a dispersive mixing step to maximize the uniformity of Compound A API particles with the intragranular excipients.

[0446] Both granulations were prepared by first conditioning the V-blender shell with MCC. Tire MCC was then mixed. After the conditioning step. Compound A, MCC, Talc, CCS, and CSD were added to the blender. The blend was then passed through the cone mill for dispersive mixing and deagglomeration. The deagglomerated blend was returned to the blender and mixed again for tire main IG blend. Last, the SSF was added to the blender for the final lubricant blending step.

[0447] The intragranular blends were then dry-granulated using a Gerteis Mini-Polygran. Dry- granulation proceeded without roll sticking or any incidents for both batches. The Gerteis roller compactor produced consistent ribbons at steady-state after approximately 90 seconds after startup. The yield for both batches, after sampling and process losses was 94%.

[0448] After each granulation, the extragranular MCC and CCS were blended with the granules for the main EG blend. Last, SSF was charged into the blender for the final lubricant blending step.Encapsulation Development and Manufacturing Process Details

[0449] Initially, Qualicaps Quali-V hypromellose capsules were used for encapsulation. However, for multiple strengths, significant issues were encountered opening and closing of empty capsules on the MG2 Labby encapsulator. Troubleshooting improved the closing issues and slightly helped with the inconsistent opening issues and associated jamming. However, due to the inability to solve the capsule issues, Capsugel VCaps Plus hypromellose capsules were used that did not have any empty capsule opening and closing issues on the MG2 Labby.Blend and Powder Density

[0450] The powder densities of the intragranular blends, dry granulations, and final blends were measured. The results of the powder characterization are reported below in Table 22. The higher drug loading formulation had poorer intragranular blend flow due to poor flow' of the small particle size API. The granulation and final blend flow metrics are considered adequate for dosator encapsulation.Table 22. Powder Characteristics Summary for Pilot Capsule Manufactures33355712 1 Page 99 of 113 398110-93HPWO (217136)Ribbon Solid Fraction

[0451] The target pilot batch ribbon solid fraction range was identified as 0.6 - 0.7. Ribbons were characterized for solid fraction by envelope density (GeoPyc) during roller compaction startup as an in- process test. Tire roll forces and associated ribbon solid fraction values are summarized in Table 23. 4.0 kN / cm and 3.5 kN / cm were selected for pilot batch granulations, respectively.Table 23. Roller Compaction Roll Force and Ribbon Solid Fraction for Pilot Batches (n = 3 per sample).Particle Size Distribution Analysis

[0452] The particle size distribution of the pilot granulations was measured by shake-sieve analysis. The particle size distributions of the pilot granulations are tabulated in Table 24 and shown graphically in FIG. 9 (histogram) and FIG. 10 (cumulative). The distributions were obtained using Gerteis roller compactors with 0.6 - 0.7 solid fraction ribbons and 1 mm mill screens. The slightly larger size distribution of 50 / 150 mgA is consistent with slightly higher solid faction ribbons. However, the amount of fines in both formulations is low to average for typical dry granulations developed for encapsulation.Table 24. Particle Size Distribution by Sieve Analysis of Pilot Granulations33355712 1 Page 100 of 113 398110-93HPWO (217136)Capsule Potency

[0453] The potency of the pilot capsules was assayed by HPLC. A summary of the results is reported below in Table 25. All lots of capsules were between 97% - 101% of LC.Table 25. Potency of Pilot CapsulesCapsule Fill Weight Variation and Uniformity of Dosage Forms (i.e., Content Uniformity)

[0454] Pilot batch capsule fill weight variation and content uniformity were analyzed. A summary of capsule weight results from in-process characterization is reported below in Table 26.Table 26. Weight Variation and Content Uniformity of Pilot Capsules* Fill weight of 50 and 150 mgA capsules calculated by subtracting average capsule shell weight from gross capsule weight. Average capsule shell weight taken as the midpoint of the manufacturer specifications. ** Based on 10 units for 10 mgA and 20 mgA capsules, 5 units for 50 mgA and 150 mgA capsules. USP <905> k-value of 2.4 was used for n = 10 and 2.6 for n = 5.Capsule Dissolution

[0455] Capsule dissolution testing was performed. The resulting profiles are shown in FIG. 11 and tabulated in Table 27. The dissolution profiles are plotted relative to the label claim. The dissolution profiles all plateau > 97%, consistent with the potency reported in Table 25. All capsules reached > 90% dissolution within 30 minutes. The higher drug loading capsules, 50 and 150 mgA, had a slower initial dissolution rate but reached the same plateau level.Table 27. Tabulated Sink Dissolution of Pilot Capsules.33355712 1 Page 101 of 113 398110-93HPWO (217136)Impurities & Related Substances

[0456] The capsules were analyzed by HPLC for impurities and related substances. Results from the analysis are summarized in Table 28. No significant increase in impurities over the reference standard is observed. Only peaks > 0.05% are reported.Table 28. Impurities and Related Substances for Pilot CapsulesWater Content

[0457] The water content of the pilot capsules was measured using coulometric Karl Fischer titration. The average results are summarized in Table 29. The slightly lower value for the high strength granulation capsules, 50 mgA and 150 mgA, is consistent with higher drug loading and lower MCC amount.Table 35. Water Content of Pilot CapsulesPilot Capsule Conclusions and Discussion

[0458] The pilot manufacturing proceeded smoothly with two exceptions. The first was challenges with Qualicaps Quali-V hypromellose capsules. Despite significant troubleshooting, the empty capsule opening and closing could not be resolved satisfactorily. No issues were encountered with Capsugel VCaps Plus33355712 1 Page 102 of 113 398110-93HPWO (217136)hypromellose capsules. The second issue was fill weight variation, especially for the lO mgA strength. Most of the variation was attributed to sticking on the dosator piston surfaces. This was not resolved using boron- coated dosators and pistons. For 50 mgA and 150 mgA encapsulation, it was discovered that decreasing bed depth, which decreased precompression consolidation, eliminated dosator tip sticking. Therefore, lower bed depths were nominated for CTM manufacturing. This was successful, as weight variation was well controlled during GMP manufacture, including 10 mgA. and there was no accumulation on dosator pistons.

[0459] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the application and claims rather than by the specific embodiments that have been represented by way of example.33355712 1 Page 103 of 113 398110-93HPWO (217136)

Claims

CLAIMSA pharmaceutical composition, formulation, and unit dosage form comprising:(a) Compound A:or a solvate or pharmaceutically acceptable salt thereof;(b) one or more filler;(c) one or more anti-adherent;(d) one or more disintegrant;(e) one or more glidant: and(f) one or more lubricant.

2. The pharmaceutical composition, formulation, or unit dosage form of claim 1, comprising an amount of Compound A or a solvate or pharmaceutically acceptable salt thereof from about 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg. about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 100 mg to about 105 mg, about 105 mg to about 110 mg, about 110 mg to about 115 mg, about 115 mg to about 120 mg, about 120 mg to about 125 mg, about 125 mg to about 130 mg, about 130 mg to about 135 mg, about 135 mg to about 140 mg, about 140 mg to about 145 mg, about 145 mg to about 150 mg, about 150 mg to about 155 mg, about 155 mg to about 160 mg, about 160 mg to about 165 mg, about 165 mg to about 170 mg, about 170 mg to about 175 mg, about33355712 1 Page 104 of 113 398110-93HPWO (217136)175 mg to about 180 mg, about 180 mg to about 185 mg, about 185 mg to about 190 mg, about 190 mg to about 195 mg, or about 195 mg to about 200 mg.

3. Tire pharmaceutical composition, formulation, or unit dosage form of either of claim 1 or 2, comprising about 10 mg, about 20 mg, about 50 mg, or about 150 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition, formulation, or unit dosage form of any one of claims 1-3, comprising an amount of filler from about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg. about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 100 mg to about 105 mg, about 105 mg to about 110 mg, about 110 mg to about 115 mg, about 115 mg to about 120 mg, about 120 mg to about 125 mg, about 125 mg to about 130 mg, about 130 mg to about 135 mg, about 135 mg to about 140 mg, about 140 mg to about 145 mg. or about 145 mg to about 150 mg.

5. The pharmaceutical composition, formulation, or unit dosage form of any one of claims 1-4, comprising about 31 mg, about 62 mg, about 67 mg, about 93 mg, or about 133 mg of filler or diluent.

6. The pharmaceutical composition, formulation, or unit dosage form of any one of claims 1-5, comprising an amount of anti -adherent from about 5 mg to about 10 mg, about 10 mg to about 15 mg. about 15 mg to about 20 mg, about 20 mg to about 25 mg. about 25 mg to about 30 mg. about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg.

7. Tire pharmaceutical composition, formulation, or unit dosage form of any one of claims 1-6, comprising about 11 mg, about 13 mg, about 22 mg, about 27 mg. or about 40 mg of anti -adherent or lubricant.

8. The pharmaceutical composition, formulation, or unit dosage form of any one of claims 1-7, comprising an amount of disintegrant from about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to33355712 1 Page 105 of 113 398110-93HPWO (217136)about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, or about 55 mg to about 60 mg.

9. Tire pharmaceutical composition, formulation, or unit dosage form of any one of claims 1-8, comprising about 16 mg, about 19 mg, about 32 mg, about 38 mg or about 57 mg of disintegrant.

10. The pharmaceutical composition, formulation, or unit dosage form of any one of claims 1-9, comprising an amount of glidant from about 0.5 mg to about 1.0 mg, about 1.0 mg to about 1.5 mg, about 1.5 mg to about 2.0 mg, about 2.0 mg to about 2.5 mg, about 2.5 mg to about 3.0 mg, about 3.0 mg to about 3.5 mg, about 3.5 mg to about 4.0 mg. about 4.0 mg to about 4.5 mg, about 4.5 mg to about 5.0 mg, about 5.0 mg to about 5.5 mg, or about 5.5 mg to about 6.0 mg.

11. The pharmaceutical composition, formulation, or unit dosage form of any one of claims 1-10, comprising about 1.4 mg, about 1.7 mg, about 2.8 mg, about 3.4 mg, or about 5 mg of glidant.

12. The pharmaceutical composition, formulation, or unit dosage form of any one of claims 1-11, comprising an amount of lubricant from about 1.5 mg to about 2.0 mg, about 2.0 mg to about 2.5 mg, about 2.5 mg to about 3.0 mg. about 3.0 mg to about 3.5 mg, about 3.5 mg to about 4.0 mg. about 4.0 mg to about 4.5 mg, about 4.5 mg to about 5.0 mg, about 5.0 mg to about 5.5 mg, about 5.5 mg to about 6.0 mg, about 6.0 mg to about 6.5 mg, about 6.5 mg to about 7.0 mg, about 7.0 mg to about 7.5 mg, about 7.5 mg to about 8.0 mg, about 8.0 mg to about 8.5 mg, or about 8.5 mg to about 9.0 mg.

13. The pharmaceutical composition, formulation, or unit dosage form of any one of claims 1-12. comprising about 2.2 mg, about 2.7 mg. about 4.4 mg. about 5.4 mg, or about 8.0 mg of lubricant.

14. The pharmaceutical composition, formulation, and unit dosage form of any one of claims 1-13, comprising:(a) from about 5 mg to about 15 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) from about 25 mg to about 35 mg of filler;(c) from about 5 mg to about 15 mg of anti -adherent;(d) from about 10 mg to about 20 mg of disintegrant;(c) from about 1.0 mg to about 2.0 mg of glidant; and(f) from about 2.0 to about 3.0 mg of lubricant.33355712 1 Page 106 of 113 398110-93HPWO (217136)15. The pharmaceutical composition, formulation, and unit dosage form of any one of claims 1-13, comprising:(a) from about 15 mg to about 25 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) from about 60 mg to about 75 mg of filler;(c) from about 10 mg to about 20 mg of anti-adherent:(d) from about 15 mg to about 25 mg of disintegrant;(e) from about 1.0 mg to about 2.0 mg of glidant; and(f) from about 2.5 to about 3.5 mg of lubricant.

16. The pharmaceutical composition, formulation, and unit dosage form of any one of claims 1-13, comprising:(a) from about 45 mg to about 55 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) from about 60 mg to about 75 mg of filler;(c) from about 15 mg to about 25 mg of anti-adherent;(d) from about 25 mg to about 40 mg of disintegrant;(e) from about 2.0 mg to about 3.5 mg of glidant; and(f) from about 4.0 to about 5.0 mg of lubricant.

17. The pharmaceutical composition, formulation, and unit dosage form of any one of claims 1-13, comprising:(a) from about 90 mg to about 110 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) from about 50 mg to about 70 mg of a filler;(c) from about 15 mg to about 35 mg of an anti-adherent;(d) from about 30 mg to about 50 mg of a disintegrant;(e) from about 3.0 mg to about 5.0 mg of a glidant; and(f) from about 4.0 mg to about 8.0 mg of a lubricant.

18. The pharmaceutical composition, formulation, and unit dosage form of any one of claims 1-13, comprising:33355712 1 Page 107 of 113 398110-93HPWO (217136)(a) from about 140 mg to about 160 mg of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) from about 125 mg to about 140 mg of filler;(c) from about 35 mg to about 45 mg of anti-adherent;(d) from about 45 mg to about 60 mg of disintegrant;(e) from about 4.0 mg to about 5.0 mg of glidant; and(f) from about 7.5 to about 8.5 mg of lubricant.

19. Tire pharmaceutical composition, formulation, and unit dosage fomr of any one of claims 1-13, comprising:(a) about 12% (w / w) of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) about 60% (w / w) of filler;(c) about 10% (w / w) of anti -adherent;(d) about 14% (w / w) of disintegrant;(e) about 1.3% (w / w) of glidant; and(f) about 2% (w / w) of lubricant.

20. The pharmaceutical composition, formulation, and unit dosage form of any one of claims 1-13, comprising:(a) about 50% (w / w) of Compound A or a solvate or pharmaceutically acceptable salt thereof;(b) about 23% (w / w) of filler;(c) about 10% (w / w) of anti -adherent;(d) about 14% (w / w) of disintegrant;(e) about 1.3% (w / w) of glidant; and(f) about 2% (w / w) of lubricant.

21. The pharmaceutical composition, formulation, and unit dosage fomr of any one of claims 1-20, comprising Compound A L-malate monohydrate.

22. The pharmaceutical composition, formulation, and unit dosage form of any one of claims 1-21. wherein the filler comprises microcrystalline cellulose.

23. The pharmaceutical composition, formulation, and unit dosage form of any one of claims 1-22, wherein the anti-adherent comprises talc.33355712 1 Page 108 of 113 398110-93HPWO (217136)24. The pharmaceutical composition, formulation, and unit dosage form of any one of claims 1-23, wherein the disintegrant comprises croscarmellose sodium.

25. The pharmaceutical composition, fonnulation, and unit dosage fonn of any one of claims 1-24, wherein the glidant comprises colloidal silicon dioxide.

26. The pharmaceutical composition, formulation, and unit dosage form of any one of claims 1-25, wherein the lubricant comprises sodium stcaryl fumarate.

27. The pharmaceutical composition, fonnulation, and unit dosage fonn of any one of claims 1-13, comprising: i) intragranularly: about 11.9% (w / w) Compound A L-malate monohydrate, about 50.5% (w / w) microcrystalline cellulose, about 10.0% (w / w) talc, about 12.0% (w / w) croscarmellose sodium, about 0.8% (w / w) colloidal silicon dioxide, and about 1.5% (w / w) sodium stcaryl fumarate; and ii) extragranularly: about 10.0% (w / w) microcrystalline cellulose, about 2.3% (w / w) croscarmellose sodium, about 0.5% (w / w) colloidal silicon dioxide, and about 0.5% (w / w) sodium stearyl fumarate.

28. The pharmaceutical composition, fonnulation, and unit dosage form of any one of claims 1-13, comprising: i) intragranularly: about 49.1% (w / w) Compound A L-malate monohydrate, about 13.3% (w / w) microcrystalline cellulose, about 10.0% (w / w) talc, about 12.0% (w / w) croscannellose sodium, about 0.8% (w / w) colloidal silicon dioxide, and about 1.5% (w / w) sodium stearyl fumarate; and ii) extragranularly: about 10.0% (w / w) microcrystalline cellulose, about 2.3% (w / w) croscarmellose sodium, about 0.5% (w / w) colloidal silicon dioxide, and about 0.5% (w / w) sodium stearyl fumarate.

29. Tire pharmacal composition, formulation, and unit dosage form of any one of claims 1-13, comprising: i) intragranularly: about 13.1 mg Compound A L-malate monohydrate, about 55.6 mg microcrystalline cellulose, about 11.0 mg talc, about 13.2 mg croscarmellose sodium, about 0.8 mg colloidal silicon dioxide, and about 1.7 mg sodium stearyl fumarate; and ii) extragranularly: about 11.0 mg microcrystalline cellulose, about 2.6 mg croscarmellose sodium, about 0.6 mg colloidal silicon dioxide, and about 0.6 mg sodium stcaryl fumarate.33355712 1 Page 109 of 113 398110-93HPWO (217136)30. The pharmaceutical composition, formulation, and unit dosage form of any one of claims 1-13, comprising: i) intragranularly: about 26.2 mg Compound A L-malate monohydrate, about 111.1 mg microcrystalline cellulose, about 22.0 mg talc, about 26.4 mg croscarmellose sodium, about 1.7 mg colloidal silicon dioxide, and about 3.3 mg sodium stearyl fumarate: and ii) extragranularly: about 22.0 mg microcrystalline cellulose, about 5.1 mg croscannellose sodium, about 1.1 mg colloidal silicon dioxide, and about 1.1 mg sodium stearyl fumarate.

31. Tire pharmaceutical composition, formulation, and unit dosage form of any one of claims 1-13, comprising: i) intragranularly: about 65.5 mg Compound A L-malate monohydrate, about 17.7 mg microcrystalline cellulose, about 13.3 mg talc, about 16.0 mg croscarmellose sodium, about 1.0 mg colloidal silicon dioxide, and about 2.0 mg sodium stearyl fumarate; and ii) extragranularly: about 13.3 mg microcrystalline cellulose, about 3.1 mg croscarmellose sodium, about 0.7 mg colloidal silicon dioxide, and about 0.7 mg sodium stearyl fumarate.

32. The pharmaceutical composition, fonnulation, and unit dosage fonn of any one of claims 1-13, comprising: i) intragranularly: about 196.6 mg Compound A L-malate monohydrate, about 53.1 mg microcrystalline cellulose, about 40.0 mg talc, about 48.0 mg croscarmellose sodium, about 3.0 mg colloidal silicon dioxide, and about 6.0 mg sodium stearyl fumarate; and ii) extragranularly: about 40.0 mg microcrystalline cellulose, about 9.3 mg croscannellose sodium, about 2.0 mg colloidal silicon dioxide, and about 2.0 mg sodium stearyl fumarate.

33. A method of treating an HPK1 -mediated disorder, disease, or condition in a patient comprising administering to said patient a pharmaceutical composition, formulation, or unit dosage form of any one of claims 1-32.

34. The method of claim 33, wherein the HPKl-mediated disorder, disease, or condition is a cancer.

35. The method of claim 34, wherein the cancer is selected from a leukemia, lymphoma, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast33355712 1 Page 110 of 113 398110-93HPWO (217136)cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer.

36. A method of producing a pharmaceutical composition, formulation, or unit dosage form, the method comprising dry granulating of a mixture comprising:(a) Compound A:or a solvate or pharmaceutically acceptable salt thereof;(b) one or more filler;(c) one or more anti-adherent;(d) one or more disintegrant;(e) one or more glidant; and(f) one or more lubricant.

37. The method of claim 36, wherein the method further comprises blending the dry granulation mixture with a mixture comprising:(b) one or more filler;(c) one or more disintegrant;(d) one or more glidant; and(c) one or more lubricant.

38. The method of claim 37, wherein the method further comprises encapsulating the blended mixture.

39. The method of any one of claims 36-38, comprising Compound A L-malate monohydrate.33355712 1 Page 111 of 113 398110-93HPWO (217136)40. The method of any one of claims 36-39, wherein: the filler comprises microcrystalline cellulose; the anti-adherent comprises talc; the disintegrant comprises croscarmellose sodium; the glidant comprises colloidal silicon dioxide; and the lubricant comprises sodium stearyl fumarate.33355712 1 Page 112 of 113 398110-93HPWO (217136)

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