AXL / MER inhibitor formulations

Abstract

To provide compounds and methods of use thereof for modulation of AXL / MER kinases in treatment of cancer.SOLUTION: A pharmaceutical formulation in a solid oral dosage form comprises: (a) N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide, or a pharmaceutically acceptable salt, solvate or hydrate thereof; (b) an organic acid; and (c) a surfactant.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present application relates to pharmaceutical formulations and solid dosage forms of AXL / MER inhibitors, or pharmaceutically acceptable salts, solvates, or hydrates thereof, which are useful in the treatment of AXL / MER-mediated diseases, such as cancer, and methods for their preparation. [Background technology]

[0002] Receptor tyrosine kinases (RTKs) are cell surface proteins that transmit signals from the extracellular environment to the cytoplasm and nucleus of the cell to regulate cellular events such as survival, growth, proliferation, differentiation, adhesion, and migration.

[0003] The TAM subfamily consists of three RTKs, including Tyro3, ​​AXL, and MER (Graham et al., 2014, Nature Reviews Cancer 14, 769-785; Linger et al., 2008, Advances in Cancer Research 100, 35-83). TAM kinases are characterized by an extracellular ligand-binding domain consisting of two immunoglobulin-like domains and two fibronectin type III domains. Two ligands for TAM kinases have been identified: growth arrest specific 6 (GAS6) and protein S (PROS1). GAS6 can bind to and activate all three TAM kinases, while PROS1 is a ligand for Mer and Tyro3 (Graham et al., 2014, Nature Reviews Cancer 14, 769-785).

[0004] AXL (also known as UFO, ARK, JTK11, and TYRO7) was originally identified as a transforming gene from the DNA of patients with chronic myeloid leukemia (O'Bryan et al., 1991, Mol Cell Biol 11, 5016-5031; Graham et al., 2014, Nature Reviews Cancer 14, 769-785; Linger et al., 2008, Advances in Cancer Research 100, 35-83). GAS6 binds to AXL and induces its subsequent autophosphorylation and activation. AXL activates several downstream signaling pathways, including PI3K-Akt, Raf-MAPK, and PLC-PKC (Feneyrolles et al., 2014, Molecular Cancer Therapeutics 13, 2141-2148; Linger et al., 2008, Advances in Cancer Research 100, 35-83).

[0005] MER (also known as MERTK, EYK, RYK, RP38, NYK, and TYRO12) was originally identified as a phosphorylated protein from a lymphoblast expression library (Graham et al., 1995, Oncogene 10, 2349-2359; Graham et al., 2014, Nature Reviews Cancer 14, 769-785; Linger et al., 2008, Advances in Cancer Research 100, 35-83). Both GAS6 and PROS1 can bind to Mer and induce phosphorylation and activation of Mer kinase (Lew et al., 2014). Like AXL, MER activation also transduces downstream signaling pathways including PI3K-Akt and Raf-MAPK (Linger et al., 2008, Advances in Cancer Research 100, 35-83).

[0006] TYRO3 (also known as DTK, SKY, RSE, BRT, TIF, and ETK2) was originally identified through PCR-based cloning studies (Lai et al., Neuron 6, 691-70, 1991; Graham et al., 2014, Nature Reviews Cancer 14, 769-785; Linger et al., 2008, Advances in Cancer Research 100, 35-83). Both GAS6 and PROS1 ligands can bind to and activate TYRO3. The downstream signaling pathway of TYRO3 activation is the least studied among TAM RTKs, but both the PI3K-Akt and Raf-MAPK pathways appear to be involved (Linger et al., 2008, Advances in Cancer Research 100, 35-83). AXL, MER, and TYRO3 have been found to be overexpressed in cancer cells.

[0007] Thus, there is a need for compounds and methods of use for modulating AXL / MER kinase in the treatment of cancer. Summary of the Invention

[0008] The present invention is directed, inter alia, to a pharmaceutical formulation comprising N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, an organic acid, and a surfactant.

[0009] The present invention is further directed to dosage forms comprising the pharmaceutical formulations provided herein.

[0010] The present invention is further directed to a method of treating a disease associated with AXL / MER activity, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical formulation or dosage form provided herein. [Brief explanation of the drawings]

[0011] [Figure 1] 1 shows an XRPD pattern representative of Compound I maleate salt. [Figure 2] 1 shows a DSC thermogram representing Compound I maleate salt. [Figure 3] 1 shows TGA data representative of Compound I maleate salt. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention relates to pharmaceutical compositions (or formulations) and dosage forms of Compound I, or a pharmaceutically acceptable salt (e.g., Compound I maleate), hydrate, or solvate thereof, having improved properties, e.g., bioavailability. In particular, the formulations and dosage forms of the present invention help to increase the bioavailability of Compound I (e.g., Compound I maleate). Bioavailability can be enhanced by including an organic acid, such as citric acid, and a surfactant, such as poloxamer (e.g., poloxamer 407).

[0013] formulation The present invention relates to, inter alia, (a) N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound I), or a pharmaceutically acceptable salt (e.g., Compound 1 maleate), solvate, or hydrate thereof; (b) organic acids, and (c) providing a solid oral dosage pharmaceutical formulation comprising a surfactant.

[0014] Compound I is an AXL / MER inhibitor and refers to N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide, having the following formula:

[0015] [ka] Compound I Compound I maleate refers to N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide maleate, which is also referred to as "Compound I maleic acid" or "Compound I maleate." The present disclosure also includes other salts of Compound I. Examples of such salts include, for example, sulfate (e.g., hemisulfate), phosphate, hydrochloride, salicylate, methanesulfonate (i.e., mesylate), ethanesulfonate (i.e., esylate), benzenesulfonate (i.e., besylate), and p-toluenesulfonate (e.g., tosylate).

[0016] Compound I can be prepared according to the procedures of U.S. Patent No. 9,981,975. See, for example, Example 83. Compound I maleate and various crystalline forms can be prepared according to the procedures of U.S. Provisional Application No. 62 / 564,070. See also, for example, the Examples provided herein.

[0017] In some embodiments, Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof used herein, is in a crystalline form. In some embodiments, Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof used herein, is amorphous. In other embodiments, Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof used herein, is a hydrate. In some embodiments, Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof used herein, is a solvate. In some embodiments, Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof used herein, is anhydrous.

[0018] In some embodiments, Compound I maleate used herein is in a crystalline form. In some embodiments, Compound I maleate used herein is amorphous. In other embodiments, Compound I maleate used herein is a hydrate. In some embodiments, Compound I maleate used herein is a solvate. In some embodiments, Compound I maleate used herein is anhydrous.

[0019] In some embodiments, the present invention provides (a) Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) organic acids, and (c) providing a pharmaceutical formulation comprising a surfactant;

[0020] In certain embodiments, the pharmaceutical formulations provided herein further comprise a diluent. In certain embodiments, the pharmaceutical formulations provided herein further comprise a lubricant. In some embodiments, the pharmaceutical formulations provided herein can further comprise a disintegrant.

[0021] In some embodiments, the pharmaceutical formulation comprises about 1% to about 20% by weight of Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the pharmaceutical formulation comprises about 2% to about 15% by weight of Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the pharmaceutical formulation comprises about 3% to about 12% by weight of Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the pharmaceutical formulation comprises about 5% to about 10% by weight of Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the pharmaceutical formulation comprises about 3% to about 8% by weight of Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the pharmaceutical formulation comprises about 2% to about 6% by weight of Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the pharmaceutical formulation comprises about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% by weight of Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the pharmaceutical formulation comprises about 3% by weight of Compound I maleate. In some embodiments, the pharmaceutical formulation comprises about 12% by weight of Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0022] In some embodiments, the pharmaceutical formulation comprises about 1% to about 20% by weight of Compound I maleate. In some embodiments, the pharmaceutical formulation comprises about 2% to about 15% by weight of Compound I maleate. In some embodiments, the pharmaceutical formulation comprises about 3% to about 12% by weight of Compound I maleate. In some embodiments, the pharmaceutical formulation comprises about 5% to about 10% by weight of Compound I maleate. In some embodiments, the pharmaceutical formulation comprises about 3% to about 8% by weight of Compound I maleate. In some embodiments, the pharmaceutical formulation comprises about 2% to about 6% by weight of Compound I maleate. In some embodiments, the pharmaceutical formulation comprises about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% by weight of Compound I maleate. In some embodiments, the pharmaceutical formulation comprises about 3% by weight of Compound I maleate. In some embodiments, the pharmaceutical formulation comprises about 4% by weight of Compound I maleate. In some embodiments, the pharmaceutical formulation comprises about 7% by weight of Compound I maleate. In some embodiments, the pharmaceutical formulation comprises about 12% by weight of Compound I maleate.

[0023] Weight percentages and amounts of Compound I described herein are calculated based on the free base of Compound I unless otherwise specified.

[0024] The surfactants present in certain formulations of the present invention help to enhance the bioavailability of Compound I, or its pharmaceutically acceptable salts (e.g., Compound I maleate), solvates, or hydrates. The term "surfactant" refers to a compound that reduces the interfacial tension between two liquids or between a liquid and a solid. In some embodiments, surfactants can also have other functions, such as detergents, wetting agents, emulsifiers, foaming agents, and dispersants. Exemplary surfactants include, but are not limited to, poloxamers. Examples of poloxamers are poloxamer 407, poloxamer 338, poloxamer 237, and poloxamer 188. In one embodiment, the poloxamer is poloxamer 188. In one embodiment, the poloxamer is poloxamer 407. Poloxamers are polyethylene-propylene glycol copolymers (known under the trade names Supronic, Pluronic, or Tetronic) that have thermoreversible and sol-gel transition properties that can aid in drug release. For example, poloxamers exist in a sol state below room temperature and transform into a gel state at body temperature (37.2°C), thereby modifying the drug release properties (D. Ramya Devi et al., J. Pharm. Sci. & Res. Vol. 5(8), 2013, 159-165; Y. Mao et al., Journal of Pharmaceutical and Biomedical Analysis 35(2004) 1127-1142).

[0025] In some embodiments, the surfactant used in the formulation is poloxamer 407. It is unexpected that poloxamer 407 would enhance the bioavailability of Compound I maleate, particularly because solubility studies have shown that the surfactant sodium lauryl sulfate (SLS) increases the solubility of Compound I maleate compared to poloxamer 407, yet the bioavailability of formulations containing SLS is lower than that of formulations containing poloxamer. See the Examples provided herein.

[0026] The surfactant content in the formulation may be about 1% to about 20% by weight. The surfactant content in the formulation may be about 5% to about 15% by weight. The surfactant content in the formulation may be about 1% to about 10% by weight. The surfactant content in the formulation may be about 5% to about 10% by weight. For example, the surfactant content in the formulation may be about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, or about 20% by weight. In some embodiments, the surfactant content in the formulation is about 5% by weight. In some embodiments, the surfactant content in the formulation is about 10% by weight.

[0027] In some embodiments, the surfactant is poloxamer 407. The poloxamer (e.g., poloxamer 407) in the formulation can be about 1% to about 20% by weight. The poloxamer (e.g., poloxamer 407) in the formulation can be about 1% to about 10% by weight. The poloxamer (e.g., poloxamer 407) in the formulation can be about 5% to about 15% by weight. The poloxamer (e.g., poloxamer 407) in the formulation can be about 5% to about 10% by weight. For example, the poloxamer (e.g., poloxamer 407) in the formulation can be about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, or about 20% by weight. In some embodiments, the poloxamer (e.g., poloxamer 407) in the formulation is about 5% by weight. In some embodiments, the poloxamer (e.g., poloxamer 407) in the formulation is about 10% by weight.

[0028] The formulations of the present invention include an organic acid that can enhance the bioavailability of Compound I. The term "organic acid" refers to an organic compound having acidic properties. In some embodiments, the organic acid is a C substituted with one or more acidic groups (e.g., one, two, or three carboxylic acid, alcohol, or sulfonic acid groups). 1~6 Alkyl, C 2~6 alkenyl, or 5-6 membered heterocycloalkyl, which 5-6 membered heterocycloalkyl is optionally substituted with one or more acidic groups (e.g., 1, 2, 3, or 4 carboxylic acid, alcohol, or sulfonic acid groups). 1~6Organic acids are C substituted with one or more acidic groups (e.g., 1, 2, 3, or 4 carboxylic acid, alcohol, or sulfonic acid groups). 1~6 Alkyl or C 2~6 In some embodiments, the organic acid is a C alkyl group substituted with 1, 2, or 3 carboxylic acid groups and 0, 1, or 2 alcohol groups. 1~6 Alkyl or C 2~6 In some embodiments, the organic acid is substituted with one or more acidic groups (e.g., 1, 2, or 3 carboxylic acid, alcohol, or sulfonic acid groups) and optionally C 1~6 5-6 membered heterocycloalkyl substituted with alkyl, C 1~6 The alkyl is optionally substituted with one or more acidic groups (e.g., one, two, or three carboxylic acid, alcohol, or sulfonic acid groups). Exemplary organic acids include, but are not limited to, citric acid, ascorbic acid, fumaric acid, malic acid, sorbic acid, tartaric acid, and hydrates or solvates thereof. The organic acid in the formulation may be about 1% to about 50% by weight. The organic acid in the formulation may be about 5% to about 40% by weight. The organic acid in the formulation may be about 5% to about 30% by weight. The organic acid in the formulation may be about 5% to about 20% by weight. The organic acid in the formulation may be about 10% to about 20% by weight. For example, the organic acid in the formulation may be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50% by weight. In some embodiments, the organic acid in the formulation is about 10% by weight, hi some embodiments, the organic acid in the formulation is about 20% by weight.

[0029] In some embodiments, the organic acid is citric acid. In some embodiments, the citric acid is citric acid monohydrate. The citric acid in the formulation may be about 1% to about 50% by weight. The citric acid in the formulation may be about 5% to about 40% by weight. The citric acid in the formulation may be about 5% to about 30% by weight. The citric acid in the formulation may be about 5% to about 20% by weight. The citric acid in the formulation may be about 10% to about 20% by weight. For example, the citric acid in the formulation may be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50% by weight. In some embodiments, the citric acid in the formulation is about 10% by weight. In some embodiments, the citric acid in the formulation is about 20% by weight.

[0030] The pharmaceutical formulations provided herein may further comprise a diluent. As used herein, the term "diluent" refers to a compound capable of diluting a composition. A diluent may also be referred to as a filler, diluent, or thinner. Exemplary diluents include, but are not limited to, lactose, lactose monohydrate, spray-dried monohydrate lactose, lactose-316 Fast Flo®, mannitol, microcrystalline cellulose, acidified cellulose, starch 1500, Prosolv MCC, and colloidal silica. In certain instances, the diluent is mannitol. The diluent in the formulation may be about 40% to about 90% by weight. The diluent in the formulation may be about 50% to about 80% by weight. The diluent in the formulation may be about 50% to about 75% by weight. The diluent in the formulation may be about 70% to about 80% by weight. The diluent in the formulation may be about 72% to about 77% by weight. For example, the diluent in the formulation can be about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, or about 90% by weight. In some embodiments, the diluent in the formulation is about 50% by weight. In some embodiments, the diluent in the formulation is about 75% by weight. In some embodiments, the diluent in the formulation is about 73% by weight. In some embodiments, the diluent in the formulation is about 76% by weight.

[0031] In some embodiments, the formulations of the present invention include a disintegrant. As used herein, the term "disintegrant" refers to a compound that can cause a formulation (e.g., a capsule or tablet) to disintegrate and release its active pharmaceutical ingredient, for example, upon contact with moisture. A disintegrant can facilitate the disintegration of, for example, a capsule, after oral administration. The disintegrant can be present in an amount of about 1% to about 10% by weight. The disintegrant in the formulation can be about 2% to about 5% by weight. The disintegrant in the formulation can be about 2% to about 3% by weight. The disintegrant in the formulation can be about 2.5% by weight. Non-limiting examples of disintegrants include croscarmellose sodium, crospovidone, starch, cellulose, and low-substituted hydroxypropyl cellulose. In some embodiments, the disintegrant is crospovidone.

[0032] In some embodiments, the formulations of the present invention include a lubricant. As used herein, the term "lubricant" refers to a compound, e.g., an organic compound, that can reduce friction between substances in a formulation. The lubricant can be present in the formulation in an amount of about 1% to about 5% by weight. In some embodiments, the lubricant is present in an amount of about 2% by weight. Non-limiting examples of lubricants include magnesium stearate, stearic acid (stearin), hydrogenated oil, polyethylene glycol, sodium stearyl fumarate, and glyceryl behenate. In some embodiments, the lubricant is sodium stearyl fumarate or stearic acid. In some embodiments, the lubricant is stearic acid.

[0033] In some embodiments, the formulations provided herein include a glidant. As used herein, the term "glidant" refers to a compound that can improve the flow of a mixture, for example, a powder mixture in a capsule. The glidant can be present in the formulation in an amount of about 0.1% to about 5% by weight. In some embodiments, the glidant in the formulation is about 0.5% to about 1% by weight. In some embodiments, the glidant in the formulation is about 0.1% to about 1% by weight. In some embodiments, the glidant in the formulation is about 0.5% by weight. Non-limiting examples of glidants include talc, colloidal silica (colloidal silicon dioxide), and corn starch. In some embodiments, the glidant is colloidal silica.

[0034] In some embodiments, for example, when the formulations and dosage forms of the present invention are intended as sustained-release dosage forms, they may contain a sustained-release matrix-forming agent. Examples of sustained-release matrix-forming agents include cellulose ethers such as hydroxypropylmethylcellulose (HPMC, hypromellose), which is a high-viscosity polymer. The sustained-release dosage forms of the present invention may contain, for example, about 10 to about 30% by weight, about 15 to about 25% by weight, or about 18 to about 24% by weight of the sustained-release matrix-forming agent.

[0035] In some embodiments, (a) Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) citric acid, and (c) Provided herein are pharmaceutical formulations comprising a poloxamer.

[0036] In some embodiments, (a) about 2% to about 15% by weight of Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) about 5% to about 30% by weight of citric acid, and (c) Provided herein is a pharmaceutical formulation comprising about 5% to about 15% by weight of a poloxamer.

[0037] In some embodiments, (a) about 2% to about 15% by weight of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) about 5% to about 30% by weight of citric acid, and (c) Provided herein is a pharmaceutical formulation comprising about 1% to about 10% by weight of a poloxamer.

[0038] In some embodiments, (a) Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) citric acid, (c) poloxamers (e.g., poloxamer 407), and (d) Provided herein are pharmaceutical formulations that include a diluent (e.g., mannitol).

[0039] In some embodiments, (a) about 2% to about 15% by weight of Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) about 5% to about 30% by weight of citric acid; (c) about 5% to about 15% by weight of a poloxamer (e.g., poloxamer 407), and (d) Provided herein are pharmaceutical formulations comprising about 50% to about 80% by weight of a diluent (e.g., mannitol).

[0040] In some embodiments, (a) Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) citric acid, (c) poloxamers (e.g., poloxamer 407), (d) a diluent (e.g., mannitol), and (e) Provided herein are pharmaceutical formulations that include a lubricant (e.g., stearic acid).

[0041] In some embodiments, (a) about 2% to about 15% by weight of Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) about 5% to about 30% by weight of citric acid; (c) about 5% to about 15% by weight of a poloxamer (e.g., poloxamer 407); (d) about 50% to about 80% by weight of a diluent (e.g., mannitol), and (e) Provided herein are pharmaceutical formulations comprising about 1% to about 5% by weight of a lubricant (e.g., stearic acid).

[0042] In some embodiments, (a) Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) citric acid, (c) poloxamers (e.g., poloxamer 407), (d) a diluent (e.g., mannitol); (e) a lubricant (e.g., stearic acid), and (f) Provided herein are pharmaceutical formulations that include a disintegrant (e.g., crospovidone).

[0043] In some embodiments, (a) about 2% to about 15% by weight of Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) about 5% to about 30% by weight of citric acid; (c) about 5% to about 15% by weight of a poloxamer (e.g., poloxamer 407); (d) about 50% to about 80% by weight of a diluent (e.g., mannitol); (e) about 1% to about 5% by weight of a lubricant (e.g., stearic acid), and (f) Provided herein are pharmaceutical formulations comprising about 2% to about 5% by weight of a disintegrant (e.g., crospovidone).

[0044] In some embodiments, (a) about 2% to about 15% by weight of Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) about 5% to about 30% by weight of citric acid; (c) about 1% to about 10% by weight of a poloxamer (e.g., poloxamer 407); (d) about 50% to about 80% by weight of a diluent (e.g., mannitol); (e) about 1% to about 5% by weight of a lubricant (e.g., stearic acid), and (f) Provided herein are pharmaceutical formulations comprising about 2% to about 5% by weight of a disintegrant (e.g., crospovidone).

[0045] In some embodiments, (a) about 2% to about 15% by weight of Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) about 5% to about 30% by weight of citric acid; (c) about 5% to about 15% by weight of poloxamer 407; (d) about 50% by weight to about 80% by weight of mannitol; (e) about 1% to about 5% by weight of stearic acid, and (f) Provided herein is a pharmaceutical formulation comprising about 2% to about 5% by weight of crospovidone.

[0046] In some embodiments, (a) about 2% to about 15% by weight of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) about 5% to about 30% by weight of citric acid; (c) about 1% to about 10% by weight of poloxamer 407; (d) about 50% by weight to about 80% by weight of mannitol; (e) about 1% to about 5% by weight of stearic acid, and (f) Provided herein is a pharmaceutical formulation comprising about 2% to about 5% by weight of crospovidone.

[0047] In some embodiments, (a) about 12% by weight of Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) about 20% by weight citric acid, and (c) Provided herein is a pharmaceutical formulation comprising about 10% by weight of poloxamer 407.

[0048] In some embodiments, (a) about 12% by weight of Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) about 20% by weight citric acid; (c) about 10% by weight of poloxamer 407; (d) about 50% by weight of mannitol; (e) about 2% by weight of stearic acid, and (f) Provided herein is a pharmaceutical formulation comprising about 5% by weight of crospovidone.

[0049] In some embodiments, (a) about 3% by weight of Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) about 20% by weight citric acid, and (c) Provided herein is a pharmaceutical formulation comprising about 10% by weight of poloxamer 407.

[0050] In some embodiments, (a) about 3% by weight of Compound I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) about 20% by weight citric acid; (c) about 10% by weight of poloxamer 407; (d) about 60% by weight of mannitol; (e) about 2% by weight of stearic acid, and (f) Provided herein is a pharmaceutical formulation comprising about 5% by weight of crospovidone.

[0051] In some embodiments, (a) Compound I maleate, or a solvate or hydrate thereof; (b) citric acid, and (c) Provided herein are pharmaceutical formulations comprising a poloxamer.

[0052] In some embodiments, (a) about 2% to about 15% by weight of Compound I maleate, or a solvate or hydrate thereof; (b) about 5% to about 30% by weight of citric acid, and (c) Provided herein is a pharmaceutical formulation comprising about 5% to about 15% by weight of a poloxamer.

[0053] In some embodiments, (a) Compound I maleate, or a solvate or hydrate thereof; (b) citric acid, (c) poloxamers (e.g., poloxamer 407), and (d) Provided herein are pharmaceutical formulations that include a diluent (e.g., mannitol).

[0054] In some embodiments, (a) about 2% to about 15% by weight of Compound I maleate, or a solvate or hydrate thereof; (b) about 5% to about 30% by weight of citric acid; (c) about 5% to about 15% by weight of a poloxamer (e.g., poloxamer 407), and (d) Provided herein are pharmaceutical formulations comprising about 50% to about 80% by weight of a diluent (e.g., mannitol).

[0055] In some embodiments, (a) Compound I maleate, or a solvate or hydrate thereof; (b) citric acid, (c) poloxamers (e.g., poloxamer 407), (d) a diluent (e.g., mannitol), and (e) Provided herein are pharmaceutical formulations that include a lubricant (e.g., stearic acid).

[0056] In some embodiments, (a) about 2% to about 15% by weight of Compound I maleate, or a solvate or hydrate thereof; (b) about 5% to about 30% by weight of citric acid; (c) about 5% to about 15% by weight of a poloxamer (e.g., poloxamer 407); (d) about 50% to about 80% by weight of a diluent (e.g., mannitol), and (e) Provided herein are pharmaceutical formulations comprising about 1% to about 5% by weight of a lubricant (e.g., stearic acid).

[0057] In some embodiments, (a) Compound I maleate, or a solvate or hydrate thereof; (b) citric acid, (c) poloxamers (e.g., poloxamer 407), (d) a diluent (e.g., mannitol); (e) a lubricant (e.g., stearic acid), and (f) Provided herein are pharmaceutical formulations that include a disintegrant (e.g., crospovidone).

[0058] In some embodiments, (a) Compound I maleate, or a solvate or hydrate thereof; (b) citric acid, (c) poloxamers (e.g., poloxamer 407), (d) a diluent (e.g., mannitol); (e) lubricants (e.g., stearic acid); (f) a disintegrant (e.g., crospovidone), and (g) Provided herein are pharmaceutical formulations that include a glidant (e.g., colloidal silica).

[0059] In some embodiments, (a) about 2% to about 15% by weight of Compound I maleate, or a solvate or hydrate thereof; (b) about 5% to about 30% by weight of citric acid; (c) about 5% to about 15% by weight of a poloxamer (e.g., poloxamer 407); (d) about 50% to about 80% by weight of a diluent (e.g., mannitol); (e) about 1% to about 5% by weight of a lubricant (e.g., stearic acid), and (f) Provided herein are pharmaceutical formulations comprising about 2% to about 5% by weight of a disintegrant (e.g., crospovidone).

[0060] In some embodiments, (a) about 2% to about 15% by weight of Compound I maleate, or a solvate or hydrate thereof; (b) about 5% to about 30% by weight of citric acid; (c) about 5% to about 15% by weight of poloxamer 407; (d) about 50% by weight to about 80% by weight of mannitol; (e) about 1% to about 5% by weight of stearic acid, and (f) Provided herein is a pharmaceutical formulation comprising about 2% to about 5% by weight of crospovidone.

[0061] In some embodiments, (a) about 12% by weight of Compound I maleate, or a solvate or hydrate thereof; (b) about 20% by weight citric acid, and (c) Provided herein is a pharmaceutical formulation comprising about 10% by weight of poloxamer 407.

[0062] In some embodiments, (a) about 12% by weight of Compound I maleate, or a solvate or hydrate thereof; (b) about 20% by weight citric acid; (c) about 10% by weight of poloxamer 407; (d) about 50% by weight of mannitol; (e) about 2% by weight of stearic acid, and (f) Provided herein is a pharmaceutical formulation comprising about 5% by weight of crospovidone.

[0063] In some embodiments, (a) about 3% by weight of Compound I maleate, or a solvate or hydrate thereof; (b) about 20% by weight citric acid, and (c) Provided herein is a pharmaceutical formulation comprising about 10% by weight of poloxamer 407.

[0064] In some embodiments, (a) about 4% by weight of Compound I maleate, or a solvate or hydrate thereof; (b) about 10% by weight citric acid, and (c) Provided herein is a pharmaceutical formulation comprising about 5% by weight of poloxamer 407.

[0065] In some embodiments, (a) about 7% by weight of Compound I maleate, or a solvate or hydrate thereof; (b) about 10% by weight citric acid, and (c) Provided herein is a pharmaceutical formulation comprising about 5% by weight of poloxamer 407.

[0066] In some embodiments, (a) about 3% by weight of Compound I maleate, or a solvate or hydrate thereof; (b) about 20% by weight citric acid; (c) about 10% by weight of poloxamer 407; (d) about 60% by weight of mannitol; (e) about 2% by weight of stearic acid, and (f) Provided herein is a pharmaceutical formulation comprising about 5% by weight of crospovidone.

[0067] In some embodiments, (a) about 4% by weight of Compound I maleate, or a solvate or hydrate thereof; (b) about 10% by weight of citric acid; (c) about 5% by weight of poloxamer 407; (d) about 76% by weight of mannitol; (e) about 2% by weight of stearic acid; (f) about 2.5% by weight of crospovidone, and (g) Provided herein is a pharmaceutical formulation comprising about 0.5% by weight of colloidal silica.

[0068] In some embodiments, (a) about 7% by weight of Compound I maleate, or a solvate or hydrate thereof; (b) about 10% by weight of citric acid; (c) about 5% by weight of poloxamer 407; (d) about 73% by weight of mannitol; (e) about 2% by weight of stearic acid; (f) about 2.5% by weight of crospovidone, and (g) Provided herein is a pharmaceutical formulation comprising about 0.5% by weight of colloidal silica.

[0069] The solid dosage pharmaceutical formulations provided herein suitable for oral administration can be prepared by blending Compound I maleate with an organic acid and a surfactant. The resulting pharmaceutical formulation can be further prepared to form a capsule.

[0070] In some embodiments, Compound I, or its pharmaceutically acceptable salt (e.g., Compound I maleate), solvate, or hydrate, is in a crystalline form. The crystalline form of Compound I maleate is disclosed in U.S. Provisional Application No. 62 / 564,070, which is incorporated by reference in its entirety. See also, for example, the Examples provided herein.

[0071] In some embodiments, the maleate salt of Compound I has at least one XRPD peak in 2-theta selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5°. In some embodiments, the maleate salt of Compound I has at least two XRPD peaks in 2-theta selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5°. In some embodiments, the maleate salt of Compound I has at least three XRPD peaks in 2-theta selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5°. In some embodiments, the maleate salt of Compound I has at least four XRPD peaks in 2-theta selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5°. In some embodiments, the maleate salt of Compound I comprises the following XRPD peaks in 2-theta: about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5°. In some embodiments, the maleate salt of Compound I comprises the following XRPD peaks in 2-theta: about 4.3°, about 8.4°, and about 13.2°.

[0072] In some embodiments, the maleate salt of Compound I has an XRPD profile substantially as shown in FIG.

[0073] Similarly, temperature readings for DSC, TGA, or other thermal experiments may vary by about ±3°C depending on the instrument, specific settings, sample preparation, etc. Accordingly, crystalline forms reported herein having a DSC thermogram "substantially" as shown in any of the figures or the term "about" are understood to accommodate such variations. In some embodiments, the maleate salt of Compound I has a DSC thermogram with an endothermic peak at about 211°C. In some embodiments, the maleate salt of Compound I has a DSC thermogram substantially as shown in Figure 2. In some embodiments, the maleate salt of Compound I has a TGA thermogram substantially as shown in Figure 3.

[0074] In some embodiments, Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate is substantially isolated. "Substantially isolated" means that the salt or compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in a salt described herein. Substantial separation can include a composition containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of a salt described herein, or a salt thereof. Methods for isolating compounds and their salts are routine in the art.

[0075] The present application also relates to solid dosage forms comprising the pharmaceutical formulations provided herein. In some embodiments, the solid dosage forms are suitable for oral administration. In some embodiments, the dosage forms provided herein are in the form of tablets, capsules, pills, powders, sachets, and soft and hard gelatin capsules. In other embodiments, the dosage forms provided herein are in the form of capsules.

[0076] When preparing a formulation, Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate thereof, can be milled to provide an appropriate particle size before combining with other ingredients. Compound I maleate can be milled to a particle size of less than 200 mesh. The particle size can be adjusted by milling, for example, to about 40 mesh, to provide a substantially uniform distribution in the formulation.

[0077] Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate thereof, can be milled using known milling procedures to obtain a particle size appropriate for tablet formation and other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by processes known in the art, see, for example, International Application No. WO 2002 / 000196.

[0078] The formulation of the present invention can contain additional excipients.Suitable examples of additional excipients include dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose.Other excipients include lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propylhydroxybenzoates; sweeteners; and flavoring agents.The composition of the present invention can be formulated to provide rapid, sustained or delayed release of active ingredients after administration to patients by using procedures known in the art.

[0079] The present invention further provides a dosage form comprising any of the above formulations of the present invention. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0080] To prepare solid dosage forms such as capsules, Compound I maleate can be mixed with excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the invention. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically dispersed evenly throughout the composition, allowing the composition to be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms (e.g., capsules) of the type described above, containing, for example, about 0.1 to about 1000 mg of Compound I, or a pharmaceutically acceptable salt (e.g., Compound I maleate), solvate, or hydrate thereof, on a free base basis. In some embodiments, the unit dosage form (e.g., capsule) contains about 1 to about 500 mg, about 1 to about 200 mg, about 1 to about 100 mg, about 1 to about 50 mg, or about 1 to about 30 mg of Compound I, or a pharmaceutically acceptable salt (e.g., Compound I maleate), solvate, or hydrate thereof, on a free base basis. In some embodiments, a unit dosage form (e.g., a capsule) contains about 5 to about 50 mg of Compound I, or a pharmaceutically acceptable salt (e.g., Compound I maleate), solvate, or hydrate thereof, based on the free base, such as about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg of Compound I, or a pharmaceutically acceptable salt (e.g., Compound I maleate), solvate, or hydrate thereof, based on the free base. In some embodiments, a unit dosage form (e.g., a capsule) contains about 5 mg of Compound I, or a pharmaceutically acceptable salt (e.g., Compound I maleate), solvate, or hydrate thereof, based on the free base. In some embodiments, a unit dosage form (e.g., a capsule) contains about 15 mg of Compound I, or a pharmaceutically acceptable salt (e.g., Compound I maleate), solvate, or hydrate thereof, on a free base basis. In some embodiments, a unit dosage form (e.g., a capsule) contains about 20 mg of Compound I, or a pharmaceutically acceptable salt (e.g., Compound I maleate), solvate, or hydrate thereof, on a free base basis.In some embodiments, the unit dosage form (e.g., capsule) contains about 25 mg of Compound I on a free base basis, or a pharmaceutically acceptable salt (e.g., Compound I maleate), solvate, or hydrate thereof.

[0081] Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate, unit dosage form (e.g., capsule) can be administered to a subject once a day, twice a day, three times a day, four times a day, etc. Those skilled in the art will know that two 5 mg capsules can be administered together to obtain a 10 mg unit dose. Compound I maleate can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by a physician according to relevant circumstances, including the condition being treated, the selected route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0082] In some embodiments, about 5 mg to about 200 mg of Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate, is administered to a subject once daily. In some embodiments, about 10 mg to about 100 mg of Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate, is administered to a subject once daily.

[0083] In some embodiments, about 5 mg to about 200 mg of Compound I maleate is administered to a subject once daily. In some embodiments, about 10 mg to about 100 mg of Compound I maleate is administered to a subject once daily. In some embodiments, about 10 mg of Compound I maleate is administered to a subject once daily (e.g., two 5 mg capsules or one 10 mg capsule per 24 hour period). In some embodiments, about 15 mg of Compound I maleate is administered to a subject once daily. In some embodiments, about 20 mg of Compound I maleate is administered to a subject once daily. In some embodiments, about 25 mg of Compound I maleate is administered to a subject once daily. In some embodiments, about 40 mg of Compound I maleate is administered to a subject once daily. In some embodiments, about 50 mg of Compound I maleate is administered to a subject once daily. In some embodiments, about 75 mg of Compound I maleate is administered to a subject once daily. In some embodiments, about 80 mg of Compound I maleate is administered to a subject once daily. In some embodiments, about 100 mg of Compound I maleate is administered to a subject once daily. In some embodiments, about 150 mg of Compound I maleate is administered to a subject once daily. In some embodiments, about 160 mg of Compound I maleate is administered to a subject once daily. In some embodiments, about 200 mg of Compound I maleate is administered to a subject once daily.

[0084] definition The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The term "substituted" refers to any level of substitution where such substitution is permitted, e.g., mono-, di-, tri-, tetra-, or penta-substitution, unless otherwise specified. Substituents are independently selected, and substitution can be at any chemically accessible position. It should be understood that substitution at a given atom is limited by valence. It should be understood that substitution at a given atom results in a chemically stable molecule. The phrase "optionally substituted" means unsubstituted or substituted. The term "substituted" means that a hydrogen atom has been removed and replaced with a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.

[0085] "C n~m " denotes an inclusive range, where n and m are integers and indicate the number of carbons. Examples include C 1~4 , C 1~6 Examples include:

[0086] The term "alkyl," used alone or in combination with other terms, refers to a saturated hydrocarbon group which may be straight-chained or branched. n~m The term "alkyl" refers to an alkyl group having n to m carbon atoms. An alkyl group formally corresponds to an alkane with one C-H bond replaced by the alkyl group's point of attachment to the rest of the compound. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, etc.

[0087] The term "alkenyl," used alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds. An alkenyl group formally corresponds to an alkene with one C-H bond replaced by the point of attachment of the alkenyl group to the rest of the compound. n~m The term "alkenyl" refers to an alkenyl group having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0088] The term "heterocycloalkyl," used alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus, and has 4 to 10 ring members, 4 to 7 ring members, or 4 to 6 ring members. The term "heterocycloalkyl" includes monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include monocyclic or bicyclic (e.g., having two fused or bridged rings) or spirocyclic ring systems. In some embodiments, heterocycloalkyl groups are monocyclic groups having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group may be optionally oxidized to form oxo or sulfido groups or other oxidized linkages (e.g., C(O), S(O), C(S), or S(O), N-oxide, etc.), or the nitrogen atom may be quaternized. A heterocycloalkyl group can be bonded through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, a heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, a heterocycloalkyl group contains 0 to 2 double bonds. Also included within the definition of heterocycloalkyl are moieties having one or more aromatic rings fused (i.e., having a common bond) to the heterocycloalkyl ring, such as benzo or thienyl derivatives, e.g., piperidine, morpholine, azepine, etc. Heterocycloalkyl groups containing fused aromatic rings can be bonded through any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. Examples of heterocycloalkyl groups include dihydroxyfuranones.

[0089] As used herein, maleic acid is also known as cis-butenedioic acid.

[0090] As used herein, and unless otherwise specified, the term "about" refers to a numerical value or range of values ​​provided to describe a particular salt or solid form, such as a particular temperature or temperature range (e.g., those describing melting, dehydration, or glass transitions), mass change (e.g., mass change as a function of temperature or humidity), solvent content or water content (e.g., in terms of mass or percentage), or peak position (e.g., 13 When used in reference to a value (e.g., in analyses by C NMR, DSC, TGA, and XRPD), the term "about" indicates that the value or range of values ​​may deviate to an extent deemed reasonable by one of ordinary skill in the art, but still describe a particular solid form. Specifically, the term "about" when used in this context indicates that the numerical value or range of values ​​may vary by 5%, 4%, 3%, 2%, or 1% of the recited value or range of values, but still describe a particular solid form. In some embodiments, the term "about" indicates that the numerical value or range of values ​​may vary by 5%. When used in reference to degree 2-theta values, the term "about" refers to + / - 0.3 degrees 2-theta or + / - 0.2 degrees 2-theta. As used herein, the terms "blend," "blending," and "blended" refer to combining or mixing different materials to obtain a mixture. The resulting blended mixture may be homogeneous.

[0091] The term "hydrate," as used herein, is meant to refer to a solid form of Compound I maleate that contains water. The water in a hydrate may be present in a stoichiometric amount relative to the amount of salt in the solid, or may be present in a variable amount, as may be found in channel hydrates. In some embodiments, Compound I maleate is a monohydrate (e.g., the molar ratio of salt to water is about 1:1). In some embodiments, Compound I maleate is a dihydrate (e.g., the molar ratio of salt to water is about 1:2). In some embodiments, Compound I maleate is a hemihydrate (e.g., the molar ratio of salt to water is about 2:1). In some embodiments, Compound I maleate has one or more water molecules per salt molecule.

[0092] Compound I or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate) may also be in the form of a solvate. The term "solvate" refers to a solid form containing solvent molecules with Compound I or a pharmaceutically acceptable salt thereof (e.g., maleate). The solvent may be an organic compound, an inorganic compound, or a mixture of both. A solvate in which the solvent is water is generally referred to as a "hydrate" or "hydrate form." The term "hydrate" refers to a solid form containing water molecules with Compound I or a pharmaceutically acceptable salt thereof (e.g., maleate).

[0093] As used herein, the term "anhydrous" refers to a compound (e.g., Compound I, Compound I maleate) that does not contain water or solvent. For example, Compound I or its maleate salt can be in a solid form that does not contain water or solvent, e.g., less than 1% by weight, less than 0.5% by weight, less than 0.4% by weight, less than 0.3% by weight, less than 0.2% by weight, or less than 0.1% by weight of water or solvent is present.

[0094] As used herein, the term "peak" or "characteristic peak" refers to a reflection having a relative height / intensity of at least about 3% of the maximum peak height / intensity.

[0095] As used herein, "crystalline" or "crystalline form" refers to a crystalline solid form of a chemical compound, including, but not limited to, a single-component crystalline form or a multi-component crystalline form, including, for example, solvates, hydrates, clathrates, and co-crystals.

[0096] The term "crystalline form" is meant to refer to a particular lattice configuration of a crystalline substance. Different crystalline forms of the same substance typically have different crystal lattices (e.g., unit cells) and typically have different physical properties resulting from those different crystal lattices, and in some cases, different water or solvent content. Different crystal lattices can be identified by solid-state characterization methods, such as X-ray powder diffraction (XRPD). Other characterization methods, such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), and the like, further aid in identifying crystalline forms, as well as determining stability and solvent / water content.

[0097] Different crystalline forms of a particular substance, e.g., Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate, can include both anhydrous forms of the substance and solvated / hydrated forms of the substance, each of which is distinguishable from the other by a different XRPD pattern or other solid-state characterization method, thereby representing a different crystalline lattice. In some cases, a single crystalline form (e.g., identified by a unique XRPD pattern) can have variable water or solvent content, and the lattice remains substantially unchanged (as well as the XRPD pattern) despite compositional variations with respect to water and / or solvent.

[0098] An XRPD pattern of reflections (peaks) is typically considered a fingerprint of a particular crystalline form. It is well known that the relative intensities of XRPD peaks can vary widely depending on, among other things, the sample preparation technique, the crystal size distribution, the filter used, the sample mounting procedure, and the particular instrument employed. In some cases, new peaks may be observed or existing peaks may disappear depending on the type or settings of the instrument (e.g., whether a Ni filter is used). As used herein, the term "peak" refers to a reflection having a relative height / intensity of at least about 3% or at least about 4% of the maximum peak height / intensity. Furthermore, instrumental variations and other factors can affect 2-theta values. Thus, peak assignments such as those reported herein may vary by plus or minus about 0.2° (2-theta) or about 0.3° (2-theta), and the term "substantially," as used herein in the context of XRPD, is meant to encompass the aforementioned variations.

[0099] Similarly, temperature readings for DSC, TGA, or other thermal experiments can vary by approximately ±3° C. depending on the instrument, the particular settings, sample preparation, etc.

[0100] Crystalline forms of a substance can be obtained by many methods known in the art, including, but not limited to, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces such as, for example, nanopores or capillaries, recrystallization on a surface or template such as, for example, on a polymer, recrystallization in the presence of additives such as, for example, co-crystallized counter molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, moisture exposure, grinding, and solvent drop grinding.

[0101] As used herein, the terms "amorphous" or "amorphous form" are intended to mean that the substance, component, or product in question is substantially not crystalline, e.g., as determined by XRPD, or that the substance, component, or product in question is not birefringent when viewed under a microscope, e.g., In certain embodiments, a sample comprising an amorphous form of a substance may be substantially free of other amorphous and / or crystalline forms. For example, an amorphous substance can be identified by an XRPD spectrum in which reflections are absent.

[0102] In some embodiments, Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate provided herein, is prepared in batches, referred to as batches, samples, or preparations. A batch, sample, or preparation can contain Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate, in any of the crystalline or amorphous forms described herein, including hydrated and non-hydrated forms, and mixtures thereof.

[0103] As used herein, the term "crystalline purity" means the percentage of a crystalline form in a preparation or sample that may contain other forms, such as an amorphous form of the same compound, or at least one other crystalline form of that compound, or a mixture thereof.

[0104] As used herein, the term "substantially crystalline" means that the majority by weight of a sample or preparation of Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate, is crystalline, with the remainder of the sample being a non-crystalline form (e.g., amorphous form) of Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate. In some embodiments, a substantially crystalline sample has at least about 95% crystallinity (e.g., about 5% amorphous form), preferably at least about 96% crystallinity (e.g., about 4% amorphous form), more preferably at least about 97% crystallinity (e.g., about 3% amorphous form), even more preferably at least about 98% crystallinity (e.g., about 2% amorphous form), still more preferably at least about 99% crystallinity (e.g., about 1% amorphous form), and most preferably about 100% crystallinity (e.g., about 0% amorphous form). In some embodiments, the term "fully crystalline" refers to a crystallinity of at least about 99% or about 100%.

[0105] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, within the scope of safe medical judgment, and commensurate with a reasonable benefit / risk ratio.

[0106] A variety of pharmaceutically acceptable excipients can be used in the formulations described herein. As used herein, a "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients are generally safe, non-toxic, and not biologically or otherwise undesirable, and include excipients that are acceptable for veterinary use as well as human pharmaceutical use. In one embodiment, each component is "pharmaceutically acceptable" as defined herein. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005, Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009, Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007, Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0107] As used herein, the term "contacting" refers to joining the indicated moieties in an in vitro system or in vivo system. For example, "contacting" AXL / MER kinase with a compound of the invention includes administering a compound of the invention to an individual or patient, such as a human, having AXL / MER kinase, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing AXL / MER kinase.

[0108] As used herein, the terms "individual," "patient," or "subject," used interchangeably, refer to any animal, including a mammal, preferably a mouse, rat, monkey, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, and most preferably a human.

[0109] As used herein, the phrase "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits the biological or pharmacological response sought in a tissue, system, animal, individual, or human by a researcher, veterinarian, physician, or other clinician. The therapeutically effective amount will vary depending on the compound, the disease, disorder, or condition and its severity, as well as the age, weight, etc., of the mammal being treated. Generally, good results in subjects have been shown to be obtained with a daily dose of about 0.1 to about 10 g / kg of the subject's body weight. In some embodiments, the daily dose ranges from about 0.10 to 10.0 mg / kg of body weight, about 1.0 to 3.0 mg / kg of body weight, about 3 to 10 mg / kg of body weight, about 3 to 150 mg / kg of body weight, about 3 to 100 mg / kg of body weight, about 10 to 100 mg / kg of body weight, about 10 to 150 mg / kg of body weight, or about 150 to 1000 mg / kg of body weight. The dosage may conveniently be administered in divided doses, for example, up to four times a day, or in sustained release form.

[0110] As used herein, the term "treat" or "treatment" refers to inhibiting a disease, e.g., inhibiting a disease, condition, or disorder (i.e., halting further development of the pathology and / or symptomology) in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder, or ameliorating a disease, e.g., ameliorating a disease, condition, or disorder (i.e., reversing the pathology and / or symptomology) in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder, e.g., reducing the severity of the disease.

[0111] How to use Compound I of the present disclosure, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate thereof, can regulate or inhibit the activity of AXL / MER kinase. For example, Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate thereof, can be used to inhibit the activity of AXL / MER enzyme in cells, individuals, or patients in need of kinase inhibition by administering an inhibitory amount of Compound I maleate to the cells, individuals, or patients. Thus, pharmaceutical formulations containing Compound I maleate can be used to inhibit the activity of AXL / MER kinase.

[0112] In some embodiments, Compound I, or a pharmaceutically acceptable salt (e.g., Compound I maleate), solvate, or hydrate thereof, is selective for AXL / MER kinase over one or more other kinases. In some embodiments, the selectivity is 2-fold or more, 3-fold or more, 5-fold or more, 10-fold or more, 25-fold or more, 50-fold or more, or 100-fold or more.

[0113] Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate thereof, can inhibit one or more of AXL and MER. In some embodiments, Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate thereof, is selective for one TAM kinase over another. By "selective," it is meant that the compound binds to or inhibits a TAM kinase with greater affinity or potency, respectively, compared to a reference enzyme, e.g., another TAM kinase. For example, Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate thereof, can be selective for AXL over MER and TYRO3, or can be selective for MER over AXL and TYRO3, or is selective for AXL and MER over TYRO3. In some embodiments, Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate thereof, is selective for AXL and MER over TYRO3 and other kinases. In some embodiments, provided herein are methods for inhibiting AXL and MER kinases, the methods comprising contacting AXL and MER kinases with compound I, or a pharmaceutically acceptable salt (e.g., compound I maleate), solvate, or hydrate thereof.

[0114] As an AXL / MER kinase inhibitor, Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate, is useful in the treatment of various diseases associated with abnormal expression or activity of AXL / MER kinase. Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate, may be particularly useful in preventing tumor growth or inducing apoptosis by inhibiting angiogenesis. Thus, Compound I, or a pharmaceutically acceptable salt thereof (e.g., Compound I maleate), solvate, or hydrate, is expected to prove useful in the treatment or prevention of proliferative disorders such as cancer. In particular, tumors with activated mutants of receptor tyrosine kinases or upregulated receptor tyrosine kinases may be particularly sensitive to inhibitors.

[0115] In certain embodiments, the present disclosure provides a method for treating a disease or disorder mediated by AXL / MER kinase in a patient in need thereof, the method comprising administering to the patient a pharmaceutical formulation comprising Compound I, or a pharmaceutically acceptable salt (e.g., Compound I maleate), solvate, or hydrate thereof.

[0116] For example, the pharmaceutical formulations of the present disclosure are useful in the treatment of cancer. Examples of cancer include bladder cancer, breast cancer, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, head and neck cancer (e.g., cancer of the larynx, hypopharynx, nasopharynx, oropharynx, lip, and mouth), kidney cancer, liver cancer (e.g., hepatocellular carcinoma, cholangiocarcinoma), lung cancer (e.g., adenocarcinoma, small cell and non-small cell lung cancer, small cell and non-small cell carcinoma, bronchial carcinoma, bronchial adenoma, pleuropulmonary blastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), stomach cancer, thyroid cancer, parathyroid cancer, skin cancer (e.g., squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer), and brain tumors (e.g., astrocytoma, medulloblastoma, ependymoma, neuroexocrine tumor, pineal tumor).

[0117] Other cancers treatable with the compounds of the present disclosure include bone cancer, intraocular cancer, gynecological cancer, cancer of the endocrine system, cancer of the adrenal gland, soft tissue sarcoma, cancer of the urethra, cancer of the penis, pituitary cancer, triple-negative breast cancer (TNBC), and environmentally induced cancers, including those induced by asbestos.

[0118] Further examples of cancer include hematopoietic malignancies such as leukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acute myeloid leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma, myeloproliferative neoplasms (e.g., polycythemia vera, essential thrombocythemia, and primary myelofibrosis), Waldenstrom's macroglobulinemia, hairy cell lymphoma, chronic myeloid lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphoma, and Burkitt's lymphoma.

[0119] Other cancers treatable with the pharmaceutical formulations of the present disclosure include eye tumors, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, and osteosarcoma.

[0120] The pharmaceutical formulations of the present disclosure may also be useful in inhibiting tumor metastasis.

[0121] In some embodiments, diseases and indications treatable using the pharmaceutical formulations of the present disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

[0122] Exemplary hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), non-Hodgkin's lymphoma (including relapsed or refractory NHL), follicular These include lymphoma (FL), Hodgkin's lymphoma, lymphoblastic lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic leukemia (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, chronic myelogenous lymphoma, and Burkitt's lymphoma.

[0123] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0124] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, chondroitin hamartoma, and mesothelioma.

[0125] Exemplary gastrointestinal cancers include cancer of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0126] Exemplary genitourinary tract cancers include cancer of the kidney (adenocarcinoma, Wilms' tumor [nephroblastoma], renal cell carcinoma), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, urothelial carcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma).

[0127] Exemplary liver cancers include hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0128] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign cartilage tumor, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor.

[0129] Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma, Lhermitte-Duclos disease, tumors of the central nervous system (CNS), primary CNS lymphoma, and tumors of the spinal axis.

[0130] Exemplary gynecological cancers include cancer of the uterus (endometrial cancer), cervix (cervical carcinoma, preneoplastic cervical dysplasia), ovary (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma)), and fallopian tube (carcinoma).

[0131] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, lenticular dysplastic nevi, lipoma, hemangioma, dermatofibroma, and keloids.

[0132] Exemplary head and neck cancers include glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cavity cancer, laryngeal cancer, nasopharyngeal cancer, nasal and paranasal sinus cancer, thyroid and parathyroid cancer.

[0133] In some embodiments, the present disclosure provides a method for treating hepatocellular carcinoma in a patient in need thereof, the method comprising administering to the patient a pharmaceutical formulation described herein.

[0134] In some embodiments, the present disclosure provides a method for treating rhabdomyosarcoma, esophageal cancer, breast cancer, or head and neck cancer in a patient in need thereof, the method comprising administering to the patient a pharmaceutical formulation described herein.

[0135] In some embodiments, the cancer is selected from hepatocellular carcinoma, breast cancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lung cancer, prostate cancer, pancreatic cancer, testicular cancer, thyroid cancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterine cancer, and rhabdomyosarcoma.

[0136] In some embodiments, the cancer is selected from hepatocellular carcinoma, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, Burkitt's lymphoma, glioblastoma, melanoma, and rhabdomyosarcoma.

[0137] In some embodiments, the cancer is selected from lung cancer, prostate cancer, colon cancer, breast cancer, melanoma, renal cell carcinoma, multiple myeloma, gastric cancer, and rhabdomyosarcoma.

[0138] Targeting TAM receptor tyrosine kinases can provide a therapeutic approach for treating viral diseases (T Shibata, et al. The Journal of Immunology, 2014, 192, 3569-3581). The present disclosure provides a method for treating infectious diseases, such as viral infections. The method includes administering a therapeutically effective amount of a pharmaceutical formulation described herein to a patient in need of treatment for the infectious disease.

[0139] Examples of viruses that cause infectious diseases treatable by the methods of the present disclosure include, but are not limited to, human immunodeficiency virus, human papillomavirus, influenza, hepatitis A, B, C, or D virus, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, Marburg virus, and measles virus. In some embodiments, viruses causing infections treatable by the methods of the present disclosure include, but are not limited to, hepatitis (A, B, or C), herpesviruses (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus (e.g., West Nile, dengue, tick-borne encephalitis, yellow fever, Zika), echovirus, rhinovirus, coxsackievirus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum contagiosum virus, poliovirus, rabies virus, JC virus, and arboviral encephalitis virus.

[0140] In some embodiments, the present disclosure provides methods for treating thrombus formation (J.M.E. Cosemans et al. J. of Thrombosis and Haemostasis 2010, 8, 1797-1808, and A. Angelillo-Scherrer et al. J. Clin. Invest. 2008, 118, 583-596).

[0141] In some embodiments, salts of the present disclosure may be useful for preventing or reducing the risk of developing a disease, for example, in preventing or reducing the risk of developing a disease, condition, or disorder in individuals who may be predisposed to the disease, condition, or disorder but who have not yet experienced or exhibited the pathology or symptomology of the disease.

[0142] It will be appreciated that certain features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment (while those embodiments are intended to be combined as if described in multiple dependent fashion). Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. [Example]

[0143] The present invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will easily recognize various non-critical parameters that can be changed or modified to produce essentially the same results.

[0144] General method Preparative LC-MS purification of some of the prepared compounds was performed on a Waters mass fractionation system. The basic instrument setup, protocols, and control software for operating these systems are described in detail in the literature. See, for example, "Two-Pump At Column Dilution Configuration for Preparative LC-MS," K. Blom, J. Combi. Chem., 4, 295 (2002); "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification," K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound-Specific Method Optimization," K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The separated compounds were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity check under the following conditions: Instrument: Agilent 1100 series, LC / MSD, Column: Waters Sunfire™ C 18 5 μm particle size, 2.1 × 5.0 mm, buffer: Mobile phase A: 0.025% TFA in water and Mobile phase B: acetonitrile; flow rate 2.0 mL / min, gradient 2% to 80% B in 3 min.

[0145] Some of the prepared compounds were also separated on a preparative scale by reversed-phase high-performance liquid chromatography (RP-HPLC) or flash chromatography (silica gel) with MS detection, as shown in the examples. Typical preparative reversed-phase high-performance liquid chromatography (RP-HPLC) column conditions are as follows: Purification at pH=2: Waters Sunfire™ C 18The column was 5 μm in particle size, 19 × 100 mm, and eluted with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile; the flow rate was 30 mL / min. The separation gradient was optimized for each compound using a Compound Specific Method Optimization protocol as described in the literature (see "Preparative LCMS Purification: Improved Compound Specific Method Optimization," K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)). Typically, the flow rate used on a 30 × 100 mm column was 60 mL / min.

[0146] Purification at pH=10: Waters XBridge C 18 The column was 5 μm particle size, 19 × 100 mm, and eluted with mobile phase A: 0.15% NH OH aqueous solution and mobile phase B: acetonitrile; the flow rate was 30 mL / min, and the separation gradient was optimized for each compound using a Compound Specific Method Optimization protocol as described in the literature (see "Preparative LCMS Purification: Improved Compound Specific Method Optimization," K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)). Typically, the flow rate used with a 30 × 100 mm column was 60 mL / min.

[0147] Example 1. Preparation of Capsules Compound I maleate capsules are prepared as follows: The Compound I maleate used in the formulations described below is crystalline and is prepared according to Examples 4-6.

[0148] 20mg (as free base) procedure [Table 1A]

[0149] Mannitol (diluent), citric acid (pH adjuster), crospovidone (disintegrant), poloxamer 407 (surfactant), and stearic acid (lubricant) were passed through a 40-mesh sieve and weighed. The excipients were added to a 20 cc glass vial. The milled drug substance was weighed and added to the vial. The components were manually mixed in the vial with a spatula. The entire contents were then passed through a 30-mesh screen (three times) to homogenize the blend. The final blend was filled into size 2 capsules (Vcaps® Plus (HPMC (hydroxypropyl methylcellulose) capsules) from Capsugel). The ratio of Compound I as base to citric acid to poloxamer 407: 1 to 2 to 1.

[0150] The other 20 mg capsules (Formulations A, C, D, and E) were prepared in a similar manner. [Table 1B] [Table 1C] [Table 1D] [Table 1E] 25mg (as free base) procedure [Table 1F]

[0151] Mannitol, citric acid monohydrate, poloxamer 407, crospovidone, and stearic acid were sieved through a 40-mesh sieve and weighed. The mannitol, citric acid, and poloxamer 407 were added to a 500 ml glass bottle and mixed for 5 minutes in a Turbula mixer at speed 32. The milled drug substance was added and then mixed for 5 minutes. The entire blend was sieved twice through a 40-mesh sieve and then returned to the bottle. Crospovidone was added and mixed for 2 minutes. 5 g of colloidal silica was added to the blend, mixed manually, sieved through a 40-mesh sieve, and returned to the bottle along with the stearic acid. The blend was mixed for an additional 3 minutes in a Turbula mixer. The final blend was filled into size 0 capsules (Vcaps Plus-Capsugel). Ratio of Compound I as base to citric acid to poloxamer 407: 1 to 1.6 to 0.8.

[0152] Alternative procedure for 25 mg (as free base) [Table 1G]

[0153] The components were weighed out. The following materials were milled using a Quadro Comil (039 screen) at a speed of 1500±100 RPM: half the required amount of mannitol, poloxamer 407, milled Compound I maleate, and crospovidone. The milled blend was collected. The citric acid and colloidal silica were mixed in a bag and then passed through the Comil, followed by the remaining mannitol. Both blends were added to a 16Q blender and blended for 18 minutes at 21 RPM. The resulting blend was passed through the Comil and blended for an additional 18 minutes. The blend was then passed through the Comil. Sieved (30 mesh) stearic acid was added and blended for an additional 3.5 minutes. The final blend was discharged and encapsulated into size 0 capsules (Vcaps Plus) using a Bosch Encapsulator with a target fill weight of 400 mg. Ratio of Compound I as base to citric acid to poloxamer 407: 1 to 1.6 to 0.8.

[0154] 5mg (as free base) procedure [Table 1H]

[0155] The components were weighed out. The following materials were milled using a Quadro Comil (039 screen) at a speed of 1500±100 RPM: 1 / 2 the required amount of mannitol, poloxamer 407, milled Compound I maleate, and crospovidone. The milled blend was collected. Citric acid and colloidal silica were mixed in a bag and then passed through the Comil, followed by the remaining mannitol. Both blends were added to a 16Q blender and blended for 18 minutes at 21 RPM. The resulting blend was passed through the Comil and blended for an additional 18 minutes. The blend was then passed through the Comil. Sieved (30 mesh) stearic acid was added and blended for an additional 3.5 minutes. The final blend was discharged and encapsulated into size 2 capsules (Vcaps Plus) using a Bosch Encapsulator with a target fill weight of 200 mg. The ratio of Compound I as base to citric acid to poloxamer 407 was 1:8:4.

[0156] 15mg (as free base) procedure [Table 1I]

[0157] The components were weighed out. The following materials were milled using a Quadro Comil (039 screen) at a speed of 1500±100 RPM: 1 / 2 the required amount of mannitol, poloxamer 407, milled Compound I maleate, and crospovidone. The milled blend was collected. The citric acid and colloidal silica were mixed in a bag and then passed through the Comil, followed by the remaining mannitol. Both blends were added to a 16Q blender and blended for 18 minutes at 21 RPM. The resulting blend was passed through the Comil and blended for an additional 18 minutes. The blend was then passed through the Comil. Sieved (30 mesh) stearic acid was added and blended for an additional 3.5 minutes. The final blend was discharged and encapsulated into size 0 capsules (Vcaps Plus) using a Bosch Encapsulator with a target fill weight of 400 mg. Ratio of Compound I as base to citric acid to poloxamer 407: 1 to 2.67 to 1.33.

[0158] Example 2. Bioavailability study Capsules of Compound I maleate (20 mg as free base) from Example 1 were used in the following bioavailability study. Specifically, the procedure for preparing Formulation B in Table 2A is detailed in Example 1. The other formulations in Table 2A were also prepared in a manner similar to the 20 mg capsules in Example 1.

[0159] The purpose of this study was to determine the effect of formulation components on the pharmacokinetic properties of Compound I maleate following administration of Compound I maleate capsules. The in vivo portion of this study was conducted at the New Iberia Research Center (NIRC) at the University of Louisiana at Lafayette and adhered to the study protocol and NIRC standard operating procedures.

[0160] Four male cynomolgus monkey subjects were fasted for at least 12 hours and then administered an oral dose containing Compound I maleate via pill gun. Serial blood samples were collected 15 and 30 minutes before administration and 1, 2, 3, 4, 6, 8, 12, 16, and 24 hours after administration. The blood was placed on wet ice and centrifuged under refrigeration to obtain plasma, which was then stored frozen at approximately -20°C. Plasma samples were shipped on dry ice to Incyte Corporation (Wilmington, DE) for analysis.

[0161] Plasma and urinary concentrations of Compound I were measured under non-GLP conditions at Incyte Corporation. The method combined protein precipitation extraction with LC / MS / MS analysis. Plasma concentration-time data were used to determine pharmacokinetic parameters for each animal by standard non-compartmental methods using the IDBS E-Workbook Suite PK template (E-Workbook version 9.4.0 Build 18, IDBS, Inc., Alameda, CA). [Table 2A]

[0162] A similar study was performed using capsules of Compound I maleate (5 mg as the free base) from Example 1. The 5 mg formulation is prepared using Vcaps® Plus capsules (HPMC (hydroxypropyl methylcellulose) capsules) from Capsugel. [Table 2B]

[0163] Example 3. Solubility Studies The solubility of Compound I maleate was measured in aqueous solution at 37°C in the presence of several surfactants. The surfactants included sodium lauryl sulfate (SLS), poloxamer 188, and poloxamer 407 at a concentration of 0.2% (w / v) in water; a container without surfactant was included as a control. Experiments were performed in a Distek 2100 dissolution bath (USP Type II dissolution apparatus) using 500 ml of medium stirred at 100 RPM. 100 mg of drug substance (free base equivalent) was added to the medium to achieve a theoretical maximum concentration of 0.20 mg / ml. 5 ml samples were taken and filtered through a 0.45 micron GHP filter before analysis by HPLC. The concentrations observed for the samples after 60 minutes of stirring are listed below. [Table 3]

[0164] The data showed that the solubility in sodium lauryl sulfate solution was significantly higher than in water or poloxamer solution. The drug substance dissolved completely in the presence of 0.2% SLS, forming a clear solution.

[0165] Example 4. Synthesis of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide maleate (Compound I maleate) Scheme 1. [ka]

[0166] Step 1. 5-Bromo-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine dihydrochloride (compound 2) A five-necked 22 L round-bottom flask equipped with a mechanical stirrer, heating mantle, thermocouple, reflux condenser, nitrogen inlet, and nitrogen outlet was charged with tert-butyl 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (Compound 1, 880 g, 2.221 mol) in dichloromethane (DCM, 8.0 L) at room temperature. To the suspension was added hydrochloric acid in 2-propanol (5.8 N, 2.7 L, 15.66 mol, 7.05 equiv.). The mixture was heated to 35°C. After 4 h, the reaction mixture was diluted with tert-butyl methyl ether (TBME, 4.5 L). The mixture was cooled to room temperature, filtered, and washed with TBME (2.0 L). The filter cake was dried on the filter under house vacuum for 24 hours to give 5-bromo-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine dihydrochloride (compound 2, 848 g, 103%) as a light brown solid. 1 H NMR (400MHz, DMSO-d6) δ9.53~9.29(m, 3H), 8.23(s, 1H), 6.91(s, 1H), 3.38(tt, J=11.8, 3.6Hz, 1H), 3.30(d , J=12.4Hz, 2H), 3.00(dtd, J=12.8, 10.1, 2.6Hz, 2H), 2.07(dd, J=14.1, 3.8Hz, 2H), 1.97~1.87(m, 2H)ppm; 13 C NMR (101MHz, DMSO-d6) δ150.34, 139.32, 138.92, 113.24, 109.67, 95.70, 43.06, 30.57, 26.89ppm;C 11 H 14 BrN5(MW295.0), LCMS(EI)m / e296.0(M + +H).

[0167] Step 2. 1-(4-(4-amino-5-bromopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one (compound 3).

[0168] A five-necked 22 L round-bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser, nitrogen inlet, and nitrogen outlet was charged with 5-bromo-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine dihydrochloride (compound 2, 1300 g, 3.522 mol) in N-methylpiperidinone (NMP, 10 L) at room temperature. To the suspension was added N,N-diisopropylethylamine (1593 g, 12.3 mol). The mixture was cooled to 10 °C and then charged with isobutyryl chloride (388 g, 3.645 mol). The reaction was stirred at room temperature and monitored by HPLC. Excess isobutyryl chloride (22.5 g, 0.211 mol) was added to consume all starting material. Upon completion of the reaction, the reaction mixture was filtered through a Celite pad. The resulting filtrate was cooled to 10°C, and water (26 L) was slowly added to precipitate the product. The solid was collected by filtration and washed with water (12 L). The filter cake was dried on the filter under house vacuum for 48 hours to give 1-(4-(4-amino-5-bromopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one (compound 3, 1095 g, 85%) as a light brown solid. 1 H NMR (400MHz, DMSO-d6) δ7.86(s, 1H), 6.64(s, 1H), 4.51(d, J=12.6Hz, 1H), 4.01(d, J=13.2Hz, 1H), 3.35~3.30(m, 1H), 3.12(t, J=12.3Hz) , 1H), 2.91~2.84(m, 1H), 2.64(t, J=12.1Hz, 1H), 2.02~1.93(m, 2H), 1.55~1.42(m, 2H), 1.02(d, J=6.5Hz, 3H), 1.00(d, J=6.5Hz, 3H)ppm; 13 C NMR (101MHz, DMSO-d6) δ174.50, 155.68, 148.37, 135.22, 111.36, 110.65, 87.27, 45.34, 41.67, 32.91, 31.30, 30.33, 29.49, 20.03, 19.87ppm;C 15 H 20 BrN5O(MW365.09), LCMS(EI)m / e366.1(M + +H).

[0169] Step 3. 1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one (compound 5).

[0170] A five-necked, 22 L round-bottom flask equipped with a mechanical stirrer, heating mantle, thermocouple, reflux condenser, nitrogen inlet, and nitrogen outlet was charged with 1-(4-(4-amino-5-bromopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one (Compound 3, 700 g, 1.911 mol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Compound 4, 502 g, 2.293 mol), and potassium carbonate (528 g, 3.822 mol) in 1-butanol (7.7 L) and water (1.4 L) at room temperature. To the mixture was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 90 g, 115 mmol) at room temperature. The reaction mixture was degassed and refilled with nitrogen, then heated to 80°C. After 2 hours at 80°C, n-heptane (8 L) was added to the reaction mixture. The resulting slurry was cooled to room temperature. The solid was collected by filtration and washed with water (6 L). The filter cake was dried on the filter under house vacuum for 72 hours to give 1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one (compound 5, 648 g, 90%) as a brown solid. 1H NMR (500MHz, DMSO-d6) δ7.85(s, 1H), 7.09(d, J=8.4Hz, 2H), 6.65(d, J=8.4Hz, 2H), 6.4 3(s, 1H), 5.24(s, 2H), 4.53(d, J=12.6Hz, 1H), 4.04(d, J=13.1Hz, 1H), 3.38(ddd, J=11 .8.8.2, 3.8Hz, 1H), 3.16(t, J=12.7Hz, 1H), 2.87(p, J=6.7Hz, 1H), 2.71~2.66(m, 1H), 2.08~2.00(m, 2H), 1.61~1.58(m, 2H), 1.02(d, J=6.5Hz, 3H), 1.00(d, J=6.5Hz, 3H)ppm; 13 C NMR (126MHz, DMSO-d6) δ174.51, 156.31, 148.51, 147.65, 133.98, 130.35, 122.57, 119.3 7, 114.57, 109.67, 108.85, 45.48, 41.81, 32.97, 31.50, 30.56, 29.50, 20.06, 19.89ppm;C 21 H 26 N6O(MW378.48), LCMS(EI)m / e379.2(M + +H).

[0171] Step 4. N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound I).

[0172] A five-necked 22 L round-bottom flask equipped with a mechanical stirrer, a thermocouple, a nitrogen inlet, and a nitrogen outlet was charged with 1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one (compound 5, 944 g, 2.494 mol) and 1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid hydrochloride (compound 6, 801 g, 2.569 mol) in tetrahydrofuran (THF, 10 L) at room temperature. Triethylamine (NEt3, 0.695 L, 4.988 mol) was added to the reaction mixture. Upon completion of the reaction, the reaction mixture was divided equally between two 22 L round-bottom flasks. Each flask was charged with water (8 L) at room temperature. The solid was collected by filtration. The resulting wet cake was transferred back to a 22 L round-bottom flask. The flask was charged with THF (3.2 L) and water (10.5 L). The slurry was heated to 55° C. and stirred at 55° C. for 2 hours. The solid was collected by filtration at 30° C. and washed with water (8 L). The cake was dried on the filter under house vacuum for 72 hours to give N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1425 g, 90%) as a light brown solid. 1H NMR (500MHz, DMSO-d6) δ10.82(s, 1H), 8.71(s, 1H), 8.64(ddd, J=4.8, 1.8, 0.8Hz, 1H), 8.06(t d, J=7.7, 1.9Hz, 1H), 7.91(s, 1H), 7.77(d, J=8.6Hz, 2H), 7.60~7.53(m, 2H), 7.43(d, J=8.6Hz , 2H), 6.58 (s, 1H), 4.78 (hept, J = 6.8 Hz, 1H), 4.54 (d, J = 12.3 Hz, 1H), 4.06 (d, J = 12.5 Hz, 1H), 3.40 (tt, J = 11.7, 3.5 Hz, 1H), 3.20 (t, J = 12.3 Hz, 1H), 2.91 (hept, J = 6.7 Hz, 1H), 2.69 (t, J = 12.3 Hz, 1H), 2.06(dd, J=27.7, 12.3Hz, 2H), 1.61(q, J=11.8Hz, 1H), 1.55~1.47(m , 1H), 1.44(d, J=6.8Hz, 6H), 1.02(d, J=6.8Hz, 3H), 1.00(d, J=6.8Hz, 3H)ppm; 13 C NMR (126MHz, DMSO-d6) δ174.51, 163.02, 160.31, 156.20, 150.18, 149.98, 149.18, 148.08, 147.79, 139.55, 137.51, 134.45, 131.24, 130.23, 1 25.09, 124.57, 120.46, 117.98, 109.90, 109.35, 105.27, 51.17, 45.46 , 41.79, 32.97, 31.48, 30.54, 29.49, 21.09(2-CH3), 20.07, 19.89ppm;C 34 H 37 N9O4(MW635.73), LCMS(EI)m / e636.3(M + +H).

[0173] Step 5. N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide maleate (Compound I maleate).

[0174] A 50 L reactor equipped with a mechanical stirrer, a heating jacket, a thermocouple, a reflux condenser, a nitrogen inlet, and a nitrogen outlet was charged with N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound I, 1401 g, 2.204 mol) in methanol (MeOH, 10 L) and dichloromethane (DCM, 20 L) at room temperature. The slurry was heated to 50° C. to obtain a solution. Activated carbon (70 g) and silica gel (70 g) were added to the solution. After stirring at 50° C. for 2 hours, the mixture was filtered through a Celite pad. To the filtrate was added maleic acid (269 g, 2.314 mol). Most of the DCM was distilled off under atmospheric pressure. A solid gradually precipitated. The solid was collected by filtration at 18 °C and washed with MeOH (3 L). The filter cake was dried on the filter under house vacuum for 72 hours to give N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide maleate (Compound I maleate, 1425 g, 86%) as an off-white solid. 1H NMR (400MHz, DMSO-d6) δ10.83(s, 1H), 8.71(s, 1H), 8.65~8.63(m, 1H), 8.06(td, J=7.8, 1.9Hz, 1H), 7.95(s, 1H), 7.77(d, J=8.6 Hz, 2H), 7.58~7.55(m, 2H), 7.44(d, J=8.5Hz, 2H), 6.62(s, 1H), 6.25(s, 2H), 4.78(Hept, J=6.7Hz, 1H), 4.54(d, J=12.3Hz, 1H), 4 .06(d, J=12.5Hz, 1H), 3.40(tt, J=11.6, 3.2Hz, 1H), 3.20(t, J=12.3Hz, 1H), 2.90(Hept, J=6.6Hz, 1H), 2.69(t, J=12.1Hz, 1H), 2 .09~2.01(m, 2H), 1.65~1.57(m, 1H), 1.56~1.49(m, 1H), 1.44(d, J=6.8Hz, 6H), 1.02(d, J=5.5Hz, 3H), 1.00(d, J=5.5Hz, 3H)ppm; 13 C NMR (101MHz, DMSO) δ174.52, 167.21, 163.03, 160.33, 155.20, 150.18, 149 .99, 149.18, 148.07, 146.26, 139.55, 137.67, 135.32, 131.34, 130.87, 13 0.22, 125.09, 124.57, 120.49, 119.30, 109.80, 109.47, 105.26, 51.17, 45 .43, 41.76, 32.97, 31.45, 30.53, 29.50, 21.09(2-CH3), 20.06, 19.89ppm;C 34 H 37 N9O4 (free base MW635.73), LCMS (EI) m / e636.3 (M + +H).

[0175] Example 5. Synthesis of tert-butyl 4-(4-amino-5-bromopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (Compound 1 in Scheme 1) Scheme 2 [ka]

[0176] Step 1. tert-Butyl 4-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Compound 13) A 3 L round-bottom flask equipped with a mechanical stirrer, heating mantle, thermocouple, reflux condenser, nitrogen inlet, and nitrogen outlet was charged with 7-bromopyrrolo[1,2-f][1,2,4]triazine-4-amine (Compound 11, 100 g, 469 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Compound 12, 174 g, 563 mmol) in 1,4-dioxane (876 mL) at room temperature. Potassium carbonate (130 g, 939 mmol) and water (218 g) were added sequentially to the reaction flask. The mixture was degassed by exposure to vacuum and refilled with nitrogen three times. After the addition of tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 13.56 g, 11.7 mmol), the reaction mixture was degassed and refilled with nitrogen three times at room temperature. The reaction mixture was then heated to 85-90 °C and stirred at that temperature for 16 h. Upon completion of the reaction, water (900 mL) was added over 30 min, while the internal temperature was above 50 °C. The mixture was cooled to room temperature. A solid gradually precipitated. The solid was collected by filtration at 18 °C and washed with water (2 × 250 mL) and methyl tert-butyl ether (MTBE, 3 × 200 mL). The wet cake was returned to the reaction flask and stirred in MTBE (750 mL) at 50 °C for 1 h. The solid was collected by filtration at room temperature. The filter cake was dried in a vacuum oven at 50° C. under vacuum with a nitrogen sweep for 72 hours to give tert-butyl 4-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate (compound 13, 123.7 g, 84%) as a brown solid. 1H NMR (500MHz, DMSO-d6) δ7.89(s, 1H), 7.69(s, 2H), 7.00(s, 1H), 6.91(d, J=4.6Hz, 1H), 6.69 (d, J=4.5Hz, 1H), 4.06(s, 2H), 3.55(t, J=5.5Hz, 2H), 2.59~2.52(m, 2H), 1.43(s, 9H)ppm;C 16 H 21 N5O2(MW315.37), LCMS(EI)m / e316.1(M + +H).

[0177] Step 2. tert-Butyl 4-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (Compound 14) A 2 L flask was charged with tert-butyl 4-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate (compound 13, 50.0 g, 159 mmol) and platinum(IV) oxide (10.0 g, 44 mmol) in acetic acid (1000 mL) at room temperature. The flask was placed on a Parr shaker with 50 psi of hydrogen gas. After 16 h, the reaction mixture was filtered through a Celite pad (50 g) and washed with methanol (500 mL). The filtrate was concentrated under reduced pressure. Methyl tert-butyl ether (MTBE, 600 mL) was added to the residue at room temperature. A solution of potassium carbonate (approximately 50 g) in water (1200 mL) was added to the MTBE solution to adjust the pH to 6-7. The solid was collected by filtration and washed with water (2 × 300 mL) and n-heptane (2 × 300 mL). The filter cake was dried in a vacuum oven at 50 °C under vacuum with a nitrogen sweep for 16 hours to give tert-butyl 4-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (Compound 14, 49.3 g, 98%) as a light brown solid. 1H NMR (500MHz, DMSO-d6) δ7.82(s, 1H), 7.59(s, 2H), 6.81(d, J=4.4Hz, 1H), 6.44(d, J=4.3Hz, 1H), 4.05(d, J=11.3Hz, 2H) ), 3.25(tt, J=11.8, 3.3Hz, 1H), 2.88(s, 2H), 1.95(d, J=11.9Hz, 2H), 1.51(qd, J=12.6, 4.0Hz, 2H), 1.42(s, 9H)ppm;C 16 H 23 N5O2(MW317.39), LCMS(EI)m / e318.1(M + +H).

[0178] Step 3. tert-Butyl 4-(4-amino-5-bromopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (Compound 1) A five-necked, 22 L round-bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser, nitrogen inlet, and nitrogen outlet was charged with tert-butyl 4-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (Compound 14, 730 g, 2.30 mol) in tetrahydrofuran (THF, 14.0 L) at room temperature. The mixture was cooled to 0-5 °C. N-bromosuccinimide (NBS, 409 g, 2.30 mol) was added to the reaction mixture over 5 min, maintaining the internal temperature below 15 °C. After stirring below 10 °C for 1 h, some of the solvent (9.0 L) was removed under reduced pressure. To the remaining solution, a solution of sodium bicarbonate (140 g, 1.67 mol) in water (14.0 L) was added over 5 min. A solid precipitated. The solid was collected by filtration and washed with water (7.0 L) and n-heptane (4 L). The wet cake was dried on the filter under house vacuum for 48 hours to give tert-butyl 4-(4-amino-5-bromopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (Compound 1, 886 g, 97%) as a brown solid. 1H NMR (400MHz, DMSO-d6) δ7.86(s, 1H), 6.66(s, 1H), 4.04(d, J=11.0Hz, 2H), 3.30~3.23(m, 1 H), 2.86(br.s, 2H), 1.92(d, J=12.4Hz, 2H), 1.50(qd, J=12.8, 4.1Hz, 2H), 1.41(s, 9H)ppm; 13 C NMR (101MHz, DMSO-d6) δ155.68, 154.29, 148.35, 135.37, 111.31, 110.68, 87.29, 79.10, 43.97, 32.63, 30.37, 28.58ppm;C 16 H 22 BrN5O2(MW395.10), LCMS(EI)m / e396.1(M + +H).

[0179] Example 6. Synthesis of 1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Compound 6 in Scheme 1) Step 3: Diethyl 2-((3-pyridine-2-yluraido)methylene)malonate [ka] To a mixture of diethyl 2-(aminomethylene)malonate (3.0 g, 16.0 mmol) and 2-isocyanatopyridine (2.02 g, 16.8 mmol) in 1,2-dichloroethane (9.0 mL) was added N,N-diisopropylethylamine (3.6 mL, 20.8 mmol) at room temperature. The reaction mixture was then stirred at 70 °C overnight, cooled to room temperature, and directly purified via column chromatography (0% to 15% MeOH in CHCl) to give the product (3.18 g, 65%). 14 H 18 N3O5(M+H) + LCMS calculated value: m / z = 308.1. Found value: 308.1.

[0180] Step 4: 1-Isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [ka] A mixture of diethyl 2-((3-(pyridin-2-yl)ureido)methylene)malonate (3.18 g, 10.4 mmol) and 2.5 M NaOEt in EtOH (6.2 mL, 15.5 mmol) in EtOH (25 mL) was stirred at room temperature for 3 hours. The resulting mixture was diluted with EtOAc and washed / acidified with 1 N citric acid solution (30 mL). The organic layer was separated, and the aqueous layer was further extracted with 3:1 CHCl3 / isopropyl alcohol (30 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product, ethyl 2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate, which was used directly in the next step. C 12 H 12 N3O4(M+H) + LCMS calculated value: m / z = 262.1. Found value: 262.2.

[0181] A mixture of crude ethyl 2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate from the previous step, 2-iodopropane (2.06 mL, 20.7 mmol), and CsCO (10.1 g, 31.0 mmol) in DMF (35 mL) was stirred at 70 °C for 3 hours. The reaction mixture was then cooled to room temperature, diluted with 3:1 CHCl / isopropyl alcohol (75 mL), washed with water, brine, dried over NaSO, and concentrated to give the crude product, ethyl 1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate, which was used directly in the next step. 15 H 18 N3O4(M+H) + LCMS calculated: m / z = 304.1. Found: 304.1.

[0182] A mixture of crude ethyl 1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate from the previous step in 4M HCl in 1,4-dioxane (20 mL, 82 mmol) and water (5.0 mL) was stirred at 80 °C for 5 hours, cooled to room temperature, and concentrated. The resulting material was then purified via column chromatography (0% to 15% MeOH in CHCl) to give the product as a slightly yellow solid (1.50 g, 47% three steps). 13 H 14 N3O4(M+H) + LCMS calculated value: m / z = 276.1. Found value: 276.1.

[0183] Example 7. Solid-State Characterization of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide maleate (Compound I maleate) X-ray powder diffraction (XRPD) of compound I maleate. X-ray powder diffraction (XRPD) was obtained from a Rigaku MiniFlex X-ray powder diffractometer (XRPD). The general experimental procedure for XRPD was as follows: (1) X-ray emission from copper at 1.054056 Å using a Kβ filter, (2) X-ray power at 30 KV, 15 mA, and (3) sample powder was dispersed on a zero-background sample holder. β The general conditions for the XRPD measurements were a start angle of 3 degrees, a stop angle of 45 degrees, a sampling of 0.02 degrees, and a scan rate of 2 degrees / min. The XRPD pattern is shown in Figure 1, and the XRPD data are provided in Table 6A. [Table 4]

[0184] Differential scanning calorimetry (DSC) of compound I maleate. DSC data were obtained from a TA Instruments differential scanning calorimetry, model Q200, with an autosampler. DSC instrument conditions were as follows: 30-300 °C at 10 °C / min; Tzero aluminum sample pan and lid; and 50 mL / min nitrogen gas flow. The DSC thermogram is shown in Figure 2. The DSC thermogram showed a major endothermic event with an onset temperature of 202.9 °C and a peak temperature of 211.0 °C, which is believed to be the melting and decomposition temperature of the compound.

[0185] Thermogravimetric analysis (TGA) of compound I maleate. TGA data were obtained from a TA Instrument Thermogravimetric Analyzer, Model Q500. Typical experimental conditions for the TGA were: 20 °C to 600 °C ramp at 20 °C / min; nitrogen purge, 40 mL / min gas flow, followed by equilibration of the purge flow; 60 mL / min sample purge flow; platinum sample pan. The TGA thermogram is shown in Figure 3. A weight loss of approximately 0.7% was observed by 150 °C and was believed to be related to loss of moisture and residual solvent. The compound begins to decompose significantly above 200 °C.

[0186] Other crystalline salts Other crystalline salts of Compound I have been discovered and prepared, including the HCl salt, monosulfate salt, hemisulfate salt, mesylate salt, and besylate salt.

[0187] Example A. Axl autophosphorylation assay Autophosphorylation of Axl was performed by incubating recombinant Axl protein (Life Technologies, PV4275) in a buffer containing 50 mM Tris, pH 7.5, 0.2 mg / ml Axl, 5 mM ATP, 20 mM MgCl2, and 2 mM DTT for 1 h at room temperature.

[0188] TAM enzyme assay The kinase assay buffer contained 50 mM HEPES, pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.01% NP-40, and 2 mM DTT. 0.1 μL of test compound dissolved in DMSO was transferred from the compound plate to a white 384-well assay plate (Greiner LUMITRAC plate). The final DMSO concentration was 1.25%. Enzyme solutions of 5.1 nM phosphorylated Axl, 0.0625 nM c-Mer (Carna Biosciences, 08-108), or 0.366 nM Tyro3 (Life Technologies, PR7480A) were prepared in assay buffer. A 1 mM stock solution of the peptide substrate biotin-EQEDEPEGDYFEWLE-amide SEQ ID NO:1 (Quality Controlled Biochemicals, MA) dissolved in DMSO was diluted to 1 μM in assay buffer containing 2000 μM ATP. 4 μl of enzyme solution (or enzyme blank assay buffer) was added to the appropriate wells of each plate, followed by 4 μl / well of substrate solution to initiate the reaction. Plates were protected from light and incubated at room temperature for 60 minutes. The reaction was stopped by adding 4 μl of detection solution containing 50 mM Tris-HCl, pH 7.8, 150 mM NaCl, 0.05% BSA, 45 mM EDTA, 180 nM SA-APC (Perkin Elmer, CR130-100), and 3 nM Eu-W1024 anti-phosphotyrosine PY20 (Perkin Elmer, AD0067). Plates were incubated at room temperature for 1 hour, and HTRF (homogeneous time-resolved fluorescence) signals were measured on a PHERAstar FS plate reader (BMG Labtech). The percentage of inhibition was calculated for each concentration, and IC50 values ​​were generated from curve fitting using GraphPad Prism software.

[0189] Compound I was found to be an inhibitor of one or more of AXL, MER, and TYRO3. The IC of the trifluoroacetate salt of Compound I 50The data are disclosed in U.S. Patent No. 9,981,975 and are provided below in Table 7A. The symbol "†" indicates an IC of 5 nM or less. 50 indicates IC > 5 nM but ≤ 10 nM, and "††" indicates IC > 5 nM but ≤ 10 nM 50 indicates IC greater than 10 nM but less than 100 nM, and "†††" indicates IC greater than 10 nM but less than 100 nM 50 Shows. [Table 5]

[0190] Example B. Generation of BAF3-AXL, BAF3-MER, and BAF3-TYRO3 Cells and Cell Proliferation Assays The cytoplasmic domain of AXL, MER, or TYRO3 fused to a dimerization sequence and HA tag was cloned into the pMSCV vector containing a puromycin resistance marker to generate three constructs (pMSCV-AXL, pMSCV-MER, and pMSCV-TYRO3). BAF3 cells were individually transfected with the three constructs by electroporation. Single clones that were IL3-independent and puromycin-resistant were selected and characterized. Cells with stable expression of AXL, MER, or TYRO3 were selected and designated BAF3-AXL, BAF3-MER, and BAF3-TYRO3 cells.

[0191] BAF3, BAF3-AXL, BAF3-MER, or BAF3-TYRO3 cell lines are maintained in RPMI 1640 (Gibco / Life Technologies, Carlsbad, CA) containing 10% FBS. To measure the effect of test compounds on cell viability, 1000 cells / well are seeded into 384-well tissue culture plates in growth medium containing serial dilutions of compound or DMSO alone at 37°C with 5% CO for 48 hours, and cell viability is measured by an ATP assay (CellTiter-Glo assay, Promega) according to the manufacturer's protocol. Data are converted to percent inhibition compared to the DMSO control and expressed as IC 50 Curves are fitted using GraphPad Prism software.

[0192] Example C. BaF3-AXL ELISA and BaF3-MER ELISA BaF3-AXL or BaF3-MER cells were maintained in RPMI medium containing 10% FBS and puromycin (1 μg / ml, Gibco / Life Technologies, Carlsbad, CA). To measure the effect of test compounds on phosphorylated AXL or MER, cells were plated (5 × 10 cells) in V-bottom polypropylene plates (Greiner bio-one) in the presence or absence of test compounds diluted in medium. 4 Cells are then plated (1000 cells / well) and incubated at 37°C with 5% CO2 for 1 hour. Cells are harvested by centrifugation and lysed in 110 μL of ice-cold lysis buffer (Cell Signaling) containing protease and phosphatase inhibitors (Halts PI, Thermo Fisher) for 30 minutes on ice. Cell lysates are stored at -80°C for ELISA. ELISA plates are prepared by incubating Costar plates with anti-HA antibody (1 μg / ml) for 1 hour at room temperature. Plates are washed and blocked with PBS containing 3% BSA. Cell lysates are loaded onto ELISA plates and incubated overnight at 4°C. Plates are washed and incubated with LANCE Eu-W1024 anti-phosphotyrosine antibody (PY-20) (Perkin Elmer) in DELFIA assay buffer (Perkin Elmer) for 1 hour and read on a Pherastar (BMG Labtech). Data are converted to percent inhibition compared to DMSO control and calculated as IC 50 Determination of is performed by curve fitting percent inhibition versus logarithm of inhibitor concentration using GraphPad Prism.

[0193] Example D. H1299 Phosphorylated AXL ELISA H1299 cells (ATCC), a human non-small cell lung cancer cell line with Axl expression, were maintained in RPMI medium (Gibco / Life Technologies, Carlsbad, CA) containing 10% FBS. To measure the effect of test compounds on phosphorylated AXL, cells were seeded (30,000 cells / well) into 96-well tissue culture plates (Costar) and incubated overnight at 37°C with 5% CO2. Appropriate concentrations of compounds were added and incubated for 1 hour at 37°C with 5% CO2. rhGas6 (R&D Systems, 6 μg / ml) was added to each well. The plate was incubated for 15 minutes at 37°C with 5% CO2. Cells were harvested and lysed in 110 μL of ice-cold lysis buffer (Cell Signaling) containing protease and phosphatase inhibitors (Halts PI, Thermo Fisher Scientific). The lysate was incubated on ice for 1 hour and stored at -80°C for ELISA. ELISA plates are prepared by incubating Costar plates with anti-HA antibody (1 μg / ml) for 1 hour at room temperature. Plates are washed and blocked with 3% BSA in PBS. Cell lysates are loaded onto ELISA plates and incubated overnight at 4°C. Plates are washed and incubated with LANCE Eu-W1024 anti-phosphotyrosine antibody (PY-20) (Perkin Elmer) in DELFIA assay buffer (Perkin Elmer) for 1 hour and read on a Pherastar (BMG Labtech). Data are converted to percent inhibition compared to DMSO control and expressed as IC 50 Determination of is performed by curve fitting percent inhibition versus logarithm of inhibitor concentration using GraphPad Prism.

[0194] Example E. Whole Blood H1299 Phosphorylated AXL ELISA H1299 cells (ATCC) were maintained in RPMI medium (Gibco / Life Technologies, Carlsbad, CA) containing 10% FBS. To measure the effect of test compounds on phosphorylated AXL in whole blood, cells were seeded (30,000 cells / well) into 96-well tissue culture plates (Costar) and incubated overnight at 37°C with 5% CO2. Blood obtained from normal donors was mixed with the test compound for 1 hour. The medium was removed from the H1299 cells, and the compound-containing blood was added to each well. After incubation at 37°C with 5% CO2 for 1 hour, rh-Gas6 (4 μg / ml, R&D Systems) was added to each well. The plate was incubated at 37°C with 5% CO2 for 15 minutes. The cells were washed with PBS and lysed in 110 μL of ice-cold lysis buffer (Cell Signaling) containing protease and phosphatase inhibitors (Halts PI, Thermo Fisher) for 1 hour on ice. Plates are stored at -80°C for ELISA. ELISA plates are prepared by incubating Costar plates with anti-HA antibody (1 ug / ml) for 1 hour at room temperature. Plates are washed and blocked with PBS containing 3% BSA. Cell lysates are loaded onto ELISA plates and incubated overnight at 4°C. Plates are washed and incubated with LANCE Eu-W1024 anti-phosphotyrosine antibody (PY-20) (Perkin Elmer) in DELFIA assay buffer (Perkin Elmer) for 1 hour and read on a Pherastar (BMG Labtech). Data are converted to percent inhibition compared to DMSO control and calculated as IC 50 Determination of is performed by curve fitting percent inhibition versus logarithm of inhibitor concentration using GraphPad Prism.

[0195] Example F. G361 Phosphorylated Akt Cell Insight ELISA G361 cells (ATCC), a human malignant melanoma cell line expressing Mer, are maintained in RPMI medium (Gibco / Life Technologies, Carlsbad, CA) containing 10% FBS. To measure the effect of test compounds on the MER signaling pathway, cells were plated at 2 × 10 in a volume of 100 μL in 96-well CellBind surface plates (Corning). 4 Cells were seeded per well and incubated overnight at 37°C with 5% CO2. 20 μL of the appropriate concentration of test compound was added to the cells and incubated for 1 hour. rhGas6 (4 μg / ml, R&D Systems) was added to each well and incubated for 20 minutes. Cells were fixed by adding 50 μL of 4% paraformaldehyde (Electron Microscopy Sciences) in PBS (Corning) for 30 minutes at room temperature. The plate was washed and incubated with 50 μL of 0.2% Triton X-100 (Sigma) in PBS for 10 minutes at room temperature. The plate was washed and incubated with 100 μL of blocking buffer (0.1% BSA in PBS) for 30 minutes. The plate was washed and incubated with phosphorylated AKT (Ser473) (D9E) rabbit mAb (Cell Signaling) diluted in 0.1% BSA (1:300 dilution) overnight at 4°C. Wash the plate and add 50 μL of Alexaflour 488 F(ab') goat anti-rabbit IgG (H+L) in PBS. 2 The fragments (Molecular Probes, 1:1000 dilution) are incubated with Hoechst 33342 (Thermo Fisher, 1:2000 dilution) for 2 hours at room temperature. The plates are washed with PBS and read on a Cell Insight CX5 (ThermoFisher).

[0196] The present invention includes the following aspects and embodiments. [1] (a) N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) organic acids, and (c) A solid oral dosage pharmaceutical formulation comprising a surfactant. [2] The pharmaceutical formulation according to [1], wherein the organic acid is citric acid, ascorbic acid, fumaric acid, malic acid, sorbic acid, or tartaric acid. [3] The pharmaceutical formulation according to [1] or [2], wherein the organic acid is citric acid. [4] The pharmaceutical formulation according to any one of [1] to [3], comprising about 1% by weight to about 50% by weight of an organic acid. [5] The pharmaceutical formulation according to any one of [1] to [3], comprising about 5% by weight to about 40% by weight of an organic acid. [6] The pharmaceutical formulation according to any one of [1] to [3], comprising about 5% by weight to about 30% by weight of an organic acid. [7] The pharmaceutical formulation according to any one of [1] to [3], comprising about 10% by weight to about 20% by weight of an organic acid. [8] The pharmaceutical formulation according to any one of [1] to [3], comprising about 10% by weight or about 20% by weight of an organic acid. [9] The pharmaceutical formulation according to any one of [1] to [8], comprising about 1% by weight to about 20% by weight of Compound I.

[10] The pharmaceutical formulation according to any one of [1] to [8], comprising about 2% by weight to about 15% by weight of Compound I.

[11] The pharmaceutical formulation according to any one of [1] to [8], comprising about 3 wt % or about 12 wt % of Compound I.

[12] The pharmaceutical formulation according to any one of [1] to

[11] , wherein the surfactant is a poloxamer.

[13] The pharmaceutical formulation according to any one of [1] to

[11] , wherein the surfactant is poloxamer 407 or poloxamer 188.

[14] The pharmaceutical formulation according to any one of [1] to

[11] , wherein the surfactant is poloxamer 407.

[15] The pharmaceutical formulation according to any one of [1] to

[14] , comprising about 1% by weight to about 20% by weight of a surfactant.

[16] The pharmaceutical formulation according to any one of [1] to

[14] , comprising about 5% by weight to about 15% by weight of a surfactant.

[17] The pharmaceutical formulation according to any one of [1] to

[14] , comprising about 5% by weight to about 10% by weight of a surfactant.

[18] The pharmaceutical formulation according to any one of [1] to

[14] , comprising about 1% by weight to about 10% by weight of a surfactant.

[19] The pharmaceutical formulation according to any one of [1] to

[18] , further comprising a diluent.

[20]

[19] The pharmaceutical formulation according to

[19] , wherein the diluent is mannitol.

[21] The pharmaceutical formulation according to

[19] or

[20] , comprising about 40% by weight to about 90% by weight of a diluent.

[22] The pharmaceutical formulation according to

[19] or

[20] , comprising about 50% by weight to about 80% by weight of a diluent.

[23] The pharmaceutical formulation according to

[19] or

[20] , comprising about 50% by weight to about 75% by weight of a diluent.

[24] The pharmaceutical formulation according to any one of [1] to

[23] , further comprising a disintegrant.

[25]

[24] The pharmaceutical formulation according to

[24] , wherein the disintegrant is crospovidone.

[26] The pharmaceutical formulation according to

[24] or

[25] , comprising about 1% by weight to about 10% by weight of a disintegrant.

[27] The pharmaceutical formulation according to

[24] or

[25] , comprising about 2% by weight to about 5% by weight of a disintegrant.

[28] The pharmaceutical formulation according to any one of [1] to

[27] , further comprising a lubricant, a glidant, or both.

[29]

[28] The pharmaceutical formulation according to

[28] , wherein the lubricant is stearic acid.

[30] The pharmaceutical formulation according to

[28] or

[29] , comprising about 1% by weight to about 5% by weight of a lubricant.

[31] The pharmaceutical formulation according to

[28] or

[29] , comprising about 2% by weight of a lubricant.

[32] The pharmaceutical formulation according to any one of

[28] to

[31] , wherein the glidant is colloidal silica.

[33] The pharmaceutical formulation according to any one of

[28] to

[32] , comprising about 0.1% by weight to about 5% by weight of a glidant.

[34] The pharmaceutical formulation according to any one of

[28] to

[32] , comprising about 0.5% by weight or about 1% by weight of a glidant.

[35] (a) N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) citric acid, and (c) A pharmaceutical formulation comprising a poloxamer.

[36] The pharmaceutical formulation according to any one of [1] to

[35] , wherein the salt is N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide maleate (Compound I maleate).

[37] The pharmaceutical formulation according to

[36] , comprising about 1% by weight to about 20% by weight of Compound I maleate.

[38] The pharmaceutical formulation according to

[36] , comprising about 2% by weight to about 15% by weight of Compound I maleate.

[39]

[36] The pharmaceutical formulation according to

[36] , comprising about 3% by weight or about 12% by weight of Compound I maleate.

[40] (a) about 2% to about 15% by weight of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) about 5% to about 30% by weight of citric acid, and (c) A pharmaceutical formulation comprising about 5% to about 15% by weight of a poloxamer.

[41] (a) about 2% to about 15% by weight of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) about 5% to about 30% by weight of citric acid; (c) about 5% to about 15% by weight of poloxamer 407; (d) about 50% by weight to about 80% by weight of mannitol; (e) about 1% to about 5% by weight of stearic acid, and (f) A pharmaceutical formulation comprising about 2% to about 5% by weight of crospovidone.

[42] (a) about 2% to about 15% by weight of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) about 5% to about 30% by weight of citric acid, and (c) A pharmaceutical formulation comprising about 1% to about 10% by weight of a poloxamer.

[43] (a) about 2% to about 15% by weight of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof; (b) about 5% to about 30% by weight of citric acid; (c) about 1% to about 10% by weight of poloxamer 407; (d) about 50% by weight to about 80% by weight of mannitol; (e) about 1% to about 5% by weight of stearic acid, and (f) A pharmaceutical formulation comprising about 2% to about 5% by weight of crospovidone.

[44] The pharmaceutical formulation according to any one of

[40] to

[43] , wherein the salt is N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide maleate (Compound I maleate).

[45] The pharmaceutical formulation according to any one of [1] to

[44] , wherein Compound I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is in a crystalline form.

[46] The pharmaceutical formulation according to any one of [1] to

[45] , wherein the dosage form is a tablet or a capsule.

[47] The pharmaceutical formulation according to any one of [1] to

[45] , wherein the dosage form is a capsule.

[48] A method for inhibiting AXL and MER kinase, the method comprising contacting the AXL and MER kinase with the pharmaceutical preparation according to any one of [1] to

[47] .

[49] A method for treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical preparation according to any one of [1] to

[47] .

[50] 49. The method of claim 49, wherein the cancer is selected from hepatocellular carcinoma, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, Burkitt's lymphoma, glioblastoma, melanoma, and rhabdomyosarcoma.

[51] The method of

[49] , wherein the cancer is lung cancer, prostate cancer, colon cancer, breast cancer, melanoma, renal cell carcinoma, multiple myeloma, gastric cancer, or rhabdomyosarcoma.

[52] 1. A method for preparing a pharmaceutical formulation suitable for oral administration, comprising blending N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, with an organic acid and a surfactant to form the pharmaceutical formulation suitable for oral administration.

[53]

[52] The method according to

[52] , further comprising compressing the pharmaceutical formulation to obtain a capsule.

[54] The pharmaceutical formulation according to any one of [1] to

[47] , which is prepared by the method according to

[52] . Various modifications of the present invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application, including all patents, patent applications, and publications, is hereby incorporated by reference in its entirety.

Claims

1. (a) about 1% to about 20% by weight of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide maleate (Compound I maleate); (b) about 1% to about 50% by weight of an organic acid, the organic acid being citric acid; and (c) about 1% to about 20% by weight of a surfactant, wherein the surfactant is a poloxamer.

1. A solid oral dosage pharmaceutical formulation comprising:

1. A pharmaceutical formulation, wherein Compound I maleate is in a crystalline form having at least one XRPD peak for 2-theta selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5°.

2. 10. The pharmaceutical formulation of claim 1, comprising about 5% to about 40% by weight of an organic acid.

3. 10. The pharmaceutical formulation of claim 1, comprising about 5% to about 30% by weight of an organic acid.

4. 10. The pharmaceutical formulation of claim 1, comprising about 10% to about 20% by weight of an organic acid.

5. 10. The pharmaceutical formulation of claim 1, comprising about 10% or about 20% by weight of an organic acid.

6. 6. The pharmaceutical formulation of any one of claims 1 to 5, comprising about 2% to about 15% by weight of Compound I maleate.

7. 6. The pharmaceutical formulation of any one of claims 1 to 5, comprising about 3% or about 12% by weight of Compound I maleate.

8. 8. The pharmaceutical formulation according to any one of claims 1 to 7, wherein the surfactant is poloxamer 407 or poloxamer 188.

9. The pharmaceutical formulation according to any one of claims 1 to 7, wherein the surfactant is poloxamer 407.

10. 10. The pharmaceutical formulation of any one of claims 1 to 9, comprising from about 5% to about 15% by weight of a surfactant.

11. 10. The pharmaceutical formulation of any one of claims 1 to 9, comprising from about 5% to about 10% by weight of a surfactant.

12. 10. The pharmaceutical formulation of any one of claims 1 to 9, comprising from about 1% to about 10% by weight of a surfactant.

13. The pharmaceutical formulation of any one of claims 1 to 12, further comprising a diluent.

14. 14. The pharmaceutical formulation of claim 13, wherein the diluent is mannitol.

15. 15. The pharmaceutical formulation of claim 13 or 14, comprising from about 40% to about 90% by weight of a diluent.

16. 15. The pharmaceutical formulation of claim 13 or 14, comprising about 50% to about 80% by weight of a diluent.

17. 15. The pharmaceutical formulation of claim 13 or 14, comprising about 50% to about 75% by weight of a diluent.

18. The pharmaceutical formulation according to any one of claims 1 to 17, further comprising a disintegrant.

19. 19. The pharmaceutical formulation of claim 18, wherein the disintegrant is crospovidone.

20. 20. The pharmaceutical formulation of claim 18 or 19, comprising about 1% to about 10% by weight of a disintegrant.

21. 20. The pharmaceutical formulation of claim 18 or 19, comprising about 2% to about 5% by weight of a disintegrant.

22. 22. The pharmaceutical formulation of any one of claims 1 to 21, further comprising a lubricant, a glidant, or both.

23. 23. The pharmaceutical formulation of claim 22, wherein the lubricant is stearic acid.

24. 24. The pharmaceutical formulation of claim 22 or 23, comprising about 1% to about 5% by weight of a lubricant.

25. 24. The pharmaceutical formulation of claim 22 or 23, comprising about 2% by weight of a lubricant.

26. 26. The pharmaceutical formulation of any one of claims 22 to 25, wherein the glidant is colloidal silica.

27. 27. The pharmaceutical formulation of any one of claims 22 to 26, comprising from about 0.1% to about 5% by weight of a glidant.

28. 27. The pharmaceutical formulation of any one of claims 22 to 26, comprising about 0.5% or about 1% by weight of a glidant.

29. (a) about 2% to about 15% by weight of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide maleate (Compound I maleate); (b) about 5% to about 30% by weight of citric acid, and (c) about 5% to about 15% by weight of a poloxamer 1. A pharmaceutical formulation in oral dosage form comprising:

1. A pharmaceutical formulation, wherein Compound I maleate is in a crystalline form having at least one XRPD peak for 2-theta selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5°.

30. (a) about 2% to about 15% by weight of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide maleate (Compound I maleate); (b) about 5% to about 30% by weight of citric acid; (c) about 5% to about 15% by weight of poloxamer 407; (d) about 50% to about 80% by weight of mannitol; (e) about 1% to about 5% by weight of stearic acid, and (f) about 2% to about 5% by weight of crospovidone 1. A pharmaceutical formulation in oral dosage form comprising:

1. A pharmaceutical formulation, wherein Compound I maleate is in a crystalline form having at least one XRPD peak for 2-theta selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5°.

31. (a) about 2% to about 15% by weight of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide maleate (Compound I maleate); (b) about 5% to about 30% by weight of citric acid, and (c) about 1% to about 10% by weight of a poloxamer 1. A pharmaceutical formulation in oral dosage form comprising:

1. A pharmaceutical formulation, wherein Compound I maleate is in a crystalline form having at least one XRPD peak for 2-theta selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5°.

32. (a) about 2% to about 15% by weight of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide maleate (Compound I maleate); (b) about 5% to about 30% by weight of citric acid; (c) about 1% to about 10% by weight of poloxamer 407; (d) about 50% to about 80% by weight of mannitol; (e) about 1% to about 5% by weight of stearic acid, and (f) about 2% to about 5% by weight of crospovidone 1. A pharmaceutical formulation in oral dosage form comprising:

1. A pharmaceutical formulation, wherein Compound I maleate is in a crystalline form having at least one XRPD peak for 2-theta selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5°.

33. 33. The pharmaceutical formulation of any one of claims 1 to 32, wherein Compound I maleate has at least two XRPD peaks in 2-theta selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5°.

34. 33. The pharmaceutical formulation of any one of claims 1 to 32, wherein Compound I maleate has at least three XRPD peaks in 2-theta selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5°.

35. 33. The pharmaceutical formulation of any one of claims 1 to 32, wherein Compound I maleate has XRPD peaks at about 4.3°, about 8.4°, and about 13.2° 2-theta.

36. 36. The pharmaceutical formulation of any one of claims 1 to 35, wherein Compound I maleate has a DSC thermogram with an endothermic peak at about 211°C.

37. 37. The pharmaceutical formulation of any one of claims 1 to 36, wherein the dosage form is a tablet or a capsule.

38. The pharmaceutical formulation according to any one of claims 1 to 36, wherein the dosage form is a capsule.

39. A pharmaceutical formulation according to any one of claims 1 to 38 for inhibiting AXL and MER kinases.

40. A pharmaceutical formulation according to any one of claims 1 to 38 for treating cancer in a patient.

41. 41. The pharmaceutical formulation of claim 40, wherein the cancer is selected from hepatocellular carcinoma, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, Burkitt's lymphoma, glioblastoma, melanoma, and rhabdomyosarcoma.

42. 41. The pharmaceutical preparation of claim 40, wherein the cancer is lung cancer, prostate cancer, colon cancer, breast cancer, melanoma, renal cell carcinoma, multiple myeloma, gastric cancer, or rhabdomyosarcoma.

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