TYK2 inhibitor formulation and method for producing same

Abstract

Pharmaceutical compositions and unit dosage forms comprising TYK2 inhibitors are provided, as well as methods of making same. Methods of treatment may include administering same to a patient.

Description

[Technical field]

[0001] Claiming priority This application claims priority from U.S. Provisional Patent Application No. 63 / 269,945, filed March 25, 2022, which is incorporated by reference in its entirety.

[0002] Technical Field The present invention relates to pharmaceutical compositions of tyrosine protein kinase 2 (TYK2) inhibitors and methods of making said compositions. The present invention also provides methods of treating disorders using said pharmaceutical compositions. [Background technology]

[0003] Protein kinases constitute a large family of structurally related enzymes responsible for the control of various signaling processes within cells. Protein kinases are thought to have evolved from a common ancestral gene because their structure and catalytic function are conserved. Almost all kinases contain a similar 250-300 amino acid catalytic domain. Kinases can be classified into families according to the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.).

[0004] In general, protein kinases mediate intracellular signaling by effecting phosphoryl transfer from a nucleoside triphosphate to a protein acceptor involved in a signaling pathway. These phosphorylation events act as molecular on / off switches that can modulate or regulate the biological function of the target protein. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H2O2), cytokines (e.g., interleukin-1 (IL-1), interleukin-8 (IL-8), and tumor necrosis factor a (TNF-a)), and growth factors (e.g., granulocyte macrophage colony stimulating factor (GM-CSF), and fibroblast growth factor (FGF)). Extracellular stimuli can affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.

[0005] Many diseases are associated with abnormal cellular responses triggered by kinase-mediated events, including, but not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases.

[0006] TYK2 catalyzes the phosphorylation of STAT proteins downstream of several cytokine receptors, including type I interferon receptors and IL-12 and IL-23 receptors. Activation of TYK2-dependent receptors by their cytokine ligands activates STAT-dependent transcriptional and cellular functional responses specific to the receptor and the cell type in which they are expressed. Cytokine signaling pathways regulated by TYK2 play important roles in several immune-mediated disorders. The cytokine IL-12 is essential for the development of type 1 T helper cells (Th1), which produce interferon-gamma, the main effector molecule of systemic autoimmune disorders such as systemic lupus erythematosus. The cytokine IL-23 is essential for the expansion and survival of Th17 cells and innate lymphoid cells, both of which have been shown to play important pathogenic roles in autoimmunity. IL-23 stimulation drives the production of important proinflammatory cytokines by Th17 cells, including IL-17A, IL-17F, and IL-22, all of which are important effector molecules in the pathogenesis of conditions such as psoriasis, psoriatic arthritis, and spondyloarthritis. Inhibition of TYK2 is predicted to impact multiple immune-mediated disorders through its effects on the IL-23 / Th17 / Th22 axis, IL-12-mediated Th1 function, and modulation of diverse immune pathways and cell types by type I interferons. Summary of the Invention

[0007] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: (a) Compound 1: [ka] or a solvate or a pharma- ceutically acceptable salt thereof, (b) one or more fillers or diluents (e.g., microcrystalline cellulose); (c) one or more solubilizers (e.g., D-α-tocopherol polyethylene glycol succinate [vitamin E TPGS]), and (d) one or more binders (e.g., povidone); The present invention provides pharmaceutical compositions, formulations, and unit dosage forms comprising:

[0008] In another aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising: (a) Compound 1: [ka] or a solvate or a pharma- ceutically acceptable salt thereof, (b) one or more fillers or diluents (e.g., microcrystalline cellulose); (c) one or more solubilizing agents (e.g., D-α-tocopherol polyethylene glycol succinate [vitamin E TPGS]), and (d) one or more binders (e.g., povidone); The present invention provides a method for making a unit dosage form, comprising:

[0009] In another aspect, the pharmaceutical compositions, formulations, and unit dosage forms comprise: (a) Compound 1: [ka] or a solvate thereof, or a pharma- ceutically acceptable salt thereof, Compound 1 is in the form of a spray-dried dispersion (SDD).

[0010] In some embodiments, the SDD may comprise a cellulosic polymer such as hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methylcellulose acetate succinate, hydroxyethyl methylcellulose acetate succinate, or carboxymethyl ethylcellulose. In some embodiments, the SDD may comprise a cellulosic polymer that is at least partially ionized at physiologically relevant pH, such as hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, or carboxymethyl ethylcellulose. In some embodiments, the SDD may comprise hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the SDD may comprise HPMC-AS-M (hydroxypropyl methylcellulose acetate succinate, grade M; also known as hypromellose acetate succinate).

[0011] In some embodiments, the SDD can be a spray dried mixture of Compound 1 and HPMC-AS-M at about 2:1 to about 1:2 (w / w).

[0012] In some embodiments, the pharmaceutical composition, formulation, or unit dosage form comprises: a) about 1-4 mg of Compound 1, or a solvate or pharma- ceutically acceptable salt thereof, optionally as an SDD, such as one of those described herein; b) about 35-140 mg of a first filler, such as mannitol; c) optionally about 35-140 mg of a second filler, such as microcrystalline cellulose; d) about 4-18 mg of a disintegrant, such as croscarmellose sodium; e) about 0.5 to 3.0 mg of a glidant, such as colloidal silicon dioxide; f) about 0.4 to 2.0 mg of a lubricant, such as sodium stearyl fumarate, and g) optionally, about 0.5-2 mg of a wetting agent, such as sodium lauryl sulfate; may include.

[0013] In some embodiments, the pharmaceutical composition, formulation, or unit dosage form comprises: a) about 2.5-10 mg of Compound 1, or a solvate or pharma- ceutically acceptable salt thereof, optionally as an SDD, such as one of those described herein; b) about 30-130 mg of a first filler, such as mannitol; c) optionally about 30-130 mg of a second filler, such as microcrystalline cellulose; d) about 4-20 mg of a disintegrant, such as croscarmellose sodium; e) about 0.5 to 4.0 mg of a glidant, such as colloidal silicon dioxide; f) optionally, about 0.5-4.0 mg of a wetting agent, such as sodium lauryl sulfate, and g) about 0.4 to 2.5 mg of a lubricant such as sodium stearyl fumarate may include.

[0014] In some embodiments, the pharmaceutical composition, formulation, or unit dosage form comprises: a) about 7.5-30 mg of Compound 1, or a solvate or pharma- ceutically acceptable salt thereof, optionally as an SDD, such as one of those described herein; b) about 25-130 mg of a first filler, such as mannitol; c) optionally about 25-130 mg of a second filler, such as microcrystalline cellulose; d) about 4-20 mg of a disintegrant, such as croscarmellose sodium; e) about 0.5 to 4.0 mg of a glidant, such as colloidal silicon dioxide; f) optionally, about 0.5-4.0 mg of a wetting agent, such as sodium lauryl sulfate, and g) about 0.4 to 4.0 mg of a lubricant such as sodium stearyl fumarate may include.

[0015] In some embodiments, the pharmaceutical composition, formulation, or unit dosage form comprises: a) about 12.5-50 mg of Compound 1, or a solvate or pharma- ceutically acceptable salt thereof, optionally as an SDD, such as one of those described herein; b) about 20-95 mg of a first filler, such as mannitol; c) optionally, about 20-95 mg of a second filler, such as microcrystalline cellulose; d) about 4-20 mg of a disintegrant, such as croscarmellose sodium; e) about 0.5 to 4.0 mg of a glidant, such as colloidal silicon dioxide; f) optionally, about 0.5-4.0 mg of a wetting agent, such as sodium lauryl sulfate, and g) about 0.4 to 4.0 mg of a lubricant such as sodium stearyl fumarate may include.

[0016] In some embodiments, the pharmaceutical composition, formulation, or unit dosage form comprises: a) about 25-75 mg of Compound 1, or a solvate or pharma- ceutically acceptable salt thereof, optionally as an SDD, such as one of those described herein; b) about 24-96 mg of a first filler, such as mannitol; c) optionally about 24-96 mg of a second filler, such as microcrystalline cellulose; d) about 6-25 mg of a disintegrant, such as croscarmellose sodium; e) about 1.0 to 5.0 mg of a glidant, such as colloidal silicon dioxide; f) optionally, about 1.0-5.0 mg of a wetting agent, such as sodium lauryl sulfate, and g) about 0.7 to 2.6 mg of a lubricant such as sodium stearyl fumarate may include.

[0017] In some embodiments, the pharmaceutical composition, formulation, or unit dosage form may comprise one of the following ingredients in the % w / w shown below. [Table 1] The spray-dried intermediate can include a spray-dried solid of Compound 1 and a cellulosic polymer, for example, Compound 1:HPMC-AS (hydroxypropyl methylcellulose acetate succinate) in a 1.5:1 to 1:1.5 w / w ratio. [Table 2] The spray-dried intermediate can include a spray-dried solid of Compound 1 and a cellulosic polymer, for example, Compound 1:HPMC-AS (hydroxypropyl methylcellulose acetate succinate) in a 1.5:1 to 1:1.5 w / w ratio. [Brief description of the drawings]

[0018] [Figure 1] 1 is a graph showing the dissolution of Compound 1 formulations in aqueous media. The "0.1N HCl" curve shows the % dissolution of a blend of crystalline Compound 1 and microcrystalline cellulose (MCC), and the other two curves show the % dissolution of crystalline Compound 1 granulations containing either 5% or 20% Vitamin E TPGS and MCC. [Diagram 2]FIG. 1 is a flow chart showing the formulation process involving wet granulation of Compound 1 with MCC (microcrystalline cellulose, diluent, Avicel PH101), Vitamin E TPGS (solubility enhancer), PVP K30 (polyvinylpyrrolidone, binder), and water. After granulation, the wet granules are dried in a fluid bed dryer to LOD≦1.5%, passed through a Comil to break down agglomerates, and blended to obtain bulk capsule fill material. Compound 1 5 mg capsules are filled using an Xcelodose system based on weight of input materials. Compound 1 25 mg capsules are filled using a Profill system based on volume. Content uniformity testing is performed after capsule filling. Both 5 mg and 25 mg strength capsules are filled into size #2 hard shell HPMC based capsules. Filled capsules are packaged in 12 counts into 60 cc HPDE bottles. [Diagram 3] 1 is a graph showing the XRPD spectrum of the Form C polymorph of Compound 1. [Figure 4] 1 is a flow chart illustrating the formulation process of a spray dried dispersion (SDD) formulation. [Diagram 5] 1 is a graph showing the XRPD spectrum of Form A of Compound 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Detailed Description Compound 1: [ka] is a TYK2 inhibitor previously disclosed by the applicant. See U.S. Patent No. 11,046,698. Solubilization of this compound is difficult and can be an obstacle when formulating the compound for administration to or treatment of a patient, for example, because solubility can affect bioavailability and therapeutic outcome. The present disclosure meets the need for solubilizing formulations of Compound 1 and provides other related advantages.

[0020] Compound 1 is an oral, allosteric, and selective TYK2 inhibitor being investigated for the treatment of psoriasis, psoriatic arthritis, and other inflammatory and autoimmune diseases. Currently, there are no approved TYK2 inhibitors, and this compound is the most selective of the TYK2 inhibitors currently in clinical development. Furthermore, the selectivity of Compound 1, plus the possibility of higher levels of TYK2 inhibition over longer periods with once-daily (QD) dosing, may provide clinical and eventual commercial advantages over other TYK2 inhibitors in development. TYK2 is a member of the Janus kinase (JAK) family of kinases, a class of intracellular signaling proteins that regulate chronic inflammation in inflammatory and autoimmune diseases. JAK inhibition can be effective in the treatment of inflammatory and autoimmune diseases, but it may also raise on-target safety issues by modulating a variety of cytokine pathways. As a result, JAK inhibitors have become an established oral treatment for a number of inflammatory and autoimmune diseases, but their clinical utility is limited by the high risk of infection and other side effects, which has led to warning panels and dose limits being mandated by the U.S. Food and Drug Administration (FDA) as part of their labeling. Due to the structural similarity between the catalytic (orthosteric or JH1) site for drug targeting on the JAK catalytic domain, and due to the specific physical properties (e.g., solubility) of JAK inhibitors such as compound 1, it is difficult to design selective JAK inhibitors in an optimized formulation for effective dissolution in vivo that directly and specifically inhibit the intended kinase function. Based on human genetic data and growing clinical evidence of the selectivity of allosteric TYK2 inhibitors, this approach to selective allosteric inhibition of TYK2 offers an optimal balance of achieving potent efficacy with the potential to avoid safety concerns associated with broader JAK inhibition for the treatment of multiple inflammatory and autoimmune diseases. Additionally, this approach to inhibitor formulation facilitates dissolution of the compounds used in treatments requiring the aforementioned drug therapy.

[0021] The formulations and methods described herein include those broadly described above, and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th In addition, the general principles of organic chemistry are specified in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry, 5th Ed. th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0022] As used herein, "Avicel® PH-101" refers to a compound of formula III: [ka] where n is from about 5 to about 2,000. In some embodiments, n is from about 50 to 500.

[0023] As used herein, "PVP30" refers to a compound of formula II: [ka] where n is from about 200 to about 1000. In some embodiments, n is from about 250 to about 500.

[0024] As used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl") and has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0025] The term "lower alkyl" means C 1-4 It refers to a straight or branched chain alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0026] The term "lower haloalkyl" refers to a C substituted with one or more halogen atoms. 1-4 It refers to a straight or branched chain alkyl group.

[0027] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (Including the case of N-substituted pyrrolidinyl, etc.).

[0028] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0029] As used herein, "divalent C 1-8 (or C 1-6 The term "saturated or unsaturated, straight or branched hydrocarbon chain" refers to divalent alkylene, alkenylene, and alkynylene chains, which are straight or branched, as defined herein.

[0030] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0031] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0032] The term "halogen" means F, Cl, Br, or I.

[0033] The term "aryl", used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic or bicyclic ring systems having a total of 5-14 ring members, where at least one ring in the system is aromatic and each ring in the system contains 3-7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In some embodiments, the term "aryl", used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic and bicyclic ring systems having a total of 5-10 ring members, where at least one ring in the system is aromatic and each ring in the system contains 3-7 ring members. In certain embodiments of the compounds of the present invention, "aryl" refers to aromatic ring systems that may bear one or more substituents, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like. As used herein, the term "aryl" also includes within its scope groups in which an aromatic ring is fused to one or more non-aromatic rings, such as, for example, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0034] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, with 6, 10, or 14 electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to the carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, with the radical or point of attachment being on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0035] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably 1-4, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (such as in 3,4-dihydro-2H-pyrrolyl), NH (such as in pyrrolidinyl), or . + It may be NR (such as in the case of N-substituted pyrrolidinyl).

[0036] The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom to provide a stable structure, and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by heterocyclyl, where the alkyl and heterocyclyl moieties independently are optionally substituted.

[0037] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0038] As described herein, the compounds of the present disclosure may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in a given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. The combinations of substituents envisioned for the compounds herein are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is substantially unchanged when subjected to conditions that allow for the production, detection, and, in certain embodiments, recovery, purification, and use of the compound for one or more purposes disclosed herein.

[0039] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen, -(CH) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0-4 SR°; optionally substituted with R° -(CH2) 0-4 Ph; optionally substituted with R° -(CH2) 0-4 O(CH2) 0-1 Ph; optionally substituted with R° -CH=CHPh; optionally substituted with R° -(CH2) 0-4 O(CH2)0-1 -Pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR-, SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°, -(CH2) 0-4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;SiR°3;-(C 1-4 Linear or branched alkylene)ON(R°)2; or -(C 1-4 linear or branched alkylene)C(O)ON(R°), where each R° may be optionally substituted as defined below and independently represents hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definitions, two independent occurrences of R° together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which may be substituted as defined below.

[0040] Suitable monovalent substituents on R° (or the ring formed by two independent occurrences of R° taken together with their intervening atoms) are independently halogen, -(CH2), 0-2 R ● , -(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 S.R. ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens; and C 1-4Aliphatic, -CH2Ph, -O(CH2) 0-1 and a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0041] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S-, wherein R * Each independent occurrence of is hydrogen, optionally substituted as defined below C 1-6 The "optionally substituted" group is selected from the group consisting of an aliphatic group, an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Preferred divalent substituents attached to a substitutable vicinal carbon of an "optionally substituted" group include -O(CR * 2) 2-3 O-, wherein R * Each independent occurrence of is hydrogen, optionally substituted as defined below C 1-6 It is selected from aliphatic and unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0042] R * Suitable substituents on the aliphatic group include halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR● , -NR ● 2, or -NO2, wherein each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0043] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † In the formula, each R † are independently hydrogen, C which may be substituted as defined below 1-6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or, notwithstanding the above definitions, two R † independent occurrences of are taken together with their intervening atom(s) to form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0044] R † Suitable substituents on the aliphatic groups are independently halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ●), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0045] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and 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, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic 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 pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxybenzoate, and the like. -ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts.

[0046] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+ (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate.

[0047] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0048] 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 between 9.9 and 10.1 (10±0.1).

[0049] The present disclosure includes embodiments that are defined as "comprising" an item. The present disclosure also contemplates similar embodiments that "consist essentially of" or "consist of" the item.

[0050] As used herein, "nominal particle size" refers to the particle size that represents the mass average of the particles.

[0051] As used herein, "loose bulk density" refers to the mass per unit volume of loose powder.

[0052] As used herein, "solubilizer" may refer to one or more compounds added to a formulation to increase its solubility in a given solvent system (e.g., water, organic solvents, biological fluids, simulated biological fluids, and mixtures thereof).

[0053] As used herein, "binder" may refer to one or more compounds that promote cohesion between other ingredients in a formulation; binders are also called adhesives and help mix other ingredients in a formulation together. Tablet binders may help turn powders into granules. This may be accomplished during the process of granulation.

[0054] As used herein, "surfactant" may refer to one or more compounds that reduce the surface tension between two liquids, between a gas and a liquid, or between a liquid and a solid. Surfactants may function as detergents, wetting agents, emulsifiers, foaming agents, or dispersing agents.

[0055] As used herein, a "glidant" is an additive substance used to improve the flow of a powder by reducing interparticle friction, surface charge, and cohesion, thereby decreasing the angle of repose. They are often incorporated as a dry powder just prior to direct compression.

[0056] As used herein, "granulation" refers to the process of producing larger or smaller granules or particles of a substance or mixture of substances. This process may also remove fine granules and improve flowability within the formulation. Both wet granulation and / or dry granulation may be used. Dry granulation is accomplished using only a combination of granules without the need for liquid thereon. Slugging uses a tablet press to form large tablets of variable weight due to the poor flowability of the formulation. The resulting slugs are then passed through a granulator to break them into granules, which are then compressed again to obtain the final granular product.

[0057] This process may include roller compaction, where the formulation is fed through a roller compactor, the mixture is fed through a top hopper, and two rollers compress the powder to form a ribbon, which then passes through a granulator, where the powder is pressed through a mesh to create granules of the desired size. In some embodiments, the granules have an average particle size of about 0.01 mm to about 10 mm. In some embodiments, the granules have an average particle size of about 0.2 mm to about 0.4 mm.

[0058] Wet granulation can be used to facilitate particle aggregation. Adhesives, usually called binders, can be incorporated in the form of a solution or suspension in a suitable liquid.

[0059] Wet granulation may use a fluidized bed granulator, where hot air is fed into the bed to spray and levitate the granules, binding them together and forming bridges between the granules. The initial stage of wet granulation may involve spraying the granules, and the spraying rate may vary. The wetting of the powder may then begin to form liquid bridges between the granules. This process continues until granules of the required size are formed with solid bridges between the granules. Once the complete granules are ready to proceed to the drying process, the spraying process may be stopped and hot air continues to flow through the bed to dry the granules. Wet granulation may be carried out in a high shear wet granulator that is commercially available or known to those skilled in the art, for example, a wet granulator 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, the entire disclosure of which is incorporated herein by reference. With regard to the drying process, such methods and equipment for carrying it out will be known to those skilled in the art. Drying can be carried out, for example, in a fluid bed dryer 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, the entire disclosure of which is incorporated herein by reference.

[0060] Screen milling of the process materials may be used, for example after drying. Screen milling procedures and equipment are well known to those skilled in the art, as described, for example, in Kotamarthy, LVG, (2018). “Understanding the effect of granulation and mill process parameters on granule critical quality attributes,” [Master's dissertation, Rutgers University]. Rutger's Library, the disclosure of which is incorporated herein by reference in its entirety.

[0061] "Blending" as used herein refers to techniques for blending solid materials that are well known to those skilled in the art. Such techniques and blending machines are described in the art, for example, in 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; Harnby 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 Stiess M. "Mechanische Verfahrenstechnik-Partikeltechnologie 1." 3rd ed. Berlin: Springer; 2009, the entire disclosures of each of which are incorporated herein by reference in their entirety.

[0062] Other granulation methods are known to those of 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 Pharm 1995;118:257-263, Selmeczi B. "The influence of the compressional force on the physical properties of tablets made by different technological processes." Arch Pharm(Weinheim) 1974;307(10):755-760, and Beg et al., 2021, "Handbook of Analytical Quality by Design," Elsevier Inc., the entire disclosures of each of which are incorporated herein by reference in their entirety.

[0063] As used herein, "disintegration" refers to the process of passing a powder formulation through a mesh screen. The screens used herein for processes such as blending or disintegration can have a mesh size of about 1 to about 100 μm, about 100 to about 500 μm, about 500 to about 1,000 μm, about 1,000 to about 5,000 μm, about 5,000 μm to about 10,000 μm, about 10,000 to about 50,000 μm, or about 50,000 to about 100,000 μm.

[0064] In one aspect, the disclosure provides pharmaceutical compositions, formulations, and unit dosage forms, which comprise: (a) Compound 1: [ka] or a solvate thereof, or a pharma- ceutically acceptable salt thereof; (b) one or more fillers or diluents; (c) one or more solubilizing agents; (d) one or more binders; (e) optionally, one or more glidants; (f) optionally, one or more lubricants; and (g) optionally, one or more surfactants may include.

[0065] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: (a) Compound 1: [ka] or a solvate thereof, or a pharma- ceutically acceptable salt thereof; (b) one or more fillers or diluents; (c) one or more solubilizing agents, and (d) one or more binders The present invention provides pharmaceutical compositions, formulations, and unit dosage forms comprising:

[0066] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: (a) Compound 1: [ka] or a solvate thereof, or a pharma- ceutically acceptable salt thereof; (b) one or more fillers or diluents; (c) one or more solubilizing agents, and (d) one or more binders The present invention provides pharmaceutical compositions, formulations, and unit dosage forms consisting essentially of:

[0067] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: (a) Compound 1: [ka] or a solvate thereof, or a pharma- ceutically acceptable salt thereof; (b) one or more fillers or diluents; (c) one or more solubilizing agents, and (d) one or more binders The present invention provides pharmaceutical compositions, formulations, and unit dosage forms comprising:

[0068] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: (a) Compound 1: [ka] or a solvate thereof, or a pharma- ceutically acceptable salt thereof; (b) one or more fillers or diluents; (c) one or more of formula I: [ka] or a pharma- ceutically acceptable salt thereof, 1 is selected from an optionally substituted aliphatic group having a mass of about 100 Da to about 500 Da, about 500 Da to about 1,000 Da, about 1,000 Da to about 2,000 Da, about 2,000 Da to about 5,000 Da, about 5,000 Da to about 10,000 Da, about 10,000 Da to about 20,000 Da, about 20,000 Da to about 50,000 Da, or about 50,000 Da to about 100,000 Da; and (d) one or more binders The present invention provides pharmaceutical compositions, formulations, and unit dosage forms comprising:

[0069] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: (a) Compound 1: [ka] or a solvate thereof, or a pharma- ceutically acceptable salt thereof; (b) one or more fillers or diluents; (c) one or more formula IA: [ka] or a pharma- ceutically acceptable salt thereof (wherein n is about 10 to about 50, about 50 to about 100, about 100 to about 200, about 200 to about 500, about 500 to about 1,000, about 1,000 to about 2,000, about 2,000 to about 5,000, or about 5,000 to about 10,000; in some embodiments, n is about 1,000); and (d) one or more binders The present invention provides pharmaceutical compositions, formulations, and unit dosage forms comprising:

[0070] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: (a) Compound 1: [ka] or a solvate thereof, or a pharma- ceutically acceptable salt thereof; (b) one or more fillers or diluents; (c) Vitamin E TPGS, and (d) one or more binders The present invention provides pharmaceutical compositions, formulations, and unit dosage forms comprising:

[0071] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: (a) Compound 1: [ka] (b) one or more fillers or diluents; (c) one or more solubilizing agents, and (d) one or more binders The present invention provides pharmaceutical compositions, formulations, and unit dosage forms comprising:

[0072] In some embodiments, the diluent is selected from microcrystalline cellulose, sucrose, lactose, starch, magnesium stearate, sorbitol, xylitol, and mannitol.

[0073] In some embodiments, compound 1 is in the form of a solvate, for example a hydrate, or a pharma- ceutically acceptable salt of such a solvate. In some embodiments, compound 1 is in the form of a free base. In some embodiments, compound 1 is in the form of a crystalline solid. In some embodiments, the crystalline solid is Form C.

[0074] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: (a) Compound 1: [ka] (b) one or more fillers or diluents; (c) Vitamin E TPGS, and (d) one or more binders The present invention provides pharmaceutical compositions, formulations, and unit dosage forms comprising:

[0075] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: (a) Compound 1: [ka] (b) microcrystalline cellulose, (c) Vitamin E TPGS, and (d) one or more binders The present invention provides pharmaceutical compositions, formulations, and unit dosage forms comprising:

[0076] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: (a) Compound 1: [ka] (b) Avicel PH101, (c) Vitamin E TPGS, and (d) one or more binders The present invention provides pharmaceutical compositions, formulations, and unit dosage forms comprising:

[0077] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: (a) Compound 1: [ka] (b) microcrystalline cellulose, (c) Vitamin E TPGS, and (d) Povidone The present invention provides pharmaceutical compositions, formulations, and unit dosage forms comprising:

[0078] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: (a) Compound 1: [ka] (b) Avicel PH101, (c) Vitamin E TPGS, and (d) PVP K30 The present invention provides pharmaceutical compositions, formulations, and unit dosage forms comprising:

[0079] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: (a) Compound 1: [ka] (b) Avicel PH101, (c) Vitamin E TPGS, and (d) PVP K30 The present invention provides pharmaceutical compositions, formulations, and unit dosage forms consisting essentially of:

[0080] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: (a) Compound 1: [ka] (b) Avicel PH101, (c) Vitamin E TPGS, and (d) PVP K30 The present invention provides pharmaceutical compositions, formulations, and unit dosage forms comprising:

[0081] In some embodiments, the solubilizer is selected from vitamin E conjugates. In some embodiments, the solubilizer is one or more of Formula I: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is selected from optionally substituted aliphatic groups having a mass of from about 100 Da to about 500 Da, from about 500 Da to about 1,000 Da, from about 1,000 Da to about 2,000 Da, from about 2,000 Da to about 5,000 Da, from about 5,000 Da to about 10,000 Da, from about 10,000 Da to about 20,000 Da, from about 20,000 Da to about 50,000 Da, or from about 50,000 Da to about 100,000 Da.

[0082] In some embodiments, the solubilizer comprises one or more of formula IA: [ka] or a pharma- ceutically acceptable salt thereof, wherein n is about 10 to about 50, about 50 to about 100, about 100 to about 200, about 200 to about 500, about 500 to about 1,000, about 1,000 to about 2,000, about 2,000 to about 5,000, or about 5,000 to about 10,000. In some embodiments, n is about 1 to about 5, about 5 to about 10, about 10 to about 20, about 20 to about 50, about 50 to about 100, about 100 to about 200, about 200 to about 500, or about 500 to about 1,000. In some embodiments, n is about 88. In some embodiments, n is about 100. In some embodiments, n is about 1,000. In some embodiments, the solubilizer may include Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS).

[0083] In another aspect, the pharmaceutical compositions, formulations, and unit dosage forms comprise: (a) Compound 1: [ka] or a solvate thereof, or a pharma- ceutically acceptable salt thereof, Compound 1 is in the form of a spray dried dispersion (SDD).

[0084] In some embodiments, the SDD may comprise a cellulosic polymer such as hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methylcellulose acetate succinate, hydroxyethyl methylcellulose acetate succinate, or carboxymethyl ethylcellulose. In some embodiments, the SDD may comprise a cellulosic polymer that is at least partially ionized at physiologically relevant pH, such as hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, or carboxymethyl ethylcellulose. In some embodiments, the SDD may comprise hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the SDD may comprise HPMC-AS-M (hydroxypropyl methylcellulose acetate succinate, grade M).

[0085] The SDD may include a plurality of particles. The plurality of particles may be powders or granules. The powders or granules may have an average particle size of less than 200 microns, less than 175 microns, less than 150 microns, less than 125 microns, less than 100 microns, less than 75 microns, less than 50 microns, less than 25 microns, less than 10 microns, or less than 5 microns. The powders or granules may have an average particle size of more than 1 micron, more than 3 microns, more than 5 microns, more than 10 microns, more than 15 microns, more than 20 microns, more than 25 microns, more than 30 microns, more than 35 microns, or more than 40 microns.

[0086] In some embodiments, the SDD may comprise a particular ratio of compound 1 or a solvate or pharma- ceutically acceptable salt thereof to the cellulosic polymer, for example, about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2.5:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or about 1:10 (as a w / w ratio). In some embodiments, the ratio is about 5:1 to about 1:5. In some embodiments, the ratio is about 10:1 to about 1:10, about 2.5:1 to about 1:2.5, or about 1.5:1 to about 1:1.5. In some embodiments, the ratio is about 1:1 (alternatively expressed as 50:50).

[0087] In some embodiments, the SDD can be about a 2:1 to about 1:2 (w / w) mixture of spray dried Compound 1 and HPMC-AS-M. In some embodiments, the SDD can be about a 1:1 (w / w) mixture of spray dried Compound 1 and HPMC-AS-M.

[0088] In some embodiments, the pharmaceutical composition, formulation, or unit dosage form comprises: a) about 1-4 mg of Compound 1, or a solvate or pharma- ceutically acceptable salt thereof, optionally as an SDD, such as one of those described herein; b) about 35-140 mg of a first filler, such as mannitol; c) optionally about 35-140 mg of a second filler, such as microcrystalline cellulose; d) about 4-18 mg of a disintegrant, such as croscarmellose sodium; e) about 0.5 to 3.0 mg of a glidant, such as colloidal silicon dioxide; f) about 0.4 to 2.0 mg of a lubricant, such as sodium stearyl fumarate, and g) optionally, about 0.5-2 mg of a wetting agent, such as sodium lauryl sulfate; Includes.

[0089] In some embodiments, each of b), c), d), and f) may be distributed between a granule comprising a) and the extragranular portion of the pharmaceutical composition, formulation, or unit dosage form.

[0090] In some embodiments, the pharmaceutical composition, formulation, or unit dosage form comprises: a) about 2.5-10 mg of Compound 1, or a solvate or pharma- ceutically acceptable salt thereof, optionally as an SDD, such as one of those described herein; b) about 30-130 mg of a first filler, such as mannitol; c) optionally about 30-130 mg of a second filler, such as microcrystalline cellulose; d) about 4-20 mg of a disintegrant, such as croscarmellose sodium; e) about 0.5 to 4.0 mg of a glidant, such as colloidal silicon dioxide; f) optionally, about 0.5-4.0 mg of a wetting agent, such as sodium lauryl sulfate, and g) about 0.4 to 2.5 mg of a lubricant such as sodium stearyl fumarate Includes.

[0091] In some embodiments, each of b), c), d), and g) may be distributed between a granule comprising a) and the extragranular portion of a pharmaceutical composition, formulation, or unit dosage form.

[0092] In some embodiments, the pharmaceutical composition, formulation, or unit dosage form comprises: a) about 7.5-30 mg of Compound 1, or a solvate or pharma- ceutically acceptable salt thereof, optionally as an SDD, such as one of those described herein; b) about 25-130 mg of a first filler, such as mannitol; c) optionally about 25-130 mg of a second filler, such as microcrystalline cellulose; d) about 4-20 mg of a disintegrant, such as croscarmellose sodium; e) about 0.5 to 4.0 mg of a glidant, such as colloidal silicon dioxide; f) optionally, about 0.5-4.0 mg of a wetting agent, such as sodium lauryl sulfate, and g) about 0.4 to 4.0 mg of a lubricant such as sodium stearyl fumarate Includes.

[0093] In some embodiments, each of b), c), d), and g) may be distributed between a granule comprising a) and the extragranular portion of a pharmaceutical composition, formulation, or unit dosage form.

[0094] In some embodiments, the pharmaceutical composition, formulation, or unit dosage form comprises: a) about 12.5-50 mg of Compound 1, or a solvate or pharma- ceutically acceptable salt thereof, optionally as an SDD, such as one of those described herein; b) about 20-95 mg of a first filler, such as mannitol; c) optionally, about 20-95 mg of a second filler, such as microcrystalline cellulose; d) about 4-20 mg of a disintegrant, such as croscarmellose sodium; e) about 0.5 to 4.0 mg of a glidant, such as colloidal silicon dioxide; f) optionally, about 0.5-4.0 mg of a wetting agent, such as sodium lauryl sulfate, and g) about 0.4 to 4.0 mg of a lubricant such as sodium stearyl fumarate Includes.

[0095] In some embodiments, each of b), c), d), and g) may be distributed between a granule comprising a) and the extragranular portion of a pharmaceutical composition, formulation, or unit dosage form.

[0096] In some embodiments, the pharmaceutical composition, formulation, or unit dosage form comprises: a) about 25-75 mg of Compound 1, or a solvate or pharma- ceutically acceptable salt thereof, optionally as an SDD, such as one of those described herein; b) about 24-96 mg of a first filler, such as mannitol; c) optionally about 24-96 mg of a second filler, such as microcrystalline cellulose; d) about 6-25 mg of a disintegrant, such as croscarmellose sodium; e) about 1.0 to 5.0 mg of a glidant, such as colloidal silicon dioxide; f) optionally, about 1.0-5.0 mg of a wetting agent, such as sodium lauryl sulfate, and g) about 0.7 to 2.6 mg of a lubricant such as sodium stearyl fumarate Includes.

[0097] In some embodiments, each of b), c), d), and g) may be distributed between a granule comprising a) and the extragranular portion of a pharmaceutical composition, formulation, or unit dosage form.

[0098] In some embodiments, the pharmaceutical composition, formulation, or unit dosage form comprises one of the following amounts or % w / w of the ingredients as indicated below. [Table 3] The spray-dried intermediate can include a spray-dried solid of Compound 1 and a cellulosic polymer, for example, Compound 1:HPMC-AS (hydroxypropyl methylcellulose acetate succinate) in a 1.5:1 to 1:1.5 w / w ratio. [Table 4] The spray-dried intermediate can include a spray-dried solid of Compound 1 and a cellulosic polymer, for example, Compound 1:HPMC-AS (hydroxypropyl methylcellulose acetate succinate) in a 1.5:1 to 1:1.5 w / w ratio.

[0099] In some embodiments, the pharmaceutical composition, formulation, or unit dosage form comprises one of the following amounts or % w / w of the ingredients as set forth below. [Table 5] The spray-dried intermediate can include a spray-dried solid of Compound 1 and a cellulosic polymer, for example, Compound 1:HPMC-AS (hydroxypropyl methylcellulose acetate succinate) in a 1.5:1 to 1:1.5 w / w ratio. [Table 6] The spray-dried intermediate can include a spray-dried solid of Compound 1 and a cellulosic polymer, for example, Compound 1:HPMC-AS (hydroxypropyl methylcellulose acetate succinate) in a 1.5:1 to 1:1.5 w / w ratio.

[0100] In another aspect, a method for producing the above-described formulation comprises the steps of: (1) providing an SDD comprising Compound 1 or a solvate or pharma- ceutically acceptable salt thereof and a cellulosic polymer such as HPMC-AS; (2) blending the SDD with an intragranular excipient; (3) disintegrating the mixture; (4) blending the mixture; (5) dry granulating the mixture, for example using a roller compactor against a 1.00 mm screen, to produce a dry granule; (6) blending the dried granules with extragranular excipients; and (7) Optionally, filling the formulation into suitable unit containers, such as capsules. Varying amounts of intragranular and extragranular excipients can be used to produce blends that make up capsules, such as capsules of 2 mg, 5 mg, 15 mg, 25 mg, and 50 mg strengths, such that 2 mg, 5 mg, 15 mg, and 25 mg blends can fit into a size #3 HPMC capsule, and 50 mg blends can fit into a size #2 HPMC capsule.

[0101] In some embodiments, the SDD comprises: (1) providing a solution of Compound 1 or a pharma- ceutically acceptable salt thereof and HPMC-AS; (2) filtering the solution, e.g., through a 100 mesh screen; (3) spray drying the solution to produce an SDI (spray dried intermediate); (4) Optionally, drying the SDI, e.g., by secondary tray drying. It is prepared with This is how the SSD is prepared.

[0102] In some embodiments, the manufacturing process is substantially as described in the flow diagram shown in FIG.

[0103] In some embodiments, the binding agent has one or more of Formula II: [ka] or a pharma- ceutically acceptable salt thereof, where n is about 10 to about 50, about 50 to about 100, about 100 to about 200, about 200 to about 500, about 500 to about 1,000, about 1,000 to about 2,000, about 2,000 to about 5,000, or about 5,000 to about 10,000. In some embodiments, n is about 1,000. In some embodiments, the binder may have a molecular weight of about 10,000 Da to about 25,000 Da, about 25,000 to about 50,000 Da, about 50,000 Da to about 60,000 Da, or about 60,000 Da to about 70,000 Da. In some embodiments, the binder may include povidone. In some embodiments, the binder may include PVP30.

[0104] In some embodiments, the diluent may include cellulose. In some embodiments, the cellulose is microcrystalline cellulose. In some embodiments, the diluent may include Avicel® PH-101. In some embodiments, the diluent may have a nominal particle size of 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 diluent may have a nominal particle size of about 50 mm. In some embodiments, the diluent may have a moisture content of 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% w / w to about 3.5% 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 diluent may have a moisture content of about 3% w / w to about 5% w / w. In some embodiments, the diluent may have a moisture content of about 0.1 g / cm 3 ~Approx. 0.15g / cm 3 , about 0.15g / cm 3 ~about 0.2g / cm 3 , about 0.2g / cm 3 ~Approx. 0.25g / cm 3 , about 0.25g / cm 3 ~about 0.3g / cm 3 , about 0.3g / cm 3 ~Approx. 0.35g / cm 3 , about 0.35g / cm 3 ~ approx. 0.4g / cm 3 , about 0.4g / cm 3 ~Approx. 0.45g / cm 3 , or about 0.45 g / cm 3 ~about 0.5g / cm 3 In some embodiments, the diluent may have a loose bulk density of about 0.26 g / cm 3 ~Approx. 0.31g / cm 3 The powder may have a loose bulk density of 0.01 to 0.05.

[0105] In some embodiments, the microcrystalline cellulose can have an average molecular weight of from about 10,000 Da to about 25,000 Da, from about 25,000 Da to about 50,000 Da, from about 50,000 Da to about 60,000 Da, or from about 60,000 Da to about 80,000 Da.

[0106] Capsule unit dosage form In certain embodiments, the unit dosage form may include a capsule or tablet. Capsules, tablets, and other unit dosage forms are described in more detail below. As noted above, pharmaceutical compositions, formulations, and unit dosage forms include: (a) Compound 1, or a solvate thereof, or a pharma- ceutically acceptable salt thereof; (b) one or more fillers or diluents; (c) one or more solubilizing agents; (d) one or more binders; (e) optionally, one or more glidants; (f) optionally, one or more lubricants; and (g) optionally, one or more surfactants may include.

[0107] In some embodiments, the unit dosage form may comprise (a), (b), (c), (d), optionally (e), optionally (f), and optionally (g), as described above. In some embodiments, the unit dosage form comprises (a), (b), (c), and (d). In some embodiments, the unit dosage form consists essentially of (a), (b), (c), and (d). In some embodiments, the unit dosage form consists of (a), (b), (c), and (d).

[0108] In some embodiments, the unit dosage form may contain an amount of about 1 mg to about 2.5 mg, about 2.5 mg to about 5 mg, about 5 mg to about 7.5 mg, about 7.5 mg to about 10 mg, about 10 mg to about 12.5 mg, about 12.5 mg to about 15 mg, about 15 mg to about 17.5 mg, about 17.5 mg to about 20 mg, about 20 mg to about 22.5 mg, about 22.5 mg to about 25 mg, about 25 mg to about 27.5 mg, about 27.5 mg to about 30 mg, about 30 mg to about 32.5 mg, about 32.5 mg to about 35 mg, about 35 mg to about 37.5 mg, about 37.5 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of Compound 1 or a solvate or pharma- ceutically acceptable salt thereof. In some embodiments, the unit dosage form may contain an amount of about 5 mg. In some embodiments, the unit dosage form may contain an amount of about 25 mg.

[0109] In some embodiments, the unit dosage form may contain Compound 1 or a solvate or pharma- ceutically acceptable salt thereof in an amount of about 1% w / w to about 2.5% w / w, about 2.5% w / w to about 5% w / w, about 5% w / w to about 7.5% w / w, about 7.5% w / w to about 10% w / w, about 10% w / w to about 12.5% ​​w / w, about 12.5% ​​w / w to about 15% w / w, about 15% w / w to about 17.5% w / w, or about 17.5% w / w to about 20% w / w. In some embodiments, the unit dosage form may contain an amount of about 10% w / w.

[0110] In some embodiments, the unit dosage form may contain an amount of (b) of about 15 mg to about 17.5 mg, about 17.5 mg to about 20 mg, about 20 mg to about 22.5 mg, about 22.5 mg to about 25 mg, about 25 mg to about 27.5 mg, about 27.5 mg to about 30 mg, about 30 mg to about 32.5 mg, about 32.5 mg to about 35 mg, about 35 mg to about 37.5 mg, about 37.5 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 75 mg, about 75 mg to about 100 mg, about 100 mg to about 125 mg, about 125 mg to about 150 mg, about 150 mg to about 175 mg, about 175 mg to about 200 mg, or about 200 mg to about 225 mg. In some embodiments, the unit dosage form may contain (b) in an amount of about 34 mg. In some embodiments, the unit dosage form may contain (b) in an amount of about 170 mg.

[0111] In some embodiments, the unit dosage form may contain (b) in an amount of about 20% w / w to about 30% w / w, about 30% w / w to about 40% w / w, about 40% w / w to about 50% w / w, about 50% w / w to about 60% w / w, about 60% w / w to about 70% w / w, about 70% w / w to about 80% w / w, or about 80% w / w to about 90% w / w. In some embodiments, the unit dosage form contains (b) in an amount of about 68% w / w.

[0112] In some embodiments, the unit dosage form is from about 1 mg to about 2.5 mg, from about 2.5 mg to about 5 mg, from about 5 mg to about 7.5 mg, from about 7.5 mg to about 10 mg, from about 10 mg to about 12.5 mg, from about 12.5 mg to about 15 mg, from about 15 mg to about 17.5 mg, from about 17.5 mg to about 20 mg, from about 20 mg to about 22.5 mg, from about 22.5 mg to about 25 mg, from about 25 mg to about 27.5 mg, mg, about 27.5 mg to about 30 mg, about 30 mg to about 32.5 mg, about 32.5 mg to about 35 mg, about 35 mg to about 37.5 mg, about 37.5 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 75 mg, about 75 mg to about 100 mg, about 100 mg to about 125 mg, or about 125 mg to about 150 mg of (c). In some embodiments, the unit dosage form comprises an amount of (c) of about 10 mg. In some embodiments, the unit dosage form comprises an amount of (c) of about 50 mg.

[0113] In some embodiments, the unit dosage form comprises (c) in an amount of about 2% w / w to about 5% w / w, about 5% w / w to about 10% w / w, about 10% w / w to about 15% w / w, about 15% w / w to about 20% w / w, about 20% w / w to about 25% w / w, about 25% w / w to about 30% w / w, about 30% w / w to about 35% w / w, or about 35% w / w to about 40% w / w. In some embodiments, the unit dosage form comprises (c) in an amount of about 20% w / w.

[0114] In some embodiments, the unit dosage form comprises an amount of (d) from about 0.25 mg to about 0.5 mg, about 0.5 mg to about 0.75 mg, about 0.75 mg to about 1 mg, about 1 mg to about 2 mg, about 2 mg to about 3 mg, about 3 mg to about 4 mg, about 4 mg to about 5 mg, about 5 mg to about 6 mg, about 6 mg to about 7 mg, about 7 mg to about 8 mg, about 8 mg to about 9 mg, or about 9 mg to about 10 mg.

[0115] In some embodiments, the unit dosage form comprises (d) in an amount of about 0.25% w / w to about 0.5% w / w, about 0.5% w / w to about 0.75% w / w, about 0.75% w / w to about 1% w / w, about 1% w / w to about 1.25% w / w, about 1.25% w / w to about 1.5% w / w, about 1.5% w / w to about 1.75% w / w, about 1.75% 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% w / w to about 3.5% w / w, or about 3.5% w / w to about 4% w / w. In some embodiments, the unit dosage form comprises (d) in an amount of about 2% w / w.

[0116] In some embodiments, the unit dosage form comprises: (a) about 2.5 mg to about 7.5 mg, (b) about 17mg to about 51mg, (c) about 5 mg to about 15 mg, and (d) About 0.5mg to about 1.5mg The present invention includes amounts of (a), (b), (c), and (d).

[0117] In some embodiments, the unit dosage form comprises: (a) about 5 mg, (b) Approximately 34 mg, (c) about 10 mg, and (d) Approximately 1 mg The present invention includes amounts of (a), (b), (c), and (d).

[0118] In some embodiments, the unit dosage form comprises: (a) Approximately 12.5 mg to approximately 37.5 mg, (b) about 85mg to about 255mg, (c) about 25 mg to about 75 mg, and (d) About 2.5mg to about 7.5mg The present invention includes amounts of (a), (b), (c), and (d).

[0119] In some embodiments, the unit dosage form comprises: (a) Approximately 25 mg, (b) Approximately 170 mg, (c) about 50 mg, and (d) Approximately 5mg The present invention includes amounts of (a), (b), (c), and (d).

[0120] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of any of the embodiments herein can include granules, and the pharmaceutical composition, formulation, or unit dosage form can include intragranular and extragranular components, such as: a) about 4 mg of an intragranular spray dried 50:50 (w / w) mixture of Compound 1 and HPMC-AS-M (hydroxypropyl methylcellulose acetate succinate, grade M); b) about 69.3 mg of intragranular mannitol; c) about 69.3 mg of intragranular microcrystalline cellulose; d) about 9 mg of intragranular croscarmellose sodium; e) about 1.8 mg of intragranular colloidal silicon dioxide; f) about 0.9 mg intragranular sodium stearyl fumarate; g) about 16.2 mg extragranular microcrystalline cellulose; h) about 9 mg of extragranular croscarmellose sodium, and i) About 0.5 mg extragranular sodium stearyl fumarate.

[0121] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of any of the embodiments herein can include granules, and the pharmaceutical composition, formulation, or unit dosage form can include intragranular and extragranular components, such as: a) about 10 mg of an intragranular spray dried 50:50 (w / w) mixture of Compound 1 and HPMC-AS-M (hydroxypropyl methylcellulose acetate succinate, grade M); b) about 65.6 mg of intragranular mannitol; c) about 65.6 mg of intragranular microcrystalline cellulose; d) about 9 mg of intragranular croscarmellose sodium; e) about 1.8 mg of intragranular colloidal silicon dioxide; f) about 1.8 mg of intragranular sodium lauryl sulfate; g) about 0.9 mg of intragranular sodium stearyl fumarate; h) about 16.2 mg extragranular microcrystalline cellulose; i) about 8.7 mg of extragranular croscarmellose sodium, and j) About 0.5 mg extragranular sodium stearyl fumarate.

[0122] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of any of the embodiments herein can include granules, and the pharmaceutical composition, formulation, or unit dosage form can include intragranular and extragranular components, such as: a) about 30 mg of an intragranular spray dried 50:50 (w / w) mixture of Compound 1 and HPMC-AS-M (hydroxypropyl methylcellulose acetate succinate, grade M); b) about 56.46 mg of intragranular mannitol; c) about 56.46 mg of intragranular microcrystalline cellulose; d) about 9 mg of intragranular croscarmellose sodium; e) about 1.8 mg of intragranular colloidal silicon dioxide; f) about 0.9 mg intragranular sodium stearyl fumarate; g) about 5 mg extragranular microcrystalline cellulose; h) about 8 mg of extragranular croscarmellose sodium, and i) About 0.38 mg extragranular sodium stearyl fumarate.

[0123] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of any of the embodiments herein can include granules, and the pharmaceutical composition, formulation, or unit dosage form can include intragranular and extragranular components, such as: a) about 50 mg of an intragranular spray dried 50:50 (w / w) mixture of Compound 1 and HPMC-AS-M (hydroxypropyl methylcellulose acetate succinate, grade M); b) about 45.6 mg of intragranular mannitol; c) about 45.6 mg of intragranular microcrystalline cellulose; d) about 9 mg of intragranular croscarmellose sodium; e) about 1.8 mg of intragranular colloidal silicon dioxide; f) about 1.8 mg of intragranular sodium lauryl sulfate; g) about 0.9 mg of intragranular sodium stearyl fumarate; h) about 16.2 mg extragranular microcrystalline cellulose; i) about 8.7 mg of extragranular croscarmellose sodium, and j) About 0.5 mg extragranular sodium stearyl fumarate.

[0124] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form of any of the embodiments herein can include granules, and the pharmaceutical composition, formulation, or unit dosage form can include intragranular and extragranular components, such as: a) about 100 mg of an intragranular spray dried 50:50 (w / w) mixture of Compound 1 and HPMC-AS-M (hydroxypropyl methylcellulose acetate succinate, grade M); b) about 48 mg of intragranular mannitol; c) about 48 mg of intragranular microcrystalline cellulose; d) about 12.5 mg of intragranular croscarmellose sodium; e) about 2.5 mg intragranular colloidal silicon dioxide; f) about 2.5 mg of intragranular sodium lauryl sulfate; g) about 1.3 mg of intragranular sodium stearyl fumarate; h) about 22.5 mg extragranular microcrystalline cellulose; i) about 12.1 mg extragranular croscarmellose sodium, and j) About 0.6 mg extragranular sodium stearyl fumarate.

[0125] In some embodiments, Compound 1 may be in the form of a solvate, such as a hydrate, or a pharma- ceutically acceptable salt of such a solvate. In some embodiments, Compound 1 may be in the form of a free base. In some embodiments, Compound 1 may be in the form of a crystalline solid. In some embodiments, the crystalline solid may be Form C. In some embodiments, the crystalline solid may be Form A.

[0126] In certain embodiments, compound 1 can be a crystalline compound of polymorphic form C, characterized by exhibiting an X-ray powder diffraction (XRPD) pattern including peaks substantially as shown in Figure 3. In certain embodiments, compound 1 can be a crystalline compound of polymorphic form A, characterized by exhibiting an X-ray powder diffraction (XRPD) pattern including peaks substantially as shown in Figure 5. Any alternative solid form can be used in the formulations described herein, such as, for example, an amorphous form, a crystalline form other than form C or A, or a mixture thereof.

[0127] In certain embodiments, Compound 1 is amorphous. In some embodiments, Compound 1 may be a hydrate. In some embodiments, Compound 1 may be a monohydrate.

[0128] Production method of the drug product In one aspect, the disclosure provides a method of producing a pharmaceutical composition, formulation, or unit dosage form, the method comprising: [ka] or a solvate thereof, or a pharma- ceutically acceptable salt thereof, and one or more solubilizing agents.

[0129] In some embodiments, the method comprises: (1) Wet granulation of the mixture; and (2) Drying the mixture may include.

[0130] In some embodiments, the method comprises: (1) Wet granulation of the mixture; (2) drying the mixture; and (3) Dry-milling the mixture may include.

[0131] In some embodiments, the method comprises: (1) Wet granulation of the mixture; (2) drying the mixture; (3) dry milling the mixture; and (4) Blending the mixture may include.

[0132] In some embodiments, the method comprises: (1) Wet granulation of the mixture; (2) drying the mixture; (3) dry milling the mixture; (4) blending the mixture; and (5) Encapsulating the mixture may include.

[0133] In some embodiments, the mixture may be de-lumped prior to wet granulation.

[0134] In some embodiments, the mixture comprises: (a) Compound 1, (b) one or more diluents; (c) one or more solubilizing agents; (d) one or more binders; (e) optionally, one or more glidants; (f) optionally, one or more lubricants; and (g) optionally, one or more surfactants may include.

[0135] In some embodiments, the mixture comprises: (a) Compound 1, (b) one or more diluents; (c) one or more solubilizing agents, and (d) one or more binders may include.

[0136] In some embodiments, the mixture comprises: (a) Compound 1, (b) one or more diluents; (c) one or more of formula I: [ka] or a pharma- ceutically acceptable salt thereof, 1 is selected from an optionally substituted aliphatic group having a mass of about 100 Da to about 500 Da, about 500 Da to about 1,000 Da, about 1,000 Da to about 2,000 Da, about 2,000 Da to about 5,000 Da, about 5,000 Da to about 10,000 Da, about 10,000 Da to about 20,000 Da, about 20,000 Da to about 50,000 Da, or about 50,000 Da to about 100,000 Da; and (d) one or more binders may include.

[0137] In some embodiments, the mixture comprises: (a) Compound 1, (b) one or more diluents; (c) one or more formula IA: [ka] or a pharma- ceutically acceptable salt thereof (wherein n is about 10 to about 50, about 50 to about 100, about 100 to about 200, about 200 to about 500, about 500 to about 1,000, about 1,000 to about 2,000, about 2,000 to about 5,000, or about 5,000 to about 10,000); (d) one or more binders may include.

[0138] In some embodiments, n is about 1 to about 5, about 5 to about 10, about 10 to about 20, about 20 to about 50, about 50 to about 100, about 100 to about 200, about 200 to about 500, or about 500 to about 1,000. In some embodiments, n is about 88. In some embodiments, n is about 100. In some embodiments, n is about 1,000.

[0139] In some embodiments, the mixture comprises: (a) Compound 1, (b) one or more diluents; (c) Vitamin E TPGS, and (d) one or more binders may include.

[0140] In some embodiments, the mixture comprises: (a) Compound 1, (b) microcrystalline cellulose, (c) Vitamin E TPGS, and (d) one or more binders Includes.

[0141] In some embodiments, the mixture comprises: (a) Compound 1, (b) one or more diluents; (c) one or more solubilizing agents, and (d) one or more binders may include.

[0142] In some embodiments, the pharmaceutical composition, formulation, or unit dosage form comprises: a) about 5% to about 15% (w / w) of Compound 1; b) about 32% to about 100% (w / w) of a diluent; c) about 10% to about 30% (w / w) of a solubilizing agent, and d) about 1% to about 3% (w / w) of a binder may include.

[0143] In some embodiments, the pharmaceutical composition, formulation, or unit dosage form comprises: a) about 10% (w / w) of Compound 1; b) about 68% (w / w) diluent; c) about 20% (w / w) of a solubilizing agent, and d) about 2% (w / w) of a binder may include.

[0144] In some embodiments, the pharmaceutical composition, formulation, or unit dosage form comprises: a) about 20% (w / w) of Compound 1; b) about 58% (w / w) diluent; c) about 20% (w / w) of a solubilizing agent, and d) about 2% (w / w) of a binder may include.

[0145] In some embodiments, the pharmaceutical composition, formulation, or unit dosage form comprises: a) about 30% (w / w) of Compound 1; b) about 48% (w / w) diluent; c) about 20% (w / w) of a solubilizing agent, and d) about 2% (w / w) of a binder may include.

[0146] In some embodiments, the pharmaceutical composition, formulation, or unit dosage form comprises: a) about 40% (w / w) of Compound 1; b) about 38% (w / w) of a diluent; c) about 20% (w / w) of a solubilizing agent, and d) about 2% (w / w) of a binder may include.

[0147] In some embodiments, the diluent can be microcrystalline cellulose, the solubilizer can be Vitamin G TPGS, and the binder can be povidone.

[0148] In some embodiments, the mixture comprises: (a) Compound 1, (b) Avicel PH101, (c) Vitamin E TPGS, and (d) one or more binders may include.

[0149] In some embodiments, the mixture comprises: (a) Compound 1, (b) microcrystalline cellulose, (c) Vitamin E TPGS, and (d) Povidone may include.

[0150] In some embodiments, the mixture comprises: (a) Compound 1, (b) Avicel PH101, (c) Vitamin E TPGS, and (d) PVP K30 may include.

[0151] In some embodiments, the mixture comprises: (a) Compound 1, (b) Avicel PH101, (c) Vitamin E TPGS, and (d) PVP K30 It essentially consists of:

[0152] In some embodiments, the mixture comprises: (a) Compound 1, (b) Avicel PH101, (c) Vitamin E TPGS, and (d) PVP K30 It consists of:

[0153] In some embodiments, the solubilizer may be selected from vitamin E conjugates. In some embodiments, the solubilizer may be one or more of Formula I: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1is selected from optionally substituted aliphatic groups having a mass of from about 100 Da to about 500 Da, from about 500 Da to about 1,000 Da, from about 1,000 Da to about 2,000 Da, from about 2,000 Da to about 5,000 Da, from about 5,000 Da to about 10,000 Da, from about 10,000 Da to about 20,000 Da, from about 20,000 Da to about 50,000 Da, or from about 50,000 Da to about 100,000 Da.

[0154] In some embodiments, the solubilizer comprises one or more of formula IA: [ka] or a pharma- ceutically acceptable salt thereof, where n is about 10 to about 50, about 50 to about 100, about 100 to about 200, about 200 to about 500, about 500 to about 1,000, about 1,000 to about 2,000, about 2,000 to about 5,000, or about 5,000 to about 10,000. In some embodiments, n is about 1,000. In some embodiments, the solubilizer may include Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS).

[0155] In some embodiments, the binding agent has one or more of Formula II: [ka] or a pharma- ceutically acceptable salt thereof, where n is about 10 to about 50, about 50 to about 100, about 100 to about 200, about 200 to about 500, about 500 to about 1,000, about 1,000 to about 2,000, about 2,000 to about 5,000, or about 5,000 to about 10,000. In some embodiments, n is about 1,000. In some embodiments, the binder may include povidone. In some embodiments, the binder may include PVP30.

[0156] In some embodiments, the diluent may include cellulose. In some embodiments, the cellulose may be microcrystalline cellulose. In some embodiments, the diluent may include Avicel PH-101. In some embodiments, the diluent may have a nominal particle size of 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 diluent may have a nominal particle size of about 50 mm. In some embodiments, the diluent may have a moisture content of 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 diluent may have a moisture content of about 3% w / w to about 5% w / w. In some embodiments, the diluent may have a moisture content of about 0.1 g / cm 3 ~Approx. 0.15g / cm 3 , about 0.15g / cm 3 ~about 0.2g / cm 3 , about 0.2g / cm 3 ~Approx. 0.25g / cm 3 , about 0.25g / cm 3 ~about 0.3g / cm 3 , about 0.3g / cm 3 ~Approx. 0.35g / cm 3 , about 0.35g / cm 3 ~ approx. 0.4g / cm 3 , about 0.4g / cm 3 ~Approx. 0.45g / cm 3 , or about 0.45 g / cm 3 ~about 0.5g / cm 3 In some embodiments, the diluent may have a loose bulk density of about 0.26 g / cm 3 ~Approx. 0.31g / cm 3 The powder may have a loose bulk density of 0.01 to 0.05.

[0157] In certain embodiments, compound 1 has the polymorphic form C of the formula: [ka] and having an X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles substantially as shown in FIG.

[0158] In certain embodiments, Compound 1 can be amorphous. In some embodiments, Compound 1 can be a hydrate. In some embodiments, Compound 1 can be a monohydrate.

[0159] In some embodiments, Compound 1 is a racemate: [ka] or a mixture of stereoisomers, or in the form of a solvate or pharma- ceutically acceptable salt thereof.

[0160] Use of the pharmaceutical composition Compound 1 and compositions described herein are generally useful for inhibiting the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by compound 1 and methods described herein is TYK2.

[0161] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. The mammalian JAK family consists of four members: TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are essential for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors, as well as interferon type I and type III receptors, and is activated by these receptors upon cytokine binding. Cytokines involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as limitin) and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin-1, cardiotrophin-like cytokine, and LIF).Velasquez et al.,“A protein kinase in the interferon α / β signalling pathway,”Cell(1992)70:313、Stahl et al.,“Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6β receptor components,”Science(1994)263:92、Finbloom et al.,“IL-10 induces the tyrosine phosphorylation of Tyk2 and Jak1 and the differential assembly of Stat1 and Stat3 complexes in human T cells and monocytes,”J.Immunol.(1995)155:1079、Bacon et al.,“Interleukin 12(IL-12)induces tyrosine phosphorylation of Jak2 and Tyk2:differential use of Janus family kinases by IL-2 and IL-12,”J.Exp.Med.(1995)181:399、Welham et al.,“Interleukin-13 signal transduction in lymphohemopoietic cells:similarities and differences in signal transduction with interleukin-4 and insulin,”J.Biol.Chem.(1995)270:12286、Parham et al.,“A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit,IL-23R,”J.Immunol.(2002)168:5699。Activated TYK2 then begins to phosphorylate additional signaling proteins, such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

[0162] Activation of TYK2 by IL-23 has been linked to inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. Duerr et al., "A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene," Science (2006) 314:1461-1463. TYK2, as a downstream effector of IL-23, has also been implicated in psoriasis, ankylosing spondylitis, and Behcet's disease. Cho et al., “Genomics and the multifactorial nature of human auto-immune disease,” N. Engl. J. Med (2011) 365: 1612-1623; Cortes et al., “Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci,” Nat. Genet. (2013) 45(7): 730-738; Remmers et al., “Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease,” Nat. Genet. (2010) 42: 698-702. A genome-wide association study of 2,622 individuals with psoriasis identified an association between disease susceptibility and TYK2. Strange et al., “A genome-wide association study identifies a new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1,” Nat. Genet. (2010) 42:985-992. Knockout of TYK2 or inhibition of tyrphostin significantly reduces both IL-23-induced and IL-22-induced dermatitis.Ishizaki et al., “Tyk2 is a therapeutic target for psoriasis-like skin inflammation,” Intl. Immunol. (2013), doi:10.1093 / intimm / dxt062.

[0163] TYK2 is also involved in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell hyperplasia (GCH) and mucus hypersecretion are mediated by IL-13-induced TYK2 activation, which in turn activates STAT6. Zhang et al., “Docking protein Gab2 regulates mucin expression and goblet cell hyperplasia through TYK2 / STAT6 pathway,” FASEB J. (2012) 26:1-11.

[0164] Reduction of TYK2 activity leads to protection of joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis. Mechanistically, reduction of Tyk2 activity reduces T h 1 / T h 17-related cytokines and matrix metalloproteinases, as well as other important inflammatory markers. Ishizaki et al., “Tyk2 deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice,” Intl. Immunol. (2011) 23(9):575-582.

[0165] TYK2 knockout mice showed complete resistance to experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) with no infiltration of CD4 T cells in the spinal cord compared to controls, suggesting that TYK2 is essential for the development of pathogenic CD4-mediated disease in MS. Oyamada et al., “Tyrosine Kinase 2 Plays Critical Roles in the Pathogenic CD4 T Cell Responses for the Development of Experimental Autoimmune Encephalomyelitis,” J. Immunol. (2009) 183: 7539-7546. This supports previous studies that linked increased TYK2 expression to MS susceptibility. Ban et al., “Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor,” Eur J. Hum. Genet. (2009) 17: 1309-1313. Loss-of-function mutations in TYK2 lead to decreased demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders.

[0166] TYK2 is the only signaling messenger common to both IL-12 and IL-23. In mice, TYK2 knockout reduced footpad thickness induced by methylated BSA injection, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzenesulfonic acid-induced colitis.

[0167] Co-linkage and association studies of various type I IFN signaling genes and systemic lupus erythematosus (SLE, an autoimmune disorder) have shown a strong and significant correlation between loss-of-function mutations in TYK2 and reduced prevalence of SLE in affected families. Sigurdsson et al., “Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupus Erythematosus,” Am. J. Hum. Genet. (2005) 76:528-537. Genome-wide association studies of SLE affected and unaffected cohorts have shown a highly significant correlation between the TYK2 locus and SLE. Graham et al., “Association of NCF2,IKZF1,IRF8,IFIH1,and TYK2 with Systemic Lupus Erythematosus,” PLoS Genetics(2011)7(10):e1002341.

[0168] TYK2 has been shown to play a key role in maintaining tumor surveillance, and TYK2 knockout mice showed impaired cytotoxic T cell responses and accelerated tumor development. However, these effects were associated with efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors would be highly suitable for the treatment of autoimmune disorders or transplant rejection. Although other JAK family members such as JAK3 have similar roles in the immune system, TYK2 has been suggested as a superior target because it is involved in fewer and more closely related signaling pathways, thus reducing off-target effects. Simma et al. “Identification of an Indispensable Role for Tyrosine Kinase 2 in CTL-Mediated Tumour Surveillance,” Cancer Res. (2009) 69: 203-211.

[0169] However, contrary to the reduced tumor surveillance observed by Simma et al., studies in T-cell acute lymphoblastic leukemia (T-ALL) have shown that T-ALL is highly dependent on IL-10 via TYK2 through STAT1-mediated signaling to maintain cancer cell survival by upregulation of the anti-apoptotic protein BCL2. Knockdown of TYK2 reduced cell growth, but this was not the case for other JAK family members. Specific activating mutations in TYK2 that promote cancer cell survival include mutations to the FERM domain (G36D, S47N, and R425H), JH2 domain (V731I), and kinase domain (E957D and R1027H). However, it was also identified that the kinase function of TYK2 is required to increase cancer cell survival, since TYK2 enzymes characterized by kinase-dead mutations (M978Y or M978F) in addition to activating mutations (E957D) failed to transform. Sanda et al. “TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia,” Cancer Disc. (2013)3(5):564-577.

[0170] Therefore, selective inhibition of TYK2 has been suggested as a suitable target for patients with IL-10 and / or BCL2-dependent tumors, such as 70% of adult T-cell leukemia cases. Fontan et al. "Discovering What Makes STAT Signalling TYK in T-ALL," Cancer Disc. (2013) 3: 494-496.

[0171] TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid beta (Aβ) peptides. Decreased TYK2 phosphorylation of STAT3 after Aβ administration leads to reduced neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer's disease patients. Wan et al. “Tyk / STAT3 Signalling Mediates β-Amyloid-Induced Neuronal Cell Death: Implications in Alzheimer's Disease,” J.Neurosci.(2010)30(20):6873-6881.

[0172] Inhibition of the JAK-STAT signaling pathway has also been implicated in hair growth and reversal of hair loss associated with alopecia areata. Xing et al., “Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition,” Nat. Med. (2014) 20:1043-1049; Harel et al., “Pharmacologic inhibition of JAK-STAT signalling promotes hair growth,” Sci. Adv. (2015) 1(9): e1500973.

[0173] Thus, compounds that inhibit the activity of TYK2, particularly those with selectivity over JAK2, would be beneficial. Such compounds should exert pharmacological responses that successfully treat one or more of the conditions described herein without the side effects associated with inhibition of JAK2.

[0174] Although TYK2 inhibitors are known in the art, there is a continuing need to provide new inhibitors with more effective or advantageous pharmacologic properties. For example, compounds with increased activity, selectivity over other JAK kinases (particularly JAK2), and ADMET (absorption, distribution, metabolism, excretion, and / or toxicity) properties. Thus, in some embodiments, a pharmaceutical composition, formulation, or unit dosage form may include a TYK2 inhibitor compound 1 that exhibits selectivity over JAK2.

[0175] The activity of compound 1 utilized as an inhibitor of TYK2 or a mutant thereof as described herein can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine the inhibition of either the phosphorylation activity and / or subsequent functional consequences, or the ATPase activity, of activated TYK2 or a mutant thereof. An alternative in vitro assay quantifies the ability of an inhibitor to bind to TYK2. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / TYK2 complex, and determining the amount of radiolabel binding. Alternatively, inhibitor binding may be determined by performing a competition experiment in which a new inhibitor is incubated with TYK2 bound to a known radioligand. Representative in vitro and in vivo assays that are useful for assaying TYK2 inhibitors include, for example, those described and disclosed in the published literature, each of which is incorporated herein by reference in its entirety.

[0176] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression 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., taking into account symptom history and / or taking into account genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay the recurrence of symptoms.

[0177] Compound 1 is an inhibitor of TYK2 and is therefore useful for treating one or more disorders associated with the activity of TYK2 or its mutants. Thus, in certain embodiments, a method for treating a TYK2-mediated disorder may include administering to a patient in need thereof a pharmaceutical composition, formulation, or unit dosage form comprising Compound 1 or a pharma-ceutically acceptable salt or hydrate thereof, as described herein.

[0178] As used herein, the term "TYK2-mediated" disorder, disease, and / or condition refers to a disease or other deleterious condition in which TYK2 or a variant thereof is known to play a role. Accordingly, another embodiment relates to treating or reducing the severity of one or more diseases in which TYK2 or a variant thereof is known to play a role. Such TYK2-mediated disorders include, but are not limited to, autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and transplant-related disorders.

[0179] In some embodiments, methods are described herein for treating one or more disorders, selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, and a transplant-related disorder, the methods comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of a pharmaceutical composition, formulation, or unit dosage form comprising compound 1 as described herein.

[0180] In some embodiments, the disorder is an autoimmune disorder, hi some embodiments, the disorder is selected from type 1 diabetes, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0181] In some embodiments, the disorder is an inflammatory disorder, hi some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, inflammatory bowel disease.

[0182] In some embodiments, the disorder is a proliferative disorder. In some embodiments, the proliferative disorder is a hematological cancer. In some embodiments, the proliferative disorder is a leukemia. In some embodiments, the leukemia is a T-cell leukemia. In some embodiments, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disorder is polycythemia vera, myelofibrosis, or essential thrombocytosis.

[0183] In some embodiments, the disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes.

[0184] In some embodiments, the disorder is a neurological disorder, hi some embodiments, the neurological disorder is Alzheimer's disease.

[0185] In some embodiments, the proliferative disorder is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation to the FERM domain, the JH2 domain, or the kinase domain. In some embodiments, the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[0186] In some embodiments, the disorder is transplant-related, hi some embodiments, the transplant-related disorder is transplant rejection or graft-versus-host disease.

[0187] In some embodiments, the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments, the disorder is associated with type I interferon signaling. In some embodiments, the disorder is associated with IL-10 signaling. In some embodiments, the disorder is associated with IL-12 signaling. In some embodiments, the disorder is associated with IL-23 signaling.

[0188] Formulations containing Compound 1 described herein are also useful in the treatment of inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, cutaneous lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0189] Formulations containing Compound 1 described herein may also be used to treat other diseases or conditions, such as diseases or conditions that have an inflammatory component, e.g., diseases and conditions of the eye, such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose, including allergic rhinitis, and inflammatory diseases that involve an autoimmune response or have an autoimmune component or etiology, e.g., autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, true erythrocytic anemia, and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, sclerosing keratoconjunctivitis, and sclerosing keratoconjunctivitis. Dermatomyositis, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, pulmonary hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, pancreatic ulcers ... Juvenile idiopathic arthritis, cryopyrin-associated periodic syndromes, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome, including e.g. idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, rhinosinusitis, ocular allergies, silica-induced disease, COPD (damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or reduction in disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, systemic sclerosis with muscle inflammation, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes, 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, fibromyalgia, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, It may also be used to treat 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.

[0190] In some embodiments, inflammatory diseases that may be treated according to the methods described herein are selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndromes (CAPS), and osteoarthritis.

[0191] In some embodiments, the inflammatory disease that may be treated according to the methods described herein is T h 1 Vector-borne disease or T h 17-mediated disease. In some embodiments, the h The 17-mediated disease is selected from cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0192] In some embodiments, inflammatory diseases that may be treated according to the methods described herein are selected from Sjogren's syndrome, allergic disorders, osteoarthritis, ocular conditions (such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis), and diseases affecting the nose, such as allergic rhinitis.

[0193] Furthermore, the formulation may contain compound 1 as defined herein for the preparation of a medicament for the treatment of an autoimmune, inflammatory or proliferative disorder, or a disorder that frequently occurs in association with transplantation.

[0194] In some embodiments, a method of treating a disease selected from psoriasis, psoriatic arthritis, ulcerative colitis, Crohn's disease, and inflammatory bowel disease in a patient in need thereof may comprise administering to the patient a therapeutically effective amount of a pharmaceutical composition, formulation, or unit dosage form described herein. In some embodiments, the disease is psoriasis. In some embodiments, the disease is psoriatic arthritis. In some embodiments, the disease is ulcerative colitis. In some embodiments, the disease is Crohn's disease. In some embodiments, the disease is inflammatory bowel disease.

[0195] In some embodiments, administration occurs daily for a period of about 1 day to about 7 days, about 1 week to about 3 weeks, about 3 weeks to about 6 weeks, about 6 weeks to about 9 weeks, about 9 weeks to 12 weeks, about 12 weeks to about 15 weeks, or about 15 weeks to about 18 weeks.

[0196] In some embodiments, the method is for the treatment of psoriasis and / or psoriatic arthritis.

[0197] In some embodiments, a mean reduction in the Psoriasis Area Severity Index (PASI) of 25% or more is achieved. In some embodiments, a mean reduction in the Psoriasis Area Severity Index (PASI) of about 45% or more is achieved. In some embodiments, a mean reduction in the Psoriasis Area Severity Index (PASI) of about 25%-50% is achieved. In some embodiments, a mean reduction in the Psoriasis Area Severity Index (PASI) of about 50-75% is achieved. In some embodiments, a mean reduction in the Psoriasis Area Severity Index (PASI) of about 75-100% is achieved.

[0198] In some embodiments, a PGA (Physician Global Assessment) of 0, 1, or 2 is achieved. In some embodiments, a PGA (Physician Global Assessment) of 0 or 1 is achieved. In some embodiments, a PGA (Physician Global Assessment) of 0 is achieved. In some embodiments, a DLQI (Dermatology Life Quality Index) score is reduced by an amount of about 1 to about 3, about 3 to about 6, about 6 to about 9, about 9 to about 12, about 12 to about 15, about 15 to about 18, about 18 to about 21, about 21 to about 24, about 24 to about 27, or about 27 to about 30.

[0199] In some embodiments, the patient's body surface area (BSA) is reduced by about 1 to about 10, about 10 to about 20, about 20 to about 30, about 30 to about 40, about 40 to about 50, about 50 to about 60, about 60 to about 70, about 70 to about 80, about 80 to about 90, or about 90 to about 100 percentage points.

[0200] In some embodiments, a reduction in pain of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 on the numeric rating scale (NRS) is achieved.

[0201] In some embodiments, a reduction in pruritus numerical scale (NRS) of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 is achieved.

[0202] In some embodiments, about 1% to about 10%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% inhibition of IL-12 / 18-induced IFNγ production is achieved.

[0203] In some embodiments, the patient has both psoriasis and psoriatic arthritis.

[0204] In some embodiments, the patient has psoriasis but does not have psoriatic arthritis.

[0205] In some embodiments, the psoriasis is moderate to severe.

[0206] In some embodiments, the psoriatic arthritis is moderate to severe.

[0207] In some embodiments, the patient has psoriatic arthritis.

[0208] In some embodiments, the method achieves an American College of Rheumatology (ACR) response of at least 20.

[0209] Combination therapy Depending on the particular condition, or disease, being treated, additional therapeutic agents that are normally administered to treat that condition may be administered in combination with the formulations containing Compound 1 described herein. 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."

[0210] In certain embodiments, the provided combinations, or compositions thereof, are administered in combination with another therapeutic agent.

[0211] The formulations and compositions described herein may be combined with, but are not limited to, drugs to treat Alzheimer's disease, such as Aricept® and Excelon®; drugs to treat HIV, such as ritonavir; drugs to treat Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; drugs to treat multiple sclerosis (MS), such as beta interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; drugs to treat asthma, such as albuterol and Singulair®; drugs to treat schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol; corticosteroids, TNF blockers, IL-1 Anti-inflammatory agents such as RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and antiparkinsonian agents; beta blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, agents for treating cardiovascular disease, such as blockers, and statins; agents for treating liver disease, such as corticosteroids, cholestyramine, interferons, and antivirals; agents for treating blood disorders, such as corticosteroids, anti-leukemia agents, and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir), and agents for treating immune deficiency disorders, such as gamma globulins.

[0212] In certain embodiments, the combination therapy described herein, or a pharma- ceutically acceptable composition thereof, is administered in combination with a monoclonal antibody or a siRNA therapeutic agent.

[0213] These additional agents may be administered separately from the combination therapy provided as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compounds described herein as a single composition. When administered as part of a multiple dose regimen, the two active agents may be provided simultaneously, sequentially, or within a period of each other (usually within 5 hours of each other).

[0214] As used herein, the terms "combination," "in combination," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the methods described herein. For example, the combinations described herein may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form.

[0215] The amount of additional therapeutic agent present in the compositions described herein will not be greater than the amount that would normally be administered in a composition containing that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure will range from about 50% to 100% of the amount that would normally be present in a composition containing that agent as the only therapeutically active agent.

[0216] In one embodiment, the composition can include Compound 1 and one or more additional therapeutic agents. The therapeutic agents can be administered together with Compound 1, or can be administered before or after administration of Compound 1. Suitable therapeutic agents are described in more detail below. In certain embodiments, Compound 1 can 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, Compound 1 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 after the therapeutic agent.

[0217] In another embodiment, the method of treating an inflammatory disease, disorder or condition by administering a formulation to a patient in need of treatment may include Compound 1 as described herein and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biological agents, such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., 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 auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimi®), ne®), 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®), trademark) and adalimumab (Humira®), "anti-IL-1" agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Ilaris®), 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 binders such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiz®), a®), laxatives such as milk of magnesia, polyethylene glycols (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alup®), ent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), trademark), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, sodium cromoglycate (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®,Theo-24®) and aminophyllines, 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®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and etravirine (Intelence®), nucleoside reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenvir®), erase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®); entry inhibitors, e.g. For example, enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and combinations of dexamethasone (Decadron®) and lenalidomide (Revlimid®), or any combination(s) thereof.

[0218] In another embodiment, the method of treating rheumatoid arthritis comprises administering to a patient in need thereof Compound 1 and nonsteroidal 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 aurothioglucose (Solganal®), aurothiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), or the like. (Tagmark), 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. and one or more additional therapeutic agents selected from mabs (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®).

[0219] In some embodiments, a method of treating osteoarthritis may include administering to a patient in need thereof a formulation comprising Compound 1 and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and monoclonal antibodies, such as tanezumab.

[0220] In some embodiments, a method of treating cutaneous or systemic lupus erythematosus may include administering to a patient in need thereof a formulation comprising Compound 1 and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (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®).

[0221] In some embodiments, a method of treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease may include administering to a patient in need thereof a formulation comprising Compound 1 and one or more additional therapeutic agents selected from mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheal agents such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders 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 therapy, steroids, and antibiotics such as Flagyl or ciprofloxacin.

[0222] In some embodiments, the method of treating asthma comprises administering to a patient in need thereof Compound 1 and one or more of the following: 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®); anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®); inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Bec and one or more additional therapeutic agents selected from lovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, sodium cromoglycate (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such as omalizumab (Xolair®).

[0223] In some embodiments, the method of treating COPD includes administering to a patient in need thereof Compound 1 and a combination of a beta-2 agonist, such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), an anticholinergic, such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), a methylxanthine, such as theophylline (Theo-D In some embodiments, the method may include administering a formulation comprising an aminophylline, an inhaled corticosteroid such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®.

[0224] In another embodiment, a method of treating a hematological malignancy may include administering to a patient in need thereof a formulation comprising Compound 1 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.

[0225] In another embodiment, a method of treating a solid tumor may include administering to a patient in need thereof a formulation comprising Compound 1 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.

[0226] In another embodiment, a method of treating a hematological malignancy may include administering to a patient in need thereof a formulation comprising Compound 1 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 signalling in diffuse large B-cell lymphoma" Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).

[0227] In another embodiment, a method of treating diffuse large B-cell lymphoma (DLBCL) may include administering to a patient in need thereof a formulation comprising Compound 1 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.

[0228] In another embodiment, a method of treating multiple myeloma may include administering to a patient in need thereof a formulation comprising compound 1 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 combination of a SYK inhibitor and lenalidomide (Revlimid®).

[0229] In another embodiment, a method of treating or lessening the severity of a disease may comprise administering to a patient in need thereof a formulation comprising Compound 1 and a BTK inhibitor, the disease being 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-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid 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, Behçet's disease, chronic fatigue, autonomic nervous system dysfunction, membranous glomerular nephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, water Bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immune deficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplants, transfusions, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, foods, insect venom, animal hair, animal dander, dust mites, or cockroach umbrellas), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis , cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein 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, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis,Sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorders such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström hypergammaglobulinemia, 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, Mann's lymphoma, Torr cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's 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, colon cancer, pancreatic cancer, bone and joint diseases (including, but not limited to, rheumatoid arthritis, seronegative spondyloarthropathy (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), systemic sclerosis, osteoporosis, bone cancer, bone metastases), thromboembolic disorders (e.g., myocardial infarction, angina pectoris, Reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transient ischemia, peripheral arterial occlusive disorder, pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis (cholocystitus), agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs Reactions, 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 Thrombocytopenic 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, Myasthenia Gravis,Selected from Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, scleroderma, mycosis fungoides, and acute inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury).

[0230] In another embodiment, a method of treating or lessening the severity of a disease may comprise administering to a patient in need thereof a formulation comprising compound 1 and a PI3K inhibitor as described herein, wherein the disease is selected from cancer, neurodegenerative disorders, angiogenic disorders, viral diseases, autoimmune diseases, inflammatory disorders, hormone-related diseases, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver diseases, pathological immune conditions involving T cell activation, cardiovascular disorders, and CNS disorders.

[0231] In another embodiment, a method of treating or lessening the severity of a disease may comprise administering to a patient in need thereof a formulation comprising Compound 1 as described herein and a PI3K inhibitor, the disease being a 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 tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer, particularly colon cancer or Diseases including colorectal adenoma, or tumors of the head and neck, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasms, epithelial neoplasms, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also known as Hodgkin or Hodgkin's disease)), breast carcinoma, follicular carcinoma, anaplastic carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, Cowden syndrome, Lhermitte-Dudos disease, and Bannayan-Zonana syndrome, or diseases in which the PI3K / PKB pathway is aberrantly activated, intrinsic ( Asthma of any type or origin, including both non-allergic (asthma) and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma, and asthma induced after bacterial infection, chronic obstructive pulmonary, airway or lung disease (COPD, COAD or COLD), including acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic bronchitis or associated dyspnea, emphysema, and exacerbation of airway hyperresponsiveness as a result of other medications, especially other inhaled medications bronchitis of any kind or genesis, including but not limited to acute, arachidic, catarrhal, croupus, chronic or tuberculous (phthinoid) bronchitis, pneumoconiosis of any kind or genesis (an inflammatory, generally occupational, lung disease, frequently associated with airway obstruction, caused by repeated inhalation of dust, whether chronic or acute) (including, for example, aluminum lung disease, anthracosis, asbestosis, stone disease, ptilosis, siderosis, silicosis, tobacco disease and byssinosis), Löffler's syndrome, eosinophilic pneumonia,Parasitic (especially metazoan) infestations (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and vernal mosquito ulcers. eosinophilic granulomas and eosinophil-related disorders affecting the airways caused by rhinitis, diseases affecting the nose, including allergic rhinitis, and inflammatory diseases involving an autoimmune response or having an autoimmune component or etiology, such as autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, true erythrocytic anemia, and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis , scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial The disease is selected from chronic pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with or without nephrotic syndrome, including, for example, idiopathic nephrotic syndrome or minimal change nephropathy), restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and cerebral ischemia, as well as neurodegenerative diseases resulting from trauma, glutamate neurotoxicity and hypoxia.

[0232] In some embodiments, the method of treating or reducing the severity of a disease may comprise administering to a patient in need thereof a formulation comprising compound 1 and a Bcl-2 inhibitor as described herein, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. 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-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematological neoplasm, or solid tumor.

[0233] In some embodiments, a method of treating or reducing the severity of a disease may include administering to a patient in need thereof a TYK2 pseudokinase (JH2) domain binding compound and a TYK2 kinase (JH1) domain binding compound. In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In some embodiments, the JH2 domain binds to compound 1. Other suitable JH2 domain binding compounds include those described in WO2014074660A1, WO2014074661A1, WO2015089143A1, each of which is incorporated herein by reference in its entirety. Suitable JH1 domain binding compounds include those described in WO2015131080A1, each of which is incorporated herein by reference in its entirety.

[0234] The composition of Compound 1 may be administered using any amount and any route of administration effective for treating or reducing the severity of an autoimmune, inflammatory, proliferative, endocrine, neurological, or transplant-related disorder. 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 specific drug, its mode of administration, and the like. Compound 1 is preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete unit of drug appropriate for the patient being treated. However, it will be understood that the total daily usage of the compounds and compositions described herein will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for a particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound being used; the specific composition being used; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and excretion rate of the specific compound being used; the duration of treatment; drugs used in combination or simultaneously with the specific compound being used, and similar factors well known in the medical field. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0235] The pharma- ceutically acceptable compositions described herein can be administered to humans and other animals orally, rectally, parenterally, intravesically, intravaginally, intraperitoneally, topically (as powders, ointments, or drops), bucally, as oral or nasal sprays, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds described herein can be administered orally or parenterally, one or more times per day, at dosage levels of about 0.01 mg / kg to about 50 mg / kg, preferably about 0.01 mg / kg to about 5 mg / kg of subject body weight per day, to obtain the desired therapeutic effect.

[0236] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. Liquid dosage forms may contain, in addition to the active compound, inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and aromatic agents.

[0237] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution (USP), and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0238] The injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0239] To prolong the effect of Compound 1, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound therefore depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the release rate of Compound 1 can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0240] Compositions for rectal or vaginal administration are preferably suppositories which may be prepared by mixing Compound 1 with a suitable non-irritating excipient or carrier (such as cocoa butter, polyethylene glycol, or a suppository wax) which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectal or vaginal cavity to release the active compound.

[0241] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharma- ceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0242] Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0243] The active compound may also be in microencapsulated form with one or more excipients as described above. In some embodiments, a hydroxypropylmethylcellulose (HMPC) capsule encapsulates the composition or formulation described herein. In some embodiments, the capsule is a size 2 hard Swedish orange HPMC capsule. The solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. According to normal practice, such dosage forms may also contain additional substances other than the inert diluent, for example, tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0244] Dosage forms for topical or transdermal administration of formulations containing Compound 1 described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier and, if necessary, with any necessary preservatives or buffers. Ophthalmic formulations, ear drops, and eye drops are also contemplated to be within the scope of the compositions and formulations described herein. In addition, the formulations and compositions described herein can be used as transdermal patches, which have the added advantage of providing a controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0245] According to one embodiment, a method for inhibiting protein kinase activity in a biological sample may comprise contacting the biological sample with a formulation comprising compound 1 as described herein.

[0246] According to another embodiment, a method of inhibiting the activity of TYK2 or a variant thereof in a biological sample may comprise contacting the biological sample with compound 1 as described herein or a composition comprising said compound. In certain embodiments, a method of irreversibly inhibiting the activity of TYK2 or a variant thereof in a biological sample may comprise contacting the biological sample with a formulation comprising compound 1 as described herein.

[0247] In another embodiment, methods are described herein for selectively inhibiting TYK2 over one or more of JAK1, JAK2, and JAK3. In some embodiments, formulations comprising compound 1 described herein have greater than 2-fold selectivity over JAK1 / 2 / 3. In some embodiments, compounds described herein have greater than 5-fold selectivity over JAK1 / 2 / 3. In some embodiments, compounds described herein have greater than 10-fold selectivity over JAK1 / 2 / 3. In some embodiments, compounds described herein have greater than 50-fold selectivity over JAK1 / 2 / 3. In some embodiments, compounds described herein have greater than 100-fold selectivity over JAK1 / 2 / 3.

[0248] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof, biopsies or extracts thereof obtained from mammals, and blood, saliva, urine, feces, sperm, tears, or other bodily fluids or extracts thereof.

[0249] Inhibition of TYK2 (or a variant thereof) activity in a biological sample is useful for a variety of purposes known to those of skill in the art, including, but not limited to, blood transfusions, organ transplants, biological specimen storage, and biological assays.

[0250] Another embodiment relates to a method of inhibiting protein kinase activity in a patient, comprising administering to the patient a formulation comprising Compound 1 as described herein.

[0251] According to another embodiment, a method of inhibiting activity of TYK2 or a mutant thereof in a patient may comprise administering to the patient a formulation comprising compound 1 as described herein. According to certain embodiments, a method of reversibly or irreversibly inhibiting activity of one or more of TYK2 or mutants thereof in a patient may comprise administering to the patient a formulation comprising compound 1 as described herein. In other embodiments, a method of treating a disorder mediated by TYK2 or mutants thereof in a patient in need of such treatment may comprise administering to the patient a formulation comprising compound 1 as described herein. Such disorders are described in detail herein.

[0252] Depending on the particular condition, or disease, being treated, additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions described herein. 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."

[0253] The formulations comprising compound 1 described herein can also be used in combination with other therapeutic compounds. In some embodiments, the other therapeutic compounds are antiproliferative compounds. Such antiproliferative compounds include aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antitumor antimetabolites; platin compounds; compounds that target / reduce protein or lipid kinase activity and further antiangiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadorelin agonists; antiandrogens; methionine aminopeptidase inhibitors ... 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 hematological malignancies; compounds that 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 (Conforma Therapeutics); temozolomide (Temodal®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 (GlaxoSmithKline), or pentamidine / chlorpromazine (CombinatoRx); MEK inhibitors, such as ARRY142886 (Array BioPharma), AZD6244 (AstraZeneca), PD181461 (Pfizer) and leucovorin. The term "aromatase inhibitor" as used herein relates to a compound which inhibits estrogen production, for example the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.The term includes, but is not limited to, steroids, particularly atamestane, exemestane and formestane, and nonsteroids, particularly aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is commercially available under the trade name Aromasin™. Formestane is commercially available under the trade name Lentaron™. Fadrozole is commercially available under the trade name Afema™. Anastrozole is commercially available under the trade name Arimidex™. Letrozole is commercially available under the trade name Femara™ or Femar™. Aminoglutethimide is commercially available under the trade name Orimeten™. The combination of compositions or formulations described herein with a chemotherapeutic agent that is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.

[0254] The term "anti-estrogen" as used herein refers to a compound that antagonizes the effect of estrogen at the estrogen receptor level. This 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™. The combination of compositions or formulations described herein with chemotherapeutic agents that are anti-estrogen agents is particularly useful for treating estrogen receptor positive tumors, such as breast tumors.

[0255] The term "antiandrogen" as used herein relates to any substance capable of inhibiting the biological effects of androgenic hormones, including, but not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist" as used herein includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin may be administered under the trade name Zoladex™.

[0256] The term "topoisomerase I inhibitors" as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the polymeric camptothecin conjugate PNU-166148. Irinotecan can be administered in the form as it is marketed, for example, under the trademark Camptosar™. Topotecan is marketed under the trademark Hycamptin™.

[0257] The term "topoisomerase II inhibitors" as used herein includes, but is not limited to, doxorubicin (including liposomal formulations such as Caelyx™), daunorubicin, epirubicin, anthracyclines such as idarubicin and nemorubicin, the anthraquinones mitoxantrone and rosoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is commercially available under the trade name Etopophos™. Teniposide is commercially available under the trade name VM 26-Bristol. Doxorubicin is commercially available under the trade name Acriblastin™ or Adriamycin™. Epirubicin is commercially available under the trade name Farmorubicin™. Idarubicin is commercially available under the trade name Zavedos™. Mitoxantrone is commercially available under the trade name Novantron.

[0258] The term "microtubule active agent" refers to microtubule stabilizing compounds, microtubule destabilizing compounds, and microtubule 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; discodermolide; cochicine and epothilones and their derivatives. Paclitaxel is commercially available under the trade name Taxol™. Docetaxel is commercially available under the trade name Taxotere™. Vinblastine sulfate is commercially available under the trade name Vinblastin RP™. Vincristine sulfate is commercially available under the trade name Farmistin™.

[0259] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is commercially available under the trade name Cyclostin™. Ifosfamide is commercially available under the trade name Holoxan™.

[0260] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit histone deacetylase and which possess antiproliferative activity, including, but not limited to, suberoylanilide hydroxamic acid (SAHA).

[0261] The 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 folate antagonists (such as pemetrexed). Capecitabine is marketed under the trade name Xeloda™. Gemcitabine is marketed under the trade name Gemzar™.

[0262] The term "platin compounds" as used herein includes, but is not limited to, carboplatin, cisplatin, 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™.

[0263] The term "compounds targeting / reducing protein or lipid kinase activity, or 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 that target, reduce or inhibit the activity of platelet derived growth factor receptor (PDGFR), e.g. compounds that target, reduce or inhibit the activity of PDGFR, in particular compounds that inhibit the PDGF receptor, e.g. N-phenyl-2-pyrimidine-amine derivatives, e.g. imatinib, SU101, SU6668 and GFB-111; b) compounds that target, reduce or inhibit the activity of fibroblast growth factor receptor (FGFR); c) compounds that target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), e.g. compounds that inhibit the activity of IGF-IR. d) compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family or ephrinB4 inhibitors; e) compounds that target, reduce or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, reduce or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, reduce or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, reduce or inhibit the activity of the C-kit receptor tyrosine kinase, which is part of the PDGFR family, such as compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular compounds that inhibit the c-Kit receptor, such as imatinib;i) Compounds that target, reduce or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase) and mutants, such as compounds that target, reduce or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 (from ParkeDavis); or dasatinib (BMS-354825); j) compounds which target, decrease or inhibit the activity of members of the protein kinase C (PKC) and Raf families of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, BTK and TEC families, and / or members of the cyclin-dependent kinase family (CDK), including staurosporine derivatives such as midostaurin; further exemplary compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531 / LY379196; isochinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors); k) compounds that target, decrease or inhibit the activity of protein tyrosine kinase inhibitors, such as compounds that target, decrease or inhibit the activity of protein tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec™) or tyrphostin A23 / RG-50810; AG99; tyrphostin AG 213; tyrphostin AG 1748; tyrphostin AG 490; tyrphostin B44; tyrphostin B44(+) enantiomer; tyrphostin AG 555; AG 494; tyrphostin AG 556, AG957 and adahostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adahostin); l) compounds which target, reduce or inhibit the activity of the epidermal growth factor receptor tyrosine kinase family (EGFR1, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and variants thereof, for example compounds which target, reduce or inhibit the activity of the epidermal growth factor receptor family, in particular compounds which inhibit members of the EGF receptor tyrosine kinase family such as EGF receptor, ErbB2, ErbB3 and ErbB4, or which inhibit 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, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds which target, reduce or inhibit the activity of the c-Met receptor, for example compounds which target, reduce or inhibit the activity of c-Met, in particular compounds which inhibit the kinase activity of the c-Met receptor, or antibodies which target the extracellular domain of c-Met or which bind to HGF, n) PRT-062070, SB- 1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds that target, decrease, or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including but not limited to ATU-02; 7, compounds that target, decrease, or inhibit the kinase activity of PI3 kinase (PI3K), including but not limited to SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib;and q) compounds that target, decrease, or inhibit the signaling effects of the Hedgehog protein (Hh) or Smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (salidegib);

[0264] The term "PI3K inhibitor" as used herein includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes of the phosphatidylinositol-3-kinase family, including, but not limited to, PI3K α, PI3K γ, PI3K δ, PI3K β, PI3K-C2 α, PI3K-C2 β, PI3K-C2 γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors useful in the subject compositions, formulations, and methods described herein include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0265] The term "BTK inhibitor" as used herein includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0266] The term "SYK inhibitors" as used herein includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0267] The term "Bcl-2 inhibitors" 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), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0268] Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with the compounds described herein, can be found in WO2008039218 and WO2011090760, which are incorporated herein by reference in their entireties.

[0269] Further examples of SYK inhibitory compounds, and conditions treatable by such compounds in combination with the compounds described herein, can be found in WO2003063794, WO2005007623, and WO2006078846, the entireties of which are incorporated herein by reference.

[0270] Further examples of PI3K inhibitory compounds, and conditions treatable by such compounds in combination with the compounds described herein, can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729, the entireties of which are incorporated herein by reference.

[0271] Further examples of JAK inhibitory compounds and conditions treatable by such compounds in combination with the compounds described herein can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entireties of which are incorporated herein by reference.

[0272] Additional anti-angiogenic compounds include, for example, compounds that have another mechanism of their activity unrelated to protein or lipid kinase inhibition, such as thalidomide (Thalomid™) and TNP-470.

[0273] Examples of proteasome inhibitors useful for use in combination with the formulations containing Compound 1 described herein include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0274] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are, for example, inhibitors of phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid or a derivative thereof.

[0275] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-γ- or δ-tocopherol, or α-γ- or δ-tocotrienol.

[0276] The term cyclooxygenase inhibitors as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives, such as celecoxib (Celebrex™), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[0277] The term "bisphosphonate" as used herein includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etridonic acid is commercially available under the trade name Didronel™. Clodronic acid is commercially available under the trade name Bonefos™. Tiludronic acid is commercially available under the trade name Skelid™. Pamidronic acid is commercially available under the trade name Aredia™. Alendronic acid is commercially available under the trade name Fosamax™. Ibandronic acid is commercially available under the trade name Bondranat™. Risedronic acid is commercially available under the trade name Actonel™. Zoledronic acid is commercially available under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0278] As used herein, the term "heparanase inhibitor" refers to a compound that targets, reduces, or inhibits the degradation of heparin sulfate. This term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to lymphokines or interferons.

[0279] The term "inhibitor of Ras oncogenic isoforms" such as H-Ras, K-Ras or N-Ras, as used herein, refers to compounds that target, reduce or inhibit the oncogenic activity of Ras, for example, "farnesyltransferase inhibitors" such as L-744832, DK8G557 or R115777 (Zarnestra™). The term "telomerase inhibitor" as used herein refers to compounds that target, reduce or inhibit the activity of telomerase. Compounds that target, reduce or inhibit the activity of telomerase are in particular compounds that inhibit the telomerase receptor, such as telomestatin.

[0280] The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of methionine peptidase. Compounds that target, reduce or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives.

[0281] As used herein, the term "proteasome inhibitor" refers to a compound that targets, decreases, or inhibits the activity of the proteasome. Compounds that target, decrease, or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade™) and MLN 341.

[0282] The term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors) as used herein includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives, such as the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

[0283] The term "compounds used in the treatment of hematological malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuranylcytosine (ara-c) and bisulfan; ALK inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase, and Bcl-2 inhibitors.

[0284] Compounds which target, decrease or inhibit the activity of the FLT-3R-like tyrosine kinase receptor are in particular compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

[0285] The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90 and degrade, target or inhibit HSP90 client proteins via the ubiquitin proteosome pathway. Compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90 are, in particular, compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors.

[0286] The term "antiproliferative antibody" as used herein includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40), and 2C4 antibodies. By antibody is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

[0287] For the treatment of acute myeloid leukemia (AML), the compounds described herein can be used in combination with standard leukemia therapy, particularly in combination with therapy used to treat AML. In particular, the formulations containing compound 1 described herein can be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs useful for the treatment of AML, such as daunorubicin, Adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum and PKC412. In some embodiments, the method of treating AML associated with ITD and / or D835Y mutation can include administering a formulation containing compound 1 described herein together with one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitor is selected from quizartinib (AC220), staurosporine derivatives (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, fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3 inhibitor is selected from quizartinib, midostaurin, lestaurtinib, sorafenib, and sunitinib.

[0288] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue, which is a 2'-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are 6-mercaptopurine (6-MP), a purine analogue of hypoxanthine, and fludarabine phosphate. Compounds that target, decrease or inhibit the activity of histone deacetylase (HDAC) inhibitors, such as sodium butyrate and suberoylanilide hydroxanoic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), trichostatin A, and compounds disclosed in US6,552,065, including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, particularly the lactate salt. As used herein, somatostatin receptor antagonist refers to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230. A method that damages tumor cells refers to a method such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs either as electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but is not limited to, radiation therapy, which is known in the art. Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 th Edition, Vol. 1, pp. 248-275 (1993).

[0289] Also included are EDG binders and ribonucleotide reductase inhibitors. The term "EDG binders" as used herein refers to a class of immunosuppressants that modulate lymphocyte recirculation, such as FTY720. The term "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 for ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are in particular hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0290] In particular, compounds, proteins, or monoclonal antibodies of VEGF such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharma- ceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilamide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamers, such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610) and bevacizumab (Avastin™).

[0291] As used herein, photodynamic therapy refers to therapy that uses certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with compounds such as Visudyne™ and porfimer sodium.

[0292] As used herein, angiogenic antisteroids refer to compounds that block or inhibit angiogenesis, such as, for example, anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0293] Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0294] 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 mechanisms of action.

[0295] Formulations containing compound 1 as described herein are also useful as combination therapeutic compounds for use in combination with other drug substances, such as anti-inflammatory, bronchodilatory or antihistamine drug substances, for example, as enhancers of the therapeutic activity of such drugs, or as a means of reducing the required dosage or potential side effects of such drugs, particularly in the treatment of obstructive or inflammatory airway diseases as mentioned herein above. Formulations containing compound 1 as described herein may be mixed with other drug substances in a given pharmaceutical composition, or may be administered separately before, simultaneously with, or after the other drug substances. Thus, a combination formulation may include compound 1 as described herein and an anti-inflammatory, bronchodilatory, antihistamine or antitussive drug substance, and the compound as described herein and the drug substance may be in the same or different pharmaceutical compositions.

[0296] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; non-steroidal glucocorticoid receptor agonists; LTB4 antagonists such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), allofilin (Almirall). PDE4 inhibitors such as Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID™ CC-10004 (Celgene), VM554 / UM565 (Vernalis), 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 pharma- ceutically acceptable salts thereof. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.

[0297] 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.

[0298] Other useful combinations of the compounds described herein with anti-inflammatory agents include, for example, antagonists of chemokine receptors such as 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, and in particular CCR-5 antagonists such as the 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).

[0299] The structures of the active compounds, identified by code number, generic name or trade name, can be obtained from the current edition of the standard abstract "The Merck Index" or from databases such as Patents International (eg IMS World Publications).

[0300] Formulations containing compound 1 described herein may be used in combination with known therapeutic processes, such as administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for the treatment of tumors that exhibit insufficient sensitivity to radiation therapy.

[0301] The formulations comprising compound 1 as described herein can be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapies are in the form of fixed combinations, or compound 1 as formulations as described herein is administered alternately or independently of one another, or a combination of a fixed combination with one or more other therapeutic compounds. Compound 1 can be administered in addition or in combination, particularly in tumor therapy, with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof. In the context of other treatment strategies as described above, long-term therapy is equally possible, as is adjuvant therapy. Other possible treatment methods are therapy to maintain the patient's condition after tumor regression, or even chemopreventive therapy, for example in patients at risk.

[0302] These additional agents may be administered separately from the composition containing the compound of the present invention as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with Compound 1 as a single formulation or composition. When administered as part of a multiple dose regimen, the two active agents may be provided simultaneously, sequentially, or within a period of each other (usually within 5 hours of each other).

[0303] As used herein, the terms "combination," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the methods described herein. For example, Compound 1 may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together in a single unit dosage form. Thus, a single unit dosage form may include Compound 1, an additional therapeutic agent, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

[0304] The amounts of both the compounds of the invention and additional therapeutic agents (in compositions containing additional therapeutic agents as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Preferably, the compositions described herein should be formulated so that a dosage of 0.01 to 10 mg / kg body weight / day of Compound 1 or a solvate or pharma- ceutically acceptable salt thereof can be administered.

[0305] In compositions containing an additional therapeutic agent, the additional therapeutic agent and compound 1 may act synergistically. Thus, the amount of the additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions, the additional therapeutic agent may be administered at a dosage of 0.01 to 1,000 μg / kg body weight / day.

[0306] The amount of additional therapeutic agent present in a composition comprising Compound 1 will not be greater 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 a composition of the present disclosure will range from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0307] Compound 1 and its pharmaceutical compositions may be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices run the risk of clot formation or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the device with a pharma- ceutically acceptable composition comprising a kinase inhibitor. An implantable device coated with the compounds described herein is another embodiment of the compositions and formulations described herein.

[0308] In some embodiments, the medicament may include at least Compound 1 formulated as described herein.

[0309] Pharmaceutical ingredients The compositions described herein are administered using any amount and any route of administration effective for treating or reducing the severity of the above diseases. 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 specific drug, its mode of administration, and the like. Compound 1 is preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete unit of drug appropriate for the patient being treated. However, it will be understood that the total daily usage of the compounds and compositions described herein will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for a particular patient or organism (e.g., cat, dog, cow, horse, pig, or bird) will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or simultaneously with the specific compound used, and similar factors well known in the medical field.

[0310] The pharma- ceutically acceptable compositions described herein can be administered to humans and other animals orally, rectally, parenterally, intravesically, intrathecally, transdermally, transmucosally, ophthalmically, by inhalation, intravaginally, intraperitoneally, topically (as powders, ointments, or drops), bucally, intranasally, as oral or nasal sprays, etc., 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, e.g., about 1 mg / kg to about 25 mg / kg of subject body weight, one or more times per day to obtain the desired therapeutic effect.

[0311] The unit dosage forms described herein may be formulated for oral administration. Pharmaceutical compositions / formulations suitable for oral administration may be provided as individual 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 a predetermined amount of active ingredient and may be prepared by methods of pharmacy known to those skilled in the art. Remington's Pharmaceutical Sciences, 18 th ed., Mack Publishing, Easton Pa. (1990). As used herein, oral administration also includes buccal, lingual, and sublingual administration.

[0312] In some embodiments, the formulation further comprises one or more pharma- ceutically acceptable excipients or carriers.

[0313] Those of skill in the art will recognize that a pharmaceutical formulation ingredient may serve multiple purposes within a formulation, and therefore, a particular formulation ingredient may be classified according to multiple functions (e.g., an ingredient may be both a filler and a binder).

[0314] In some embodiments, the unit dosage forms provided herein are prepared according to conventional pharmaceutical compounding techniques by combining the active ingredient in an intimate mixture with one or more pharma- ceutically acceptable excipients or carriers, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye transfer inhibitors, sweeteners, flavoring agents, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and carbon dioxide sources. 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 colorants. Examples of excipients or carriers suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants.

[0315] In some embodiments, the active ingredient, such as Compound 1 or a pharma- ceutically acceptable salt thereof, is incorporated into the pharmaceutical composition as a spray-dried powder or granules. The use of spray drying to produce powders from fluid feedstocks is well known, with applications ranging from milk powder to bulk chemicals and pharmaceuticals. See U.S. Pat. No. 4,187,617 and Mujumbar et al., 91 Drying, pages 56-73 (1991). The use of spray drying to form solid amorphous dispersions of drugs and concentration-enhancing polymers is also known. See commonly owned European Patent Applications Nos. 0901786, 1027886, 1027887, 1027888, and commonly owned PCT Applications Nos. WO00 / 168092 and WO00 / 168055, each of which is incorporated herein by reference. A typical spray drying apparatus comprises a drying chamber, an atomizing means for atomizing a solvent-containing liquid fed to the drying chamber, a source of heated drying gas directed into the drying chamber, and a dried product collection means for separating the dried product from the cooled drying gas and vaporized solvent stream after it exits the drying chamber. Examples of such apparatus include Niro models PSD-1, PSD-2, and PSD-4 (Niro A / S, Soeborg, Denmark).

[0316] Spray-dried powders or granules generally contain active compounds in combination with polymers, such as concentration-enhancing polymers.One class of polymers suitable for use in the compositions and formulations described herein includes non-ionizable (neutral) non-cellulosic polymers.Exemplary polymers include vinyl polymers and copolymers having at least one substituent selected from the group consisting of hydroxyl, alkylacyloxy, and cyclic amide; polyvinyl alcohol having at least a portion of the repeating units in non-hydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinylpyrrolidone; and polyethylene polyvinyl alcohol copolymers; and polyoxyethylene-polyoxypropylene copolymers.

[0317] An exemplary neutral non-cellulosic polymer is composed of a vinyl copolymer of at least one hydrophilic, hydroxyl-containing repeat unit and at least one hydrophobic, alkyl- or aryl-containing repeat unit. Such neutral vinyl copolymers are referred to as "amphiphilic hydroxyl-functional vinyl copolymers". It is believed that amphiphilic hydroxyl-functional vinyl copolymers provide high concentration enhancement because their amphiphilicity provides both sufficient hydrophobic groups to interact with hydrophobic low-solubility drugs and sufficient hydrophilic groups to have sufficient water solubility for good dissolution. The copolymer structure of amphiphilic hydroxyl-functional vinyl copolymers also allows them to adjust their hydrophilicity and hydrophobicity to maximize the performance of certain low-solubility drugs.

[0318] Another class of polymers suitable for use in the compositions and formulations described herein includes ionizable non-cellulosic polymers.Exemplary polymers include carboxylic acid functionalized vinyl polymers, such as carboxylic acid functionalized polymethacrylates and polyacrylates, such as the EUDRAGIT™ series manufactured by Rohm Tech Inc., Malden, Mass.; amine functionalized polyacrylates and polymethacrylates; proteins, such as gelatin and albumin; and carboxylic acid functionalized starches, such as starch glycolate.

[0319] Amphiphilic non-cellulosic polymers are copolymers of relatively hydrophilic and relatively hydrophobic monomers. Examples include acrylate and methacrylate copolymers. Exemplary commercial grades of such copolymers include the EUDRAGIT™ series, which are copolymers of methacrylates and acrylates.

[0320] An additional class of polymers includes ionizable and neutral (or non-ionizable) cellulosic polymers having at least one ester-linked and / or ether-linked substituent, the polymer having a degree of substitution of at least 0.05 for each substituent. Note that in the polymer nomenclature used herein, the ether-linked substituent is described before "cellulose" as a moiety attached to an ether group. For example, "cellulose ethyl benzoate" has an ethoxybenzoic acid substituent. Similarly, the ester-linked substituent is described after "cellulose" as a carboxylate. For example, "cellulose phthalate" has one carboxylic acid of each phthalic acid moiety ester-linked to the polymer and the other carboxylic acid unreacted.

[0321] It should also be noted that a polymer name such as "cellulose acetate phthalate" (CAP) refers to any of a family of cellulosic polymers that have acetate and phthalate groups attached via ester bonds to the majority of the hydroxyl groups of the cellulosic polymer. In general, the degree of substitution of each substituent can range from 0.05 to 2.9, so long as the other criteria of the polymer are met. "Degree of substitution" refers to the average number of three hydroxyls per saccharide repeat unit on the cellulose chain that is substituted. For example, if all hydroxyls on the cellulose chain are phthalate substituted, the degree of phthalate substitution is 3. Each polymer family type also includes cellulosic polymers to which relatively small amounts of additional substituents have been added that do not substantially change the performance of the polymer.

[0322] Amphiphilic cellulose includes polymers in which the parent cellulosic polymer is substituted with at least one relatively hydrophobic substituent at any or all of the three hydroxyl groups present on each saccharide repeat unit. The hydrophobic substituent can be essentially any substituent that can render the cellulosic polymer essentially water insoluble when substituted to a sufficiently high level or degree of substitution. Examples of hydrophobic substituents include ether-linked alkyl groups such as methyl, ethyl, propyl, butyl, etc.; or ester-linked alkyl groups such as acetate, propionate, butyrate; and ether-linked and / or ester-linked aryl groups such as phenyl, benzoate, or phenylate. The hydrophilic regions of the polymer can be either the portions that are relatively unsubstituted because the unsubstituted hydroxyls themselves are relatively hydrophilic, or the regions that are substituted with hydrophilic substituents. Hydrophilic substituents include ether-linked or ester-linked non-ionizable groups, such as hydroxyalkyl substituents hydroxyethyl, hydroxypropyl, and alkyl ether groups such as ethoxyethoxy or methoxyethoxy. Particularly preferred hydrophilic substituents are those that are ether- or ester-linked ionizable groups, such as carboxylic acids, thiocarboxylic acids, substituted phenoxy groups, amines, phosphates, or sulfonates.

[0323] One class of cellulosic polymers includes neutral polymers, meaning that the polymer is substantially non-ionizable in aqueous solution. Such polymers contain non-ionizable substituents, which may be either ether- or ester-linked. Exemplary ether-linked non-ionizable substituents include alkyl groups such as methyl, ethyl, propyl, butyl, hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, and aryl groups such as phenyl. Exemplary ester-linked non-ionizable substituents include alkyl groups such as acetate, propionate, butyrate, and aryl groups such as phenylate. However, when aryl groups are included, it may be necessary for the polymer to include a sufficient amount of hydrophilic substituents so that the polymer has at least some aqueous solubility at any of the physiologically relevant pHs from 1 to 8.

[0324] Exemplary non-ionizable cellulosic polymers that can be used as the polymer include hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethyl cellulose.

[0325] An exemplary class of neutral cellulosic polymers are those that are amphiphilic, such as hydroxypropyl methylcellulose and hydroxypropyl cellulose acetate, in which cellulose repeat units having a relatively large number of methyl or acetate substituents compared to the unsubstituted hydroxyl or hydroxypropyl substituents constitute hydrophobic regions compared to other repeat units on the polymer.

[0326] A particular class of cellulosic polymers includes polymers that are at least partially ionizable at physiologically relevant pH and contain at least one ionizable substituent that can be either ether- or ester-linked.Exemplary ether-linked ionizable substituents include carboxylic acids, such as acetic acid, propionic acid, benzoic acid, salicylic acid, alkoxybenzoic acids such as ethoxybenzoic acid or propoxybenzoic acid, various isomers of alkoxyphthalic acids such as ethoxyphthalic acid and ethoxyisophthalic acid, various isomers of alkoxynicotinic acids such as ethoxynicotinic acid, and various isomers of picolinic acid such as ethoxypicolinic acid; thiocarboxylic acids such as thioacetic acid; substituted phenoxy groups such as hydroxyphenoxy; amines such as aminoethoxy, diethylaminoethoxy, trimethylaminoethoxy; phosphates such as phosphateethoxy; and sulfonates such as sulfonateethoxy. Exemplary ester-linked ionizable substituents include carboxylic acids, such as succinate, citrate, phthalate, terephthalate, isophthalate, trimellitate, and various isomers of pyridine dicarboxylic acid; thiocarboxylic acids, such as thiosuccinate; substituted phenoxy groups, such as aminosalicylic acid; amines, such as natural or synthetic amino acids, such as alanine or phenylalanine; phosphates, such as acetyl phosphate; and sulfonates, such as acetyl sulfonate.To provide the aromatic substituted polymer with the required water solubility, it is also desirable to attach sufficient hydrophilic groups, such as hydroxypropyl or carboxylic acid functional groups, to the polymer to make it water-soluble, at least at the pH value at which the ionizable group is ionized.In some cases, the aromatic substituent may itself be ionizable, such as a phthalate or trimellitate substituent.

[0327] Exemplary cellulosic polymers that are at least partially ionized at physiologically relevant pH include hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methylcellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxyethyl methylcellulose acetate succinate, hydroxyethyl methylcellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, carboxymethyl ethyl cellulose, ethyl carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methylcellulose acetate acetate succinate, hydroxypropyl methylcellulose acetate succinate cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methylcellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridine dicarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethyl benzoic acid cellulose acetate, hydroxypropyl ethyl benzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid cellulose acetate, and ethyl picolinic acid cellulose acetate.

[0328] Exemplary cellulosic polymers that meet the definition of amphiphilic, having hydrophilic and hydrophobic regions, include polymers such as cellulose acetate phthalate and cellulose acetate trimellitate, in which cellulose repeat units having one or more acetate substituents are hydrophobic relative to those having no acetate substituents or having one or more ionized phthalate or trimellitate substituents.

[0329] A further subset of cellulosic ionizable polymers are those that have both carboxylic acid functional aromatic and alkylate substituents and are therefore amphiphilic. Exemplary polymers include cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxylpropyl methyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxyl cellulose acetate trimellitate, hydroxypropyl ... cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridine dicarboxylate, cellulose acetate salicylate, hydroxypropyl salicylate cellulose acetate, ethyl benzoate cellulose acetate, hydroxypropyl ethyl benzoate cellulose acetate, ethyl phthalate cellulose acetate, ethyl nicotinate cellulose acetate, and ethyl picolinate cellulose acetate.

[0330] Another subset of ionizable cellulose-based polymers is one that has a non-aromatic carboxylate substituent. Exemplary polymers include hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methylcellulose acetate succinate, hydroxyethyl methylcellulose acetate succinate, and carboxymethyl ethylcellulose. These cellulose-based polymers that are at least partially ionized at physiologically relevant pH include, for example, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, and carboxymethyl ethylcellulose. In some embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0331] Another class of polymers consists of neutralized acidic polymers. By "neutralized acidic polymer" is meant any acidic polymer in which the majority of the "acidic moieties" or "acidic substituents" are "neutralized", i.e., present in their deprotonated form. By "neutralized acidic cellulosic polymer" is meant any cellulosic "acidic polymer" in which the majority of the "acidic moieties" or "acidic substituents" are "neutralized". By "acidic polymer" is meant any polymer having a significant number of acidic moieties. Generally, a significant number of acidic moieties is about 0.1 milliequivalents of acidic moieties per gram of polymer or more. An "acidic moiety" includes any functional group that is sufficiently acidic that, upon contact with or dissolution in water, it is capable of increasing the hydrogen ion concentration by at least partially donating hydrogen cations to the water. This definition includes any functional group or functional groups having a pK of less than about 10. aThe term "substituent" includes when a functional group is covalently attached to a polymer having the formula: Exemplary classes of functional groups included in the above description include carboxylic acids, thiocarboxylic acids, phosphates, phenolic groups, and sulfonates. Such functional groups may form the primary structure of a polymer such as polyacrylic acid, but are more commonly covalently attached to the backbone of the parent polymer and are therefore referred to as "substituents."

[0332] The amount of concentration-enhancing polymer relative to the amount of drug (compound 1) present in the spray-dried dispersion depends on the drug and the concentration-enhancing polymer, and can vary widely between drug-to-polymer weight ratios of 0.01 to 5. However, in most cases, except when the drug dose is very low, such as 25 mg or less, the drug-to-polymer ratio is typically greater than 0.05 and less than 2.5, and in many cases, improvements in drug concentration or relative bioavailability are observed at drug-to-polymer ratios of 1 or less, and even 0.2 or less for some drugs. When the drug dose is about 25 mg or less, the drug-to-polymer weight ratio can be significantly less than 0.05. In general, regardless of dose, improvements in drug concentration or relative bioavailability increase as the drug-to-polymer weight ratio decreases. However, because there are practical limits to keeping the total mass of a tablet, capsule, or suspension low, it is often desirable to use a relatively high drug-to-polymer ratio as long as satisfactory results are obtained. The maximum drug:polymer ratio that will give satisfactory results will vary from drug to drug and is best determined by dissolution testing, as described below.

[0333] The spray-dried solid described herein can be a solid dispersion containing the compound described herein and pharma-ceutically acceptable polymer.The specific compounds described herein generally have low water solubility, and their absorption in vivo is limited by dissolution rate.The solid dispersion containing the compound can improve the bioavailability of the compound by increasing the solubility / dissolution of the compound.

[0334] The term "solid dispersion" as used herein refers to a dispersion of a pharma- ceutical active ingredient, such as a compound described herein, in a solid-state inert polymer matrix. A solid dispersion can be prepared by methods well known in the art, such as spray drying or hot melt extrusion. The matrix can be crystalline or amorphous. A solid dispersion contains a co-precipitate of a pharma- ceutical active ingredient with one or more water-soluble polymers, in which the pharma- ceutical active ingredient is uniformly dispersed within the polymer matrix formed from the polymer. The pharma- ceutical active ingredient can be present in an amorphous state, a crystalline dispersion form, or a combination thereof. It can also be finely dispersed or dissolved as a single molecule in the polymer matrix. A solid dispersion is typically prepared by spray drying or hot melt extrusion.

[0335] The method for preparing the solid dispersion includes (i) mixing the compound described herein with a polymer in an organic solvent to provide a feeder solution, and (ii) spray-drying the feeder solution as a fine spray through a nozzle into a chamber, where the solvent evaporates quickly to produce particles containing the compound and the polymer. Following the formation of the solid dispersion, the resulting spray-dried particles may be subjected to a secondary drying step to remove residual solvent. The secondary drying step may be carried out in a static or agitated dryer. Gas, humidified gas, vacuum may be applied to the secondary drying step, which is useful for more quickly removing residual solvent remaining in the spray-dried particles.

[0336] Any organic solvent may be used as long as it can easily dissolve or disperse the above-mentioned compounds and polymers. Examples of organic solvents include low carbon number alcohols such as methanol, ethanol, propanol, and isopropanol; ketones such as methyl ethyl ketone and butanone; and combinations thereof.

[0337] In some embodiments, the pharma- ceutically acceptable excipients and carriers are selected from fillers, binders, diluents, disintegrants, glidants, and lubricants.

[0338] In some embodiments, a capsule or tablet may contain a provided pharmaceutical composition in the form of a solid dosage form. In some embodiments, the solid dosage form may be a capsule. In some embodiments, the solid dosage form may be a tablet.

[0339] In certain embodiments, the dosage form is a tablet, and the tablet is manufactured using standard tablet processing procedures and equipment recognized in the art. In certain embodiments, the method of forming the tablet is direct compression of a powdered, crystalline and / or granular composition that includes the solid form provided herein alone or in combination with one or more excipients or carriers, such as carriers, additives, polymers, etc. In certain embodiments, instead of direct compression, the tablet may be prepared using a wet granulation or dry granulation process. In certain embodiments, the tablet is formed, rather than compressed, starting from a moist or otherwise easy-to-handle material. In certain embodiments, compression and granulation techniques are used.

[0340] In certain embodiments, the dosage form is a capsule, and the capsule may be manufactured using standard capsule processing procedures and equipment recognized in the art. In certain embodiments, soft gelatin capsules may be prepared, in which the capsule contains a mixture comprising the solid forms provided herein and a vegetable oil or a non-aqueous water-miscible material, such as, for example, polyethylene glycol. In certain embodiments, hard gelatin capsules may be prepared, containing granules of the solid forms provided herein in combination with a solid powdered carrier, such as, for example, lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin. In certain embodiments, hard gelatin capsule shells may be prepared from capsule compositions comprising gelatin and small amounts of plasticizers, such as glycerol. In certain embodiments, the capsule shells may be made from carbohydrate materials instead of gelatin. In certain embodiments, the capsule compositions may further comprise polymers, colorants, flavorings, and opacifiers, as required. In certain embodiments, the capsules comprise HPMC.

[0341] In some embodiments, the pharmaceutical composition comprises one or more fillers. In certain embodiments, the filler is selected from ammonium alginate, calcium carbonate, calcium lactate, calcium phosphate, calcium silicate, calcium sulfate, cellulose acetate, compressible sugars (e.g., lactose, glucose, and sucrose), corn starch, dextrates, erythritol, ethylcellulose, glyceryl palmitostearate, isomalt, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, medium chain triglycerides, microcrystalline cellulose, pregelatinized starch, polydextrose, polymethacrylate, silicic acid, simethicone, sodium alginate, sodium chloride, sorbitol, starch, sugar spheres, sulfobutyl ether beta-cyclodextrin, talc, tragacanth, trehalose, and xylitol, or combinations thereof.

[0342] In some embodiments, the filler is selected from talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0343] 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 microcrystalline cellulose. In some embodiments, the filler is a combination of two or three of the above components. In some embodiments, the filler comprises at least microcrystalline cellulose, lactose, and mannitol.

[0344] In certain embodiments, the dosage forms provided herein include one or more diluents. Diluents can be used, for example, to increase the volume so that a tablet or capsule of practical size is finally obtained. Suitable diluents include, among others, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, microcrystalline cellulose (e.g., AVICEL), microfine cellulose, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrate, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (e.g., EUDRAGIT), potassium chloride, sodium chloride, sorbitol, and talc. Diluents also include, for example, ammonium alginate, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, compressible sugar, powdered sugar, dextrate, dextrin, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, isomalt, kaolin, lacitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, polydextrose, polymethylacrylate, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, sulfobutylether-β-cyclodextrin, talc, tragacanth, trehalose, and xylitol.

[0345] In some embodiments, the pharmaceutical composition includes one or more binders. Binders can be used, for example, to provide cohesion to tablets or capsules, ensuring that the formulation remains intact after compression. In some embodiments, the binder is selected from the group consisting of acacia gum, agar, alginic acid, calcium carbonate, calcium lactate, carbomer (e.g., acrylic acid polymers, carboxypolymethylene, polyacrylic acid, carboxyvinyl polymers), sodium carboxymethylcellulose, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, copovidone, corn starch, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydrogenated vegetable oil type I, hydroxyethylcellulose ... The polysaccharide extract is selected from methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellose, inulin, lactose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, microcrystalline cellulose, pectin, poloxamer, polycarbohyl, polydextrose, polyethylene oxide, polymethacrylate, polyvinylpyrrolidone, pregelatinized starch, povidone, sodium alginate, starch, stearic acid, sucrose, tricaprylin, vitamin E polyethylene glycol succinate, and zein.

[0346] Suitable binders include, but are not limited to, starches (including potato starch, corn starch, and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, and lactose), polyethylene glycol, propylene glycol, waxes, and natural and synthetic gums such as acacia, sodium alginate, polyvinylpyrrolidone (PVP), cellulosic polymers (including hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose, ethylcellulose, hydroxyethylcellulose (HEC), carboxymethylcellulose, and the like), veegum, carbomers (e.g., Carbopol), sodium, dextrin, guar gum, hydrogenated vegetable oils, magnesium aluminum silicate, maltodextrin, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), microcrystalline cellulose, among others. Binders also include, for example, acacia, agar, alginic acid, cabomer, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, powdered sugar, copovidone, dextrate, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylstarch, hypromellose, inulin, lactose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethylacrylate, povidone, sodium alginate, sodium carboxymethylcellulose, starch, pregelatinized starch, stearic acid, sucrose, and zein.

[0347] Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (FMC Corporation, Marcus Hook, Pa.), and mixtures thereof. In some embodiments, a specific binder is a mixture of microcrystalline cellulose sold as AVICEL RC-581 and sodium carboxymethylcellulose. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103™ and Starch 1500 LM.

[0348] In some embodiments, the pharmaceutical composition comprises one or more disintegrants. In certain embodiments, the disintegrants are selected from alginic acid, calcium alginate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, cellulose, chitosan, colloidal silicon dioxide, corn starch, croscarmellose sodium, crospovidone, docusate sodium, glycine, guar gum, hydroxypropylcellulose, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, pregelatinized starch, polacrilin potassium, povidone, silicates, sodium alginate, sodium carbonate, and sodium starch glycolate.

[0349] Suitable disintegrants include, but are not limited to, agar-agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and Veegum HV; citrus pulp; crosslinked celluloses such as croscarmelose; crosslinked polymers such as crospovidone; crosslinked starches; calcium carbonate; microcrystalline celluloses such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clays; algins; and mixtures thereof.

[0350] In some embodiments, the pharmaceutical composition comprises one or more surfactants, hi some embodiments, the surfactants are 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.

[0351] In some embodiments, the pharmaceutical composition comprises one or more pore-forming agents. In some embodiments, the pore-forming agent is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, poloaxamer 188, povidone (e.g., Kollidon K25 / K30), or sugar (e.g., glucose, mannose, fructose, and sucrose).

[0352] In some embodiments, the pharmaceutical 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., Boston, MA), and asbestos-free talc.

[0353] In some embodiments, the pharmaceutical composition comprises one or more lubricants, hi some embodiments, the lubricant is selected from calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, myristic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, solid polyethylene glycol, stearic acid, and talc.

[0354] Lubricants that may be used in pharmaceutical compositions and dosage forms 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 oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, syloid silica gel (AEROSIL 200, manufactured by W. R. Grace Co., Baltimore, Md.), coagulated aerosol of synthetic silica (marketed by Degussa Co., Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co., Boston, Mass.), and mixtures thereof.

[0355] In some embodiments, the pharmaceutical composition comprises one or more film coating agents. In some embodiments, the film coating comprises a poly(vinyl alcohol) base. In some embodiments, the film coating comprises a colorant or pigment. In some embodiments, the film coating is Opadry II®, such as Opadry II® yellow.

[0356] 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 a combination of a water soluble dye adsorbed onto a hydrous oxide of a heavy metal resulting in an insoluble form of the dye.

[0357] 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.

[0358] Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame.

[0359] Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (Tween-20), polyoxyethylene sorbitan 80 monooleate (Tween-80), and triethanolamine oleate.

[0360] Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.

[0361] Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol.

[0362] Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

[0363] Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup.

[0364] Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil.

[0365] Suitable organic acids include, but are not limited to, citric acid and tartaric acid.

[0366] Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

[0367] The pharmaceutical compositions for oral administration provided herein may be provided as compressed tablets, tablet triturates, chewable lozenges, fast dissolving tablets, multiple compressed tablets, or enteric coated tablets, sugar coated tablets, or film coated tablets. Enteric coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but protects the active ingredient from the acidic environment of the stomach as it dissolves or disintegrates in the intestine. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar coated tablets are compressed tablets that are encased in a sugar coating that may help to mask unpleasant tastes or odors and protect the tablet from oxidation. Film coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets and press- or dry-coated tablets.

[0368] Tablet dosage forms may be prepared from the active ingredient in powdered, crystalline, or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents, and / or colorants.

[0369] The tablets of the present disclosure may be formulated for immediate, sustained, extended, or modified release.

[0370] In some embodiments, the unit dosage forms described herein comprise one or more pharma- ceutically acceptable excipients selected from microcrystalline cellulose, lactose monohydrate (modified), croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate.

[0371] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. Liquid dosage forms may contain, in addition to the active compound, inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and aromatic agents.

[0372] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution (USP), and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0373] The injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0374] In order to prolong the effect of the compounds described herein, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound thus depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0375] Compositions for rectal or vaginal administration are preferably suppositories which may be prepared by mixing a compound described herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectal or vaginal cavity releasing the active compound.

[0376] The active compound may also be in microencapsulated form with one or more excipients as described above. The solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. According to normal practice, such dosage forms may also contain additional substances other than inert diluents, for example, tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0377] The dosage form for topical or transdermal administration of the compounds described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier and, if necessary, with any necessary preservatives or buffers. Ophthalmic preparations, ear drops, and eye drops are also contemplated. In addition, transdermal patches may be used, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms may be made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers may also be used to increase the flux of the compound through the skin. The rate may be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0378] In some embodiments, the compositions described herein may include a prodrug of Compound 1. As used herein, the term "prodrug" means a compound that is convertible in vivo by metabolic means (e.g., hydrolysis) to the compound. Various general forms of prodrugs are known in the art, such as those described in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed.). Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, 9 9=., Journal of Drug Delivery Reviews, 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975), each of which is incorporated herein by reference in its entirety.

[0379] For oral administration in the form of tablets or capsules (e.g., gelatin capsules), the active drug components can be combined with oral non-toxic pharma- ceutically acceptable inert carriers, such as ethanol, glycerol, water, etc. Furthermore, if desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth, or sodium alginate, polyethylene glycol, wax, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, silica, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan, gum starch, agar, alginic acid or its sodium salt, or effervescent mixture, croscarmellose or its sodium salt, etc. Diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine.

[0380] Tablets contain the active ingredient in a mixture with non-toxic pharma- ceutically acceptable excipients suitable for tablet manufacture.These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch, or alginic acid; binders such as starch, gelatin, or acacia, and lubricants such as magnesium stearate, stearic acid, or talc.Tablets can be uncoated or can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time.

[0381] The therapeutically effective dose of the compounds described herein in oral formulations may vary from 0.15 mg / kg to 20 mg / kg of patient body weight per day, more specifically 0.015 to 1.0 mg / kg, and may be administered in one or multiple doses per day. For oral administration, the drug may be delivered in the form of a tablet or capsule containing 1 mg to 100 mg, specifically 1 mg, 5 mg, 10 mg, 20 mg, 50 mg, or 100 mg of active ingredient, or at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50% (w / w) of active ingredient. For example, a capsule may contain 50 mg of active ingredient, or 5 to 10% (w / w) of active ingredient. For example, a tablet may contain 100 mg of active ingredient, or 20 to 50% (w / w) of active ingredient. For example, tablets may contain, in addition to the active ingredient, disintegrants or emollients (e.g., croscarmellose or its sodium salt and methylcellulose), diluents (e.g., microcrystalline cellulose), and lubricants (e.g., sodium stearate and magnesium stearate). Drugs may be administered daily, either once, twice or more times a day.

[0382] For administration by inhalation, the compounds can be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, such as a gas like carbon dioxide, or a nebulizer.

[0383] For transmucosal or transdermal administration, a penetrant appropriate for the barrier to be permeated is used in the formulation. Such penetrants are widely known in the art and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be achieved through the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated into an ointment, salve, gel, or cream, as is widely known in the art. Penetration enhancers promote the penetration of drugs through the corneal barrier and alter the integrity of the epithelial cell layer. Penetration enhancers frequently used in ophthalmic formulations include cyclodextrin, dimethyl sulfoxide (DMSO), ethylenediaminetetraacetic acid (EDTA), sodium glycocholate and related cholates, Tween 20 (nonionic polysorbate surfactant), Brij 35 (polyoxyethylene lauryl ether), saponin, and bile salts. In general, penetration enhancers such as EDTA and cholates temporarily loosen the tight junctions between adjacent cells of the corneal epithelium. Thus, permeation enhancers when applied topically to the eye have been successfully applied to the delivery of proteins and peptides across the corneal epithelium. In some embodiments, the formulations described herein include a penetration enhancer such as polyoxyethylene-9-lauryl ether, sodium deoxycholate, sodium glycocholate, or sodium taurocholate.

[0384] In some embodiments, the pharma- ceutically acceptable excipient in the ophthalmic or transmucosal formulations described herein is cyclodextrin. Cyclodextrins are known to act as permeation enhancers and mucoadhesives. In some embodiments, the cyclodextrin is α-, β-, or γ-cyclodextrin. In some embodiments, the cyclodextrin is a pharma- ceutically acceptable derivative of cyclodextrin, including, but not limited to, hydroxyalkyl derivatives of α-, β-, and γ-cyclodextrin (particularly hydroxyethyl and hydroxypropyl derivatives of β-cyclodextrin and γ-cyclodextrin), randomly methylated β-cyclodextrin, sulfobutyl ether β-cyclodextrin, sulfobutyl ether γ-cyclodextrin, and so-called branched β- and γ-cyclodextrin derivatives, such as glucosyl-β-cyclodextrin and glucosyl-γ-cyclodextrin. Natural cyclodextrins may be used alone or in mixtures of two or more cyclodextrins, non-limiting examples of which include mixtures of γ-cyclodextrin and the more water-soluble hydroxypropyl γ-cyclodextrin, or mixtures of γ-cyclodextrin and sulfobutyl ether γ-cyclodextrin, or mixtures of β-cyclodextrin and hydroxypropyl-β-cyclodextrin, or mixtures of β-cyclodextrin and sulfobutyl ether β-cyclodextrin.

[0385] In some embodiments, the cyclodextrin in the ophthalmic solutions or transmucosal formulations described herein is at a concentration of 0-20% w / v. In some embodiments, the cyclodextrin in the ophthalmic solutions described herein is at a concentration of 1-18% w / v, 1-16% w / v, 1-14% w / v, 2-12% w / v, 4-10% w / v, 5-9% w / v, or 6-8% w / v. In some embodiments, the cyclodextrin in the ophthalmic solutions described herein is at a concentration of 7%-11% w / v. In some embodiments, the cyclodextrin in the ophthalmic solutions described herein is at a concentration of about 1% w / v, 2% w / v, 3% w / v, 4% w / v, 5% w / v, 6% w / v, 7% w / v, 8% w / v, 9% w / v, 10% w / v, 11% w / v, 12% w / v, 13% w / v, 14% w / v, 15% w / v, 16% w / v, 17% w / v, 18% w / v, 19% w / v, or 20% w / v.

[0386] In some embodiments, the pharma- ceutically acceptable excipient in the ophthalmic solutions or transmucosal formulations described herein is sulfobutylether-β-cyclodextrin, particularly at any of the specified concentrations and ranges of concentrations set forth above, such as about 7% w / v. In some embodiments, the pharma- ceutically acceptable excipient in the ophthalmic solutions described herein is hydroxypropyl-β-cyclodextrin, particularly at any of the specified concentrations and ranges of concentrations set forth above, such as about 7% w / v.

[0387] In some embodiments, the ophthalmic solutions described herein include a pharma- ceutically acceptable buffer. In some embodiments, the pharma-ceutically acceptable buffer is a phosphate buffer, a citrate buffer, a Tris buffer, a histidine buffer, or an acetate buffer.

[0388] In some embodiments, the pharma- ceutically acceptable buffer is sodium phosphate dibasic. In some embodiments, the pharma-ceutically acceptable buffer is sodium phosphate monobasic. In some embodiments, the pharma-ceutically acceptable buffer is a mixture of sodium phosphate dibasic and sodium phosphate monobasic. In some embodiments, the ophthalmic solution described herein comprises about 0.083% w / v of sodium phosphate dibasic and about 0.017% w / v of sodium phosphate monobasic.

[0389] In some embodiments, the ophthalmic solutions described herein have an approximately neutral pH. In some embodiments, the ophthalmic solutions described herein have a pH of 6.5 to 8. In some embodiments, the ophthalmic solutions described herein have a pH of 6.9 to 7.7. In some embodiments, the ophthalmic solutions described herein have a pH of 7.1 to 7.5. In some embodiments, the ophthalmic solutions described herein have a pH of about 7.3.

[0390] To adjust the pH, pharma- ceutically acceptable acids and / or bases can be used in the ophthalmic solutions. In some embodiments, the ophthalmic solutions described herein include a pharma- ceutically acceptable acid. In some embodiments, the ophthalmic solutions described herein include a pharma- ceutically acceptable base. In some embodiments, the ophthalmic solutions described herein include a pharma- ceutically acceptable acid and a base. In some embodiments, the pharma- ceutically acceptable acid is hydrochloric acid. In some embodiments, the pharma- ceutically acceptable base is sodium hydroxide.

[0391] In some embodiments, the ophthalmic solutions described herein comprise a tonicity agent. In some embodiments, the tonicity agent is selected from the group consisting of dextrose, potassium chloride, propylene glycol, and sodium chloride. In some embodiments, the ophthalmic solutions described herein comprise a tonicity agent at a concentration of less than about 0.5% w / v. In some embodiments, the ophthalmic solutions described herein comprise a tonicity agent at a concentration of about 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15%, or 0.1% w / v. In some embodiments, the tonicity agent is sodium chloride.

[0392] Parenteral formulations containing the compounds described herein can be prepared as isotonic aqueous solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The preparations may be sterilized and / or contain adjuvants such as preservatives, stabilizing agents, wetting agents or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure and / or buffers. In addition, they may contain other therapeutically valuable substances. The compositions are prepared according to conventional methods and may contain about 0.1-75%, preferably about 1-50%, of the compounds described herein.

[0393] The phrases "parenteral administration" and "administered parenterally" are art-recognized terms and include modes of administration other than enteral and topical administration, such as by injection, including, but not limited to, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0394] Formulations for topical administration to the skin can include, for example, ointments, creams, gels, and pastes that contain the primary amine compound in a pharma- ceutically acceptable carrier. Formulations of the primary amine compound for topical use include the preparation of oily or water-soluble ointment bases, as is well known to those skilled in the art. For example, these formulations can include vegetable oils, animal fats, and semi-solid hydrocarbons obtained, for example, from petroleum. Specific ingredients used can include white ointment, yellow ointment, cetyl esters wax, oleic acid, olive oil, paraffin, petrolatum, white petrolatum, spermaceti, starch glycerite, white wax, yellow wax, lanolin, anhydrous lanolin, and glyceryl monostearate. A variety of water-soluble ointment bases can also be used, including glycol ethers and derivatives, polyethylene glycol, polyoxyl 40 stearate, and polysorbates.

[0395] Formulations for topical administration may contain the compounds used in the present application in the range of 0.001-10%, 0.05-10%, 0.1-10%, 0.2-10%, 0.5-10%, 1-10%, 2-10%, 3-10%, 4-10%, 5-10%, or 7-10% (weight / volume), or in the range of 0.001-2.0%, 0.001-1.5%, or 0.001-1.0% (weight / volume), or in the range of 0.05-2.0%, 0. The compound may be contained in a concentration ranging from 0.05 to 1.5%, or 0.05 to 1.0% (weight / volume), or from 0.1 to 5.0%, 0.1 to 2.0%, 0.1 to 1.5%, or 0.1 to 1.0% (weight / volume), or from 0.5 to 5.0%, 0.5 to 2.0%, 0.5 to 1.5%, or 0.5 to 1.0% (weight / volume), or from 1 to 5.0%, 1 to 2.0%, or 1 to 1.5% (weight / volume). Formulations for topical administration may also contain the compounds used in the present application in concentrations ranging from 0.001-2.5%, 0.01-2.5%, 0.05-2.0%, 0.1-2.0%, 0.2-2.0%, 0.5-2.0%, or 1-2.0% (weight / weight), or from 0.001-2.0%, 0.001-1.5%, 0.001-1.0%, or 0.001-5% (weight / weight).

[0396] In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered systemically. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered orally as part of a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid. In some embodiments, the pharmaceutical composition is administered as a liquid via a nasogastric tube.

[0397] In some embodiments, the compound or its pharmaceutically acceptable salt is administered once, twice, three times, or four times a day. In some embodiments, the compound or its pharmaceutically acceptable salt is administered twice a day. In some embodiments, the dose of the compound or its pharmaceutically acceptable salt is about 1 mg BID (i.e., twice a day) to about 20 mg BID.

[0398] In some embodiments, the pharmaceutical composition is administered in one or more divided doses daily. In some embodiments, the composition is administered once a day (qua diem, QD). In some embodiments, the composition is administered twice a day (bis in die, BID). In some embodiments, the composition is administered three times a day (ter in die, TID). In some embodiments, the composition is administered four times a day (quater in die, QID). In some embodiments, the composition is administered every four hours (quaque four hours, q4h).

[0399] In some embodiments, the solid form of Compound 1 is substantially amorphous or crystalline, or a mixture thereof. In some embodiments, the solid form is substantially free of impurities.

[0400] In certain embodiments, Compound 1 is a crystalline solid. In some embodiments, Compound 1 is a crystalline solid and is substantially free of amorphous Compound 1. As used herein, the term "substantially free of amorphous Compound 1" means that the compound does not contain a significant amount of amorphous Compound 1. In some embodiments, at least about 95% by weight of crystalline Compound 1 is present. In still other embodiments described herein, at least about 99% by weight of crystalline Compound 1 is present.

[0401] The compound may be formulated as an SDD formulation. As used herein, "SDD" refers to a pharmaceutical formulation (e.g., of Compound 1 or a pharma- ceutically acceptable salt thereof) that is a spray-dried formulation. In some embodiments, the formulation comprises a compound of the present disclosure (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof) and hypromellose acetate succinate (HPMCAS). In one embodiment, the HMPCAS is HPMCAS-M, where "M" indicates (acetyl content 7.0%-11.0%, succinoyl content 10%-14%). The use of spray drying to produce powders from fluid feedstocks is well known, with applications ranging from milk powder to bulk chemicals and pharmaceuticals. See U.S. Pat. No. 4,187,617 and Mujumbar et al., 91 Drying, pages 56-73 (1991). The use of spray drying to form solid amorphous dispersions of drugs and concentration-enhancing polymers is also known. See European Patent Application Nos. 0901786, 1027886, 1027887, 1027888, and PCT Application Nos. WO00 / 168092 and WO00 / 168055, each of which is incorporated herein by reference. A typical spray drying apparatus comprises a drying chamber, an atomizing means for atomizing the solvent-containing liquid fed into the drying chamber, a source of heated drying gas directed into the drying chamber, and a dried product collecting means for separating the dried product from the cooled drying gas and the vaporized solvent stream after exiting the drying chamber. Examples of such apparatus include Niro models PSD-1, PSD-2, and PSD-4 (Niro A / S, Soeborg, Denmark).

[0402] As used herein, "TPGS" or "vitamin E TPGS" as a descriptor for a pharmaceutical formulation of a compound of the present disclosure refers to a pharmaceutical formulation (e.g., of compound 1 or a pharma- ceutically acceptable salt thereof) that includes the following components: (a) an active compound (e.g., compound 1 or a pharma- ceutically acceptable salt thereof), (b) one or more diluents (e.g., microcrystalline cellulose), (c) one or more solubilizers (e.g., D-α-tocopherol polyethylene glycol succinate [vitamin E TPGS]), and (d) one or more binders (e.g., povidone). The formulation may be prepared using a granulation process (e.g., wet granulation). As used herein, "granulation" refers to a process that produces larger or smaller granules or particles of a substance or mixture of substances. This process may also remove fine granules and improve flowability within the formulation. Both wet granulation and / or dry granulation may be used. Dry granulation is achieved using only a combination of granules without the need for a liquid thereon. Slugging uses a tablet press to form large tablets of variable weight due to the poor flowability of the formulation. The resulting slugs are then run through a granulator to break them into granules, which are then compressed again to produce the final granular product.

[0403] All publications, patents, patent applications, and other documents cited in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other document was individually indicated to be incorporated by reference for all purposes.

[0404] All features of each aspect of the invention apply mutatis mutandis to all other aspects.

[0405] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner. EXAMPLES

[0406] Example 1: Dissolution of Compound 1 and the effect of excipients on it The main formulation challenge presented by Compound 1 was its poor aqueous solubility, which may limit its absorption in vivo. Two anhydrous nonsolvated forms of Compound 1 (Forms C and Material D) were identified in polymorph screening, as well as two variable hydrates (Form A with up to 3 moles of water, and Form J with 1-2 moles of water) and several solvates. Through competitive slurry studies, Form C was determined to be the most stable anhydrous nonsolvated form. The hydrate Form A converted to Form C upon dehydration, and possibly Form J as well.

[0407] The conversion of anhydrous form C to hydrate form A is achieved by increasing the water activity (a w ) was about 0.62 to greater than 0.82. After 1 day, no conversion of Form C to Form A was observed in water itself, likely due to its low solubility. After 11 days of storage of Form C at room temperature at 90% RH, no conversion to Form A was observed. As shown in Table 1 below, poor solubility of the two polymorphic forms of Compound 1 (Form C and Form A) in various aqueous systems (left column) is observed. [Table 7] [Table 8]

[0408] Partition coefficient ClogP = 1.96.

[0409] Dissociation constant Based on the pKa of the protonated form of 1.94, the dissociation constant K a =1.15×10 -2 .

[0410] Hygroscopic Compound 1 form C showed limited hygroscopicity with hysteresis-free water sorption of 1.75% between 5 and 95% relative humidity. The variable hydrate form A showed significant hygroscopicity with water sorption of 4.58% between 5 and 95% RH.

[0411] Melting point Compound 1 Form C had a melting onset of 244.5°C with a peak at 244.8°C by DSC.

[0412] pKa and pH values The pKa of the protonated form of Compound 1 was determined to be 1.94±0.01. The pH of a saturated aqueous solution of Compound 1 was 8.6.

[0413] We hypothesized that the use of Vitamin E TPGS in a pharmaceutical formulation would increase the solubility of Compound 1 and overcome the solubility issue. A capsule dissolution study was used as a screening tool to compare different preclinical formulations. Figure 1 shows the dissolution of crystalline Compound 1 as Form C blended with microcrystalline cellulose (MCC; bottom curve) versus two granulations of Compound 1 as Form C with 5% (second-lowest or middle curve) or 20% (top curve) Vitamin E TPGS and MCC. As can be seen in Figure 1, the addition of Vitamin E TPGS significantly increased the dissolution rate and overall solubility.

[0414] The TPGS formulation was used in early Phase I clinical trials. Late Phase I and current Phase II clinical trials utilize an alternative SDD formulation, which is described below. Optimization of the SDD formulation included evaluation of several polymers and comparison of drug loading of selected polymers. From the SDD screening run, it was found that a 50:50 ratio of compound 1 and polymer HPMC-AS-M (a moderately substituted grade of HPMC-AS) provided the best combination of properties including overall spray drying yield, lowest hygroscopicity under high humidity conditions, and best dissolution performance, while balancing the need for a relatively small capsule size for clinical use. X-ray powder diffraction confirmed that the SDD process produced an amorphous API dispersion. A human PK evaluation of the relative bioavailability of the TPGS formulation versus the SDD formulation was performed. Overall, exposure was similar or slightly better, with a calculated relative %F of 128%.

[0415] As described herein, SDD formulations containing 50% Compound 1:50% HPMC-AS-M have been successfully formulated into size #3 capsules containing 2 mg, 5 mg, 15 mg, or 25 mg of Compound 1, and size #2 capsules containing 50 mg of Compound 1. These HPMC-AS-M based SDD formulations are expected to provide good exposure of Compound 1 when administered orally in a clinical setting.

[0416] Initial toxicity studies utilized a formulation of Compound 1 in 10% Cremophor EL / 10% propylene glycol / 80% water. However, repeated administration of this formulation to rats demonstrated a "plateau" in systemic exposure where higher doses did not result in significantly higher exposure. Therefore, additional formulations were evaluated in both rats and monkeys, including a nanodispersion formulation in 0.5% hydroxypropylmethylcellulose (HPMC) E5 and 0.5% Tween® 80 in deionized water, and a spray-dried dispersion (SDD) formulation in 0.5% MC 400cP and 0.1% Tween® 80 in deionized water. The copolymer used in the initial SDD formulation was polyvinylpyrrolidone / vinyl acetate (PVP-VA) with a drug loading of 20%. This spray-dried dispersion formulation demonstrated good solubility compared to the crystalline material and reproducibly demonstrated the highest systemic exposure achievable in animals. This formulation was used in the initial pivotal repeat-dose toxicity study (28 days total), as well as in vivo safety pharmacology and genotoxicity studies. Subsequent development of the SDD formulation was undertaken to increase drug loading and optimize the formulation properties for clinical use. These efforts resulted in an SDD formulation with 50% drug loading using hydroxypropyl methylcellulose acetate succinate (HPMCAS) as the polymer. This improved SDD formulation was used in long-term repeat-dose toxicity studies in rabbits and developmental toxicity studies, and also served as the basis for the clinical formulation.

[0417] Example 2: Development of an oral capsule formulation of Compound 1 Drug products of Compound 1 in strengths of 5 mg and 25 mg were prepared. Drug product descriptions are shown in Table 3. [Table 9]

[0418] composition The compositions of Compound 1 pharmaceuticals at doses of 5 mg and 25 mg are shown in Tables 4 and 5. [Table 10] [Table 11]

[0419] excess amount There is no excess.

[0420] Sealing of containers Container closure systems for Compound 1 drug product 5 mg and 25 mg are provided in Table 6 below. [Table 12]

[0421] Pharmaceutical ingredients drug substance Compatibility of drug substance and excipients Excipient suitability was determined by conducting accelerated and real-time stability studies of the formulated drug in capsules identical in composition and preparation method to the intended clinical dosage form.

[0422] Physicochemical characteristics of the drug substance physical properties The physical properties of Compound 1 are summarized above. Two major polymorphic forms, A and C, were evaluated during development. Form A is a low melting hydrate containing up to 3 equivalents of water, which can convert to Form C upon heating or drying. Form C is the most stable polymorph observed to date and was selected for development. GLP and GMP batches of drug substance were supplied as Form C. [Table 13]

[0423] chemical properties pKa: 1.94 Chemical stability in the solid state (crystalline and amorphous) and in solution: Compound 1 drug substance was stress tested to gain insight into the intrinsic stability of the molecule, to identify potential degradation products, and to facilitate the development of stability-indicating analytical methods.

[0424] Excipients MCC (microcrystalline cellulose) was used as an inert filler in capsule formulation. The addition of MCC increases the volume of the fill material, thus increasing the accuracy of the volumetric filling operation. Furthermore, MCC generally has good density and powder flow properties, which is helpful for capsule filling operations.

[0425] PVP K30 (Polyvinylpyrrolidone) is used as a binder in the wet granulation process. PVP is a very commonly used binder that helps hold the agglomerates of API and filler (MCC) particles together.

[0426] Vitamin E TPGS is a commercially available non-ionic surfactant derived from vitamin E. It is commonly used to improve the bioavailability of poorly water-soluble drugs administered orally. It was selected based on the high solubility of the drug substance compound 1 in this excipient.

[0427] Container Closing System explanation Compound 1 drug capsules, 5 mg and 25 mg, are packaged in 60 cc HDPE bottles with induction seals and child resistant caps.

[0428] Material Selection HDPE bottles are the type of container closure system most commonly used in the pharmaceutical industry for capsule and tablet formulations and are readily available. HDPE is chemically inert and offers good protection from moisture and light.

[0429] Moisture protection Capsules of Compound 1 showed no sensitivity to moisture. As a result, the use of a desiccant was not necessary.

[0430] Light protection An ICH photostability study demonstrated that Compound 1 is not light sensitive. Additionally, the bottle is opaque, minimizing exposure to light during drug storage.

[0431] safety Because the Compound 1 drug product is delivered in a capsule, the acceptance criteria for microbial limits are set forth in Table 8. These limits are in accordance with the USP <1111> It is based on the "Acceptance Criteria for Microbiological Quality of Nonsterile Dosage Forms" stipulated in "Microbiological Examination of Nonsterile Products:Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use." [Table 14]

[0432] USP <61> and <62> Microbial limit testing for release and stability performed in accordance with the FDA guidelines showed that total aerobic microbial counts and total yeast and mold counts did not exceed the acceptance criteria, and no microbial growth was observed. Escherichia coli was absent in all lots tested.

[0433] Manufacturing process description According to the flow diagram shown in FIG. 2 of this disclosure, the formulation process included wet granulation of Compound 1 with MCC (microcrystalline cellulose, diluent, Avicel PH101), Vitamin E TPGS (solubility enhancer), PVP K30 (polyvinylpyrrolidone, binder), and water. After granulation, the wet granules were dried in a fluid bed dryer to LOD≦1.5%, passed through a Comil to break down agglomerates, and blended to obtain bulk capsule fill material. 5 mg capsules were filled using an Xcelodose system based on the weight of the input material. 25 mg capsules were filled using a Profill system based on the volume. Content uniformity testing was performed after capsule filling. Both 5 mg and 25 mg strength capsules were filled into size #2 hard shell HPMC-based capsules. Filled capsules were packaged in 12 counts into 60 cc HPDE bottles.

[0434] In-process control explained [Table 15]

[0435] Standard: Compound 1 drug, capsule The quality control specifications for Compound 1 pharmaceutical capsules 5 mg and 25 mg are shown in Table 10. [Table 16]

[0436] HPLC method for identification and impurities Identification The retention times and UV spectra of the samples were compared to those of Compound 1 drug substance reference standard. The conditions for the reverse phase HPLC method are listed in Table 11.

[0437] impurities The HPLC method for impurities was based on that of the drug substance. The peak area of ​​each related substance was divided by the total peak area to obtain the percentage of each. Total impurities were expressed as the sum of each individual impurity. Purity was obtained by subtracting the total impurities from 100%. Table 11 shows a description of the method. [Table 17]

[0438] Potency, Percent Label Claims, and Dosage Uniformity Potency, percent label claim, and dose uniformity were determined by HPLC with UV detection. The peak area of ​​the Compound 1 peak was compared to that of the reference standard. Table 12 shows the method conditions for obtaining chromatographic purity. For percent label claim, potency was compared to that of the nominal value. For dose uniformity, the USP <905> Calculate the tolerance according to. [Table 18]

[0439] Dissolution Dissolved in USP <711> The dissolution was performed according to the USP Apparatus II with a paddle speed set at 75 rpm in 900 mL of dissolution medium at 37° C. After the 60 minute time point, the paddle speed was increased to 200 rpm. The dissolution medium was 0.1 N HCl with 1% sodium lauryl sulfate. Samples were removed and analyzed by HPLC with UV detection at 343 nm against reference standards. The chromatographic conditions for the HPLC method are listed in Table 13. [Table 19]

[0440] Validation of analytical procedures: Compound 1 Drugs, capsules Analytical procedures were evaluated to a level appropriate for the current stage of development. HPLC methods for identification and quantification of impurities in Compound 1 drug product were qualified for accuracy, precision, linearity, specificity, limits of quantification and detection, range, peak purity, and solution stability. Methods for potency, percent label claim, and dose uniformity were qualified for accuracy, precision, linearity, specificity, range, and solution stability. Methods for dissolution were qualified for accuracy, precision, reproducibility, linearity, specificity, limits of quantification and detection, range, filter compatibility, and solution stability.

[0441] Batch analysis [pharmaceuticals, capsules] Batch Description [Table 20-1] [Table 20-2]

[0442] Impurity characterization Compound 1 was free of new drug-specific impurities.

[0443] Stability Summary and Conclusions Summary of stability studies One-month data are available for representative non-GMP batches of Compound 1 drug product 5 mg and 25 mg at both the proposed long-term storage conditions of 2-8°C and the accelerated storage conditions of 25°C / 60% RH and 40°C / 75% RH.

[0444] No significant changes were observed in any of the test parameters.

[0445] Stability study design The stability of Compound 1 is presented in Table 15. The protocol was performed under both the proposed long-term storage conditions of 2-8° C. and accelerated storage conditions of 25° C. / 60% RH and 40° C. / 75% RH. [Table 21]

[0446] A representative stability protocol for Compound 1 stability is provided in Table 16. The protocol was designed for a 2-year study under both the proposed long-term storage conditions of 2-8°C and accelerated storage conditions of 25°C / 60% RH and 40°C / 75% RH. [Table 22]

[0447] Batches and packages tested Table 17 summarizes the Compound 1 drug product lots that were at steady state. [Table 23]

[0448] Stability Data Results of stability data under established storage and stress conditions The stability data available for the pilot batches (5 mg and 25 mg respectively) are given in the table below. [Table 24] [Table 25] [Table 26] [Table 27] [Table 28] [Table 29]

[0449] Example 3: Batch formulation of pharmaceutical capsule IMPD (such as 2 mg). The table below shows a summary of the batches of the various dosage forms. [Table 30] [Table 31] [Table 32] [Table 33] [Table 34] [Table 35]

[0450] Description of manufacturing process and process control According to the flow diagram shown in Figure 4 for the manufacture of Compound 1 SDD drug product, SDD was prepared by a formulation process by dissolving Compound 1 and HPMC-AS in an organic solvent, then passing the liquid through a 100 mesh screen, followed by spray drying to produce SDI (spray dried intermediate), followed by secondary tray drying to remove residual solvent. After spray drying, in-process testing is performed to ensure that the residual solvent is below ICH levels.

[0451] Once dried, the SDI is blended with intragranular excipients, then milled using a Comil, blended again, and finally dry granulated using a roller compactor against a 1.00 mm screen. This also produces ribbons that are milled at the same time. The resulting dry granules are further blended with extragranular excipients before being filled into capsules using a Profill capsule filling system. Fill weights can be adjusted based on the results of in-process control over potency. Varying amounts of intragranular and extragranular excipients are used to produce blends that make up capsules of 2 mg, 5 mg, 15 mg, 25 mg, and 50 mg strengths, such that the 2 mg, 5 mg, 15 mg, and 25 mg blends can fit into size #3 HPMC capsules, and the 50 mg blends can fit into size #2 HPMC capsules.

[0452] The spray-dried intermediate of compound 1 was stored in a double HDPE bag with desiccant between the bags and then further enclosed in a heat-sealed Mylar pouch at 15-30 °C.

[0453] Compound 1 SDI was placed under stability conditions to support long-term storage. Data is available for 12 months at long-term conditions and 6 months at accelerated conditions. Stability protocols were run at both the proposed long-term storage conditions of 25° C. / 60% RH and accelerated storage conditions of 40° C. / 75% RH. Available data are shown in Tables 30 and 31, respectively. No changes were observed under either condition. Stability studies may be extended beyond 24 months to support longer-term storage of this intermediate. [Table 36] [Table 37] [Table 38]

[0454] Dose Uniformity, Assay, and Impurities Dose uniformity and assay were determined by HPLC with UV detection. Peak area of ​​Compound 1 peak was compared to that of the reference standard. Peak area of ​​each related substance was divided by total peak area to obtain percentage of each. Total impurities are expressed as the sum of each individual impurity. Purity was obtained by subtracting total impurities from 100%. Method conditions are shown in Table 32. In a typical batch produced by these methods, SDD drug product produced a chromatogram with very high purity of Compound 1 (retention time about 14.57 minutes) and very low levels of impurities. [Table 39] [Table 40] [Table 41]

[0455] Dissolution Dissolved in USP <711> The dissolution was performed according to the USP Apparatus II with a paddle speed set at 100 rpm in 900 mL of dissolution medium at 37° C. After the 60 minute time point, the paddle speed was increased to 250 rpm. The dissolution medium was 20 mM KH2PO4 aqueous solution pH 6.8 containing 1% sodium lauryl sulfate. Samples were removed and analyzed by HPLC with UV detection at 266 nm against reference standards. The chromatographic conditions for the HPLC method are listed in Table 35. Purity was assessed by chromatograms. [Table 42]

[0456] Validation of analytical procedures The analytical procedures described herein have been validated to a level appropriate to the current stage of development.

[0457] HPLC methods for identity, assay, dose uniformity, and quantitation of impurities in Compound 1 SDD drug product were qualified for accuracy, precision, linearity, specificity, limit of quantitation, range, and solution stability. Methods for dissolution were qualified for accuracy, precision, linearity, specificity, range, and solution stability. Karl Fischer method for water content was qualified for accuracy and precision.

[0458] Summary of stability studies For Compound 1 SDD drug product, data are available for representative non-GMP batches of 5 mg and 50 mg at both the proposed long-term storage conditions of 25°C / 60% RH for 12 months and at the accelerated storage conditions of 40°C / 75% RH for 6 months.

[0459] For the GMP SDD drug product of Compound 1, 18 months of data are available for the proposed long-term storage conditions of 25°C / 60% RH for GMP batches of 5 mg, 25 mg, and 50 mg, and 6 months of data are available for the accelerated storage conditions of 40°C / 75% RH.

[0460] Compound 1 SDD drug capsules of 2 mg, 5 mg, 15 mg, and 25 mg were placed on stability to reflect the change to blisters packaging. Six month data is available for the 2 mg, 5 mg, and 15 mg strengths at both the proposed long term storage conditions of 25° C. / 60% RH and the accelerated storage conditions of 40° C. / 75% RH.

[0461] No significant changes were observed in any of the test parameters. For capsules in blisters, some variability in individual impurities was observed at 3 months and was monitored at subsequent time points.

[0462] A stability protocol for the bottled non-GMP Compound 1 SDD drug product was conducted at both the proposed long-term storage conditions of 25°C / 60% RH and the accelerated storage conditions of 40°C / 75% RH. This stability program will support the clinical use of the Compound 1 SDD drug product.

[0463] The stability protocol for blister-packaged GMP drug products is designed for a three-year study at both the proposed long-term storage conditions of 25°C / 60% RH and the accelerated storage conditions of 40°C / 75% RH.

[0464] Tested batch and package Table 36 summarizes the lots of SDD drug products currently in stable condition. [Table 43]

[0465] Shelf life The shelf life of SDD medicines is 30 months from the date of manufacture, based on available stability.

[0466] Stability Data The stability data available for the SDD drug demonstration doses of 5 mg and 50 mg, respectively, are listed in the tables below.

[0467] The stability data available for the GMP batches of SDD drug product, 5 mg, 25 mg, and 50 mg, respectively, are set forth in the tables below.

[0468] The stability data available for GMP batches of 2 mg, 5 mg, and 15 mg of SDD drug product in blister packaging, respectively, are set forth in the tables below.

[0469] The acceptance criteria and analytical methods utilized for stability testing are the same as those for release specifications. [Table 44]

Table 45

Table 46

Table 47

Table 48

Table 49

Table 50

Table 51

Table 52

Table 53

Table 54

Table 55

Table 56

Table 57

Table 58

Table 59

Table 60

Table 61

Table 62

Table 63

Table 64

Table 65

Table 66

Table 67

Table 68

Table 69

Table 70

Table 71

[0470] The details of one or more embodiments are set forth in the accompanying drawings and specification. Other features, objects, and advantages will become apparent from the description, drawings, and claims. Although several embodiments of the invention have been described, it will be understood that various modifications can be made without departing from the spirit and scope of the invention. It will also be understood that the accompanying drawings are not necessarily to scale, and that they depict various features and underlying principles of the invention in a somewhat simplified manner.

Claims

1. Compound 1: 【Transformation 3】 or comprising its solvate or a pharmaceutically acceptable salt thereof, A pharmaceutical composition, formulation, or unit dosage form in which compound 1 is in the form of a spray-dried dispersion (SDD).

2. The pharmaceutical composition, formulation, or unit dosage form according to claim 1, wherein SDD comprises a cellulosic polymer selected from hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methylcellulose acetate succinate, hydroxyethyl cellulose acetate succinate, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, and carboxymethyl ethylcellulose.

3. The pharmaceutical composition, formulation, or unit dosage form according to Claim 2, wherein the SDD comprises compound 1 or a solvate thereof, or a pharmaceutically acceptable salt thereof, in a ratio of about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2.5:1, about 2:1, about 1.5:1, about 1:1, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10 (w / w) relative to a cellulosic polymer.

4. The SDD comprises compound 1 or its solvate or a pharmaceutically acceptable salt thereof relative to a cellulosic polymer. a) For example, approximately 5:1 to approximately 1:5 (w / w), b) For example, approximately 2.5:1 to approximately 1:2.5 (w / w), c) Approximately 1:1 (w / w) A pharmaceutical composition, preparation, or unit dosage form according to claim 3, comprising:

5. The pharmaceutical composition, formulation, or unit dosage form according to Claim 1, wherein the SDD comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS), and optionally, the SDD comprises compound 1 or a solvate or a pharmaceutically acceptable salt thereof and HPMCAS in about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2.5:1, about 2:1, about 1.5:1, about 1:1, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10 (w / w).

6. The pharmaceutical composition, formulation, or unit dosage form according to claim 2, wherein the SDD comprises a mixture of compound 1 and HPMC-AS-M (hydroxypropyl methylcellulose acetate, succinate, grade M) in a ratio of approximately 2:1 to approximately 1:2 (w / w).

7. The pharmaceutical composition, formulation, or unit dosage form according to claim 1, further comprising one or more pharmaceutically acceptable excipients or carriers, wherein the pharmaceutically acceptable excipients or carriers are selected from fillers, binders, diluents, disintegrants, flow promoters, and lubricants.

8. The pharmaceutical composition, formulation, or unit dosage form according to claim 1, further comprising one or more of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, sodium lauryl sulfate, and sodium stearyl fumarate.

9. The pharmaceutical composition, formulation, or unit dosage form according to claim 1, further comprising one or more of mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and stearyl fumarate sodium.

10. The pharmaceutical composition, formulation, or unit dosage form according to claim 7, wherein one or more pharmaceutically acceptable excipients or carriers are distributed between granules containing SDD and the granular portion of the pharmaceutical composition, formulation, or unit dosage form.

11. The pharmaceutical composition, formulation, or unit dosage form according to Claim 1, wherein the SDD contains compound 1 in a ratio of 2:1 to 1:2 (w / w) with respect to HPMC-AS (hydroxypropyl methylcellulose acetate, succinate), for example, the SDD contains compound 1 in a ratio of 1.5:1 to 1:1.5 (w / w) with respect to HPMC-AS, for example, the SDD contains compound 1 in a ratio of 1:1 (w / w) with respect to HPMC-AS.

12. a) 7.0 to 40.0% spray-dried intermediate, b) 18.0–70.0% microcrystalline cellulose, c) 18.0-70.0% mannitol, e) 4.6-20.0% croscarmellose sodium, d) 0.5-2.2% colloidal silicon dioxide, f) 0.0-2.0% sodium lauryl sulfate, and g) 0.1-0.5% sodium stearyl fumarate A pharmaceutical composition, formulation, or unit dosage form according to claim 1, comprising:

13. The spray-dried intermediate comprises a spray-dried solid containing compound 1:HPMC-AS (hydroxypropyl methylcellulose acetate, succinate) in a ratio of 1.5:1 to 1:1.5 w / w, and optionally contains one of the following components in the % w / w shown below. Table 1 The pharmaceutical composition, formulation, or unit dosage form according to claim 12.

14. A method for producing a pharmaceutical composition, preparation, or unit dosage form according to any one of claims 1 to 13, (1) A step of preparing an SDD (spray-dried dispersion) containing compound 1 or its solvate or pharmaceutically acceptable salt and a cellulosic polymer, (2) A step of blending SDD with the granular excipient, (3) Step of crushing the mixture, (4) Step of blending the mixture, (5) Step of dry granulation of the mixture, (6) The step of blending the dried granules with an external excipient, (7) Optionally, a step of filling capsules with the formulation. Methods that include...

15. The SSD is as follows: (1) Prepare a solution of compound 1 or a pharmaceutically acceptable salt thereof and a cellulosic polymer (optionally HPMCAS). (2) Filter the solution, (3) Spray drying the solution to produce SDI (spray drying intermediate), and (4) Optionally, the SDI may be dried by secondary tray drying. This is how you prepare an SSD. Prepared as follows: The method according to claim 14.

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