Salts of pyrrolotriazine derivatives useful as TAM inhibitors

Abstract

To provide compounds which are useful as inhibitors of TAM kinases.SOLUTION: The present application provides salt forms 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 (I) and 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (II), as well as processes and intermediates related thereto.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure provides 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 and 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide in the form of salts, which are useful as inhibitors of TAM kinase, and related production methods and intermediates thereof.

Background Art

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

[0003] The TAM subfamily consists of three RTKs, namely 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, growth arrest specific 6 (GAS6) and protein S (PROS1), have been identified for TAM kinases. While GAS6 can bind to and activate all three TAM kinases, 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 initially 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 subsequently induces autophosphorylation and activation of the AXL tyrosine kinase. 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 initially identified as a phosphorylated protein from a lymphoblastoid 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 the Mer kinase (Lew et al, 2014). Activation of MER also transmits downstream signaling pathways, including PI3K-Akt and Raf-MAPK, similar to AXL (Linger et al., 2008, Advances in Cancer Research 100, 35-83).

[0006] TYRO3 (also known as Dtk, Sky, Rse, BRT, Tif, Etk2) was initially identified by 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 ligands, GAS6 and PROS1, can bind to and activate TYRO3. The signaling pathways downstream of TYRO3 activation are the least studied among the TAM RTKs, although 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] Accordingly, there is a need for compounds for modulating TAM kinases in the treatment of cancer and methods of using them. SUMMARY OF THE INVENTION

[0008] This application provides salts of compounds of formula I: [Chemical formula] which are useful as inhibitors of TAM.

[0009] This application further provides maleate salts of the compounds of formula I.

[0010] This application further provides methods for preparing salts of the compounds of formula I.

[0011] This application provides salts of compounds of formula II: [Chemical formula] which are useful as inhibitors of TAM.

[0012] This application further provides the hemisulfate salt of the compound of formula II.

[0013] This application further provides the phosphate salt of the compound of formula II.

[0014] This application further provides the maleate salt of the compound of formula II.

[0015] This application further provides the hydrochloride salt of the compound of formula II.

[0016] This application further provides the salicylate salt of the compound of formula II.

[0017] This application further provides the methanesulfonate salt (i.e., mesylate salt) of the compound of formula II.

[0018] This application further provides the ethanesulfonate salt (i.e., esylate salt) of the compound of formula II.

[0019] This application further provides a method for preparing the salt of the compound of formula II.

[0020] This application further provides a pharmaceutical composition comprising any of the above salts of the compounds of formula I and II.

[0021] This application also provides a method for inhibiting TAM kinase, the method comprising contacting the TAM kinase with any of the above salts of the compounds of formula I and II.

[0022] This application also provides a method for inhibiting AXL kinase and MER kinase, the method comprising contacting the AXL kinase or MER kinase with any of the above salts of the compounds of formula I and II.

[0023] This application also provides a method for treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of any of the above salts of the compounds of formula I and II. BRIEF DESCRIPTION OF THE DRAWINGS

[0024]

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Figure 34

Mode for Carrying Out the Invention

[0025] Compounds and salts This application provides a salt of a compound of formula I: [Chemical formula] or a pharmaceutically acceptable hydrate and solvate thereof, which is useful as an inhibitor of TAM.

[0026] Accordingly, in some embodiments, this application provides 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 (also referred to herein as the maleate salt of the compound of formula I, the maleate salt of Compound I, Compound I maleate salt, or any variation thereof).

[0027] In some embodiments, the above salt is a salt with a stoichiometric ratio of 1:1 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 to maleic acid.

[0028] Different forms of the same substance have different bulk properties related to, for example, hygroscopicity, solubility, stability, etc. The form with a high melting point often has good thermodynamic stability, and this good thermodynamic stability is advantageous for extending the shelf life of the formulation containing the solid form. The form with a low melting point often has lower thermodynamic stability, but is advantageous in that it has improved water solubility, leading to improved bioavailability of the drug. The form with low hygroscopicity is more desirable for their stability against heat and humidity and is resistant to degradation during long-term storage.

[0029] The solid forms (e.g., crystalline forms) described herein may have certain advantages. For example, the form may have desirable properties such as ease of handling, ease of processing, storage stability, and ease of purification. Further, the above crystalline forms may be useful for improving the performance characteristics of pharmaceutical products such as dissolution profiles, shelf life, and bioavailability.

[0030] In some embodiments, the maleate salt of the compound of formula I provided herein is crystalline. As used herein, "crystalline" or "crystalline form" means referring to a specific lattice structure of a crystalline substance. Different crystalline forms of the same substance generally have different crystal lattices (e.g., unit cells) due to different physical properties characteristic of each crystalline form. In some cases, different lattice structures result in different water or solvent contents.

[0031] The above different salt forms can be identified by solid-state characterization methods such as powder X-ray diffraction (XRPD). Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and dynamic vapor sorption (DVS) not only further assist in the identification of the above forms but also in the measurement of stability and solvent / water content.

[0032] The pattern of XRPD reflections (peaks) is generally considered to be the fingerprint of a particular crystalline form. It is well known that the relative intensities of XRPD peaks can vary significantly depending, inter alia, on the sample preparation technique, the crystal size distribution, the various filters used, the sample mounting operation, and the particular equipment employed. In some cases, depending on the type or setting of the apparatus, new peaks may be observed or existing peaks may disappear. In this specification, the term "peak" refers to a reflection having a relative height / intensity of at least about 4% of the maximum peak height / intensity. Further, differences in equipment and other factors can affect the 2θ value. Accordingly, the assignment of peaks such as those reported herein may vary within a width of plus or minus about 0.2° (2θ), and in the context of XRPD in this specification, the terms "substantially" and "about" are meant to encompass such variations.

[0033] Similarly, temperature readings associated with DSC, TGA, or other thermal experiments can vary within a width of about ±3 °C depending on the equipment, specific settings, sample preparation, etc. Accordingly, the crystalline forms or the term "about" reported herein where the DSC curve is "substantially" shown in any figure should be understood to take into account such variations.

[0034] In some embodiments, the salts and compounds described herein (e.g., a compound of formula I or a maleate salt of a compound of formula I) are 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 the salts described herein. Substantial separation can include compositions containing at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt% of the salts described herein, or salts thereof. Methods for isolating compounds and their salts are conventional in the art.

[0035] The maleate salt of the compound of formula I can be prepared in various crystalline forms, including, for example, Form I, Form II, Form III, Form IV, or Form V.

[0036] Maleate salt of the compound of formula I, Form I: In this specification, embodiments (i) to (x) of the crystalline form of the compound of formula I referred to as Form I are provided, and the crystalline form is described in Examples 1 and 7 below.

[0037] (i) In some embodiments, the maleate salt of the compound of formula I has at least one XRPD peak selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5° as represented by 2θ.

[0038] (ii) In some embodiments, the maleate salt of the compound of formula I has at least two XRPD peaks selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5° as represented by 2θ.

[0039] (iii) In some embodiments, the maleate salt of the compound of formula I has at least three XRPD peaks selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5° as represented by 2θ.

[0040] (iv) In some embodiments, the maleate salt of the compound of formula I has at least four XRPD peaks selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5° as represented by 2θ.

[0041] (v) In some embodiments, the maleate salt of the compound of formula I has the following XRPD peaks, namely, about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5° as represented by 2θ.

[0042] (vi) In some embodiments, the maleate salt of the compound of formula I has the following XRPD peaks, namely, about 4.3°, about 8.4°, and about 13.2°, as represented by 2θ.

[0043] (vii) In some embodiments, the maleate salt of the compound of formula I has an XRPD profile substantially shown in Figure 1.

[0044] (viii) In some embodiments, the maleate salt of the compound of formula I has an endothermic peak at about 211 °C in the DSC curve.

[0045] (ix) In some embodiments, the maleate salt of the compound of formula I has a DSC curve substantially shown in Figure 2.

[0046] (x) In some embodiments, the maleate salt of the compound of formula I has a TGA curve substantially shown in Figure 3.

[0047] Maleate salt of the compound of formula I, Form II: As used herein, a crystalline form of Compound I, referred to as Form II, is provided, and this crystalline form is described in Examples 16 and 17 below.

[0048] In some embodiments, Form II of the maleate salt of the compound of formula I has at least one XRPD peak selected from about 3.8°, about 7.8°, about 23.5°, and about 26.0°, as represented by 2θ.

[0049] In some embodiments, Form II of the maleate salt of the compound of formula I has at least two XRPD peaks selected from about 3.8°, about 7.8°, about 23.5°, and about 26.0°, as represented by 2θ.

[0050] In some embodiments, Form II of the maleate salt of the compound of formula I has at least three XRPD peaks selected from about 3.8°, about 7.8°, about 23.5°, and about 26.0°, as represented by 2θ.

[0051] In some embodiments, Form II of the maleate salt of the compound of Formula I has the following XRPD peaks, expressed as 2θ, namely, about 3.8°, about 7.8°, about 23.5°, and about 26.0°.

[0052] In some embodiments, Form II of the maleate salt of the compound of Formula I has the following XRPD peaks, expressed as 2θ, namely, about 3.8°, about 7.8°, and about 23.5°.

[0053] In some embodiments, Form II of the maleate salt of the compound of Formula I has an XRPD profile substantially as shown in Figure 25.

[0054] Maleate salt of the compound of Formula I, Form III: Provided herein is a crystalline form of Compound I, referred to as Form III, which is described hereinafter in Examples 16 and 18.

[0055] In some embodiments, Form III of the maleate salt of the compound of Formula I has at least one XRPD peak selected from about 3.8°, about 7.7°, about 12.1°, about 18.9°, and about 20.6°, expressed as 2θ.

[0056] In some embodiments, Form III of the maleate salt of the compound of Formula I has at least two XRPD peaks selected from about 3.8°, about 7.7°, about 12.1°, about 18.9°, and about 20.6°, expressed as 2θ.

[0057] In some embodiments, Form III of the maleate salt of the compound of Formula I has at least three XRPD peaks selected from about 3.8°, about 7.7°, about 12.1°, about 18.9°, and about 20.6°, expressed as 2θ.

[0058] In some embodiments, Form III of the maleate salt of the compound of formula I has at least 4 XRPD peaks selected from about 3.8°, about 7.7°, about 12.1°, about 18.9°, and about 20.6° as represented by 2θ.

[0059] In some embodiments, Form III of the maleate salt of the compound of formula I comprises the following XRPD peaks, namely, about 3.8°, about 7.7°, about 12.1°, about 18.9°, and about 20.6° as represented by 2θ.

[0060] In some embodiments, Form III of the maleate salt of the compound of formula I comprises the following XRPD peaks, namely, about 3.8°, about 7.7°, about 12.1°, and about 18.9° as represented by 2θ.

[0061] In some embodiments, Form III of the maleate salt of the compound of formula I has an XRPD profile substantially shown in Figure 26.

[0062] In some embodiments, Form III of the maleate salt of the compound of formula I has endothermic peaks at about 165.4 °C and about 195.4 °C in the DSC curve. In some embodiments, Form III of the maleate salt of the compound of formula I has an endothermic peak at about 165.4 °C in the DSC curve. In some embodiments, Form III of the maleate salt of the compound of formula I has an endothermic peak at about 195.4 °C in the DSC curve.

[0063] In some embodiments, Form III of the maleate salt of the compound of formula I has a DSC curve substantially shown in Figure 27.

[0064] In some embodiments, Form III of the maleate salt of the compound of formula I has a TGA curve substantially shown in Figure 28.

[0065] Maleate salt of the compound of formula I, Form IV: In this specification, a crystalline form of Compound I, referred to as Form IV, is provided, which is described in Examples 16 and 19 below.

[0066] In some embodiments, Form IV of the maleate salt of the compound of Formula I above has at least one XRPD peak selected from about 3.9°, about 4.6°, about 7.8°, about 9.1°, and about 22.8° as represented by 2θ.

[0067] In some embodiments, Form IV of the maleate salt of the compound of Formula I above has at least two XRPD peaks selected from about 3.9°, about 4.6°, about 7.8°, about 9.1°, and about 22.8° as represented by 2θ.

[0068] In some embodiments, Form IV of the maleate salt of the compound of Formula I above has at least three XRPD peaks selected from about 3.9°, about 4.6°, about 7.8°, about 9.1°, and about 22.8° as represented by 2θ.

[0069] In some embodiments, Form IV of the maleate salt of the compound of Formula I above has at least four XRPD peaks selected from about 3.9°, about 4.6°, about 7.8°, about 9.1°, and about 22.8° as represented by 2θ.

[0070] In some embodiments, Form IV of the maleate salt of the compound of Formula I above comprises the following XRPD peaks, namely, about 3.9°, about 4.6°, about 7.8°, about 9.1°, and about 22.8° as represented by 2θ.

[0071] In some embodiments, Form IV of the maleate salt of the compound of Formula I above comprises the following XRPD peaks, namely, about 3.9°, about 4.6°, about 7.8°, and about 9.1° as represented by 2θ.

[0072] In some embodiments, the XRPD profile of Form IV of the maleate salt of the compound of Formula I above is substantially shown in Figure 29.

[0073] In some embodiments, Form IV of the maleate salt of the compound of Formula I has endothermic peaks in the DSC curve at about 152.1 °C and about 202.6 °C. In some embodiments, Form IV of the maleate salt of the compound of Formula I has an endothermic peak in the DSC curve at about 152.1 °C. In some embodiments, Form IV of the maleate salt of the compound of Formula I has an endothermic peak in the DSC curve at about 202.6 °C.

[0074] In some embodiments, Form IV of the maleate salt of the compound of Formula I has a DSC curve substantially as shown in Figure 30.

[0075] In some embodiments, Form IV of the maleate salt of the compound of Formula I has a TGA curve substantially as shown in Figure 31.

[0076] Maleate salt of the compound of Formula I, Form V: As used herein, a crystalline form of Compound I, referred to as Form V, is provided, and this crystalline form is described in Examples 16 and 20 below.

[0077] In some embodiments, Form V of the maleate salt of the compound of Formula I has at least one XRPD peak selected from about 4.1°, about 8.3°, about 8.8°, about 18.0°, and about 27.3° as represented by 2θ.

[0078] In some embodiments, Form V of the maleate salt of the compound of Formula I has at least two XRPD peaks selected from about 4.1°, about 8.3°, about 8.8°, about 18.0°, and about 27.3° as represented by 2θ.

[0079] In some embodiments, Form V of the maleate salt of the compound of Formula I has at least three XRPD peaks selected from about 4.1°, about 8.3°, about 8.8°, about 18.0°, and about 27.3° as represented by 2θ.

[0080] In some embodiments, Form V of the maleate salt of the compound of formula I has at least four XRPD peaks selected from about 4.1°, about 8.3°, about 8.8°, about 18.0°, and about 27.3°, represented by 2θ.

[0081] In some embodiments, Form V of the maleate salt of the compound of formula I comprises the following XRPD peaks, namely, about 4.1°, about 8.3°, about 8.8°, about 18.0°, and about 27.3°, represented by 2θ.

[0082] In some embodiments, Form V of the maleate salt of the compound of formula I comprises the following XRPD peaks, namely, about 4.1°, about 8.3°, about 8.8°, and about 27.3°, represented by 2θ.

[0083] In some embodiments, Form V of the maleate salt of the compound of formula I has an XRPD profile substantially as shown in Figure 32.

[0084] In some embodiments, Form V of the maleate salt of the compound of formula I has an endothermic peak at about 200.1 °C in the DSC curve.

[0085] In some embodiments, Form V of the maleate salt of the compound of formula I has a DSC curve substantially as shown in Figure 33.

[0086] In some embodiments, Form V of the maleate salt of the compound of formula I has a TGA curve substantially as shown in Figure 34.

[0087] This application provides salts of the compound of formula II:

Chemical formula

[0088] Accordingly, in some embodiments, this application 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide phosphate 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide maleate 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide hemisulfate 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide hydrochloride 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide salicylate 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide methanesulfonate, and 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide ethanesulfonate a salt selected from or a pharmaceutically acceptable solvate and hydrate thereof. To provide.

[0089] In some embodiments, the present application provides 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide phosphate (hereinafter also referred to as the phosphate salt of the compound of Formula II, Compound II phosphate salt, Compound II phosphate, or any variation thereof).

[0090] In some embodiments, the above salt is a salt with a stoichiometric ratio of 1:1 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide to phosphoric acid.

[0091] In some embodiments, the phosphate salt of the compound of Formula II is crystalline.

[0092] In some embodiments, the phosphate salt of the compound of Formula II is substantially isolated.

[0093] In some embodiments, the phosphate salt of the compound of Formula II has at least one XRPD peak selected from about 5.3°, about 9.1°, about 14.9°, about 15.8°, and about 19.3° as represented by 2θ. In some embodiments, the phosphate salt of the compound of Formula II has at least two XRPD peaks selected from about 5.3°, about 9.1°, about 14.9°, about 15.8°, and about 19.3° as represented by 2θ. In some embodiments, the phosphate salt of the compound of Formula II has at least three XRPD peaks selected from about 5.3°, about 9.1°, about 14.9°, about 15.8°, and about 19.3° as represented by 2θ. In some embodiments, the phosphate salt of the compound of Formula II has at least four XRPD peaks selected from about 5.3°, about 9.1°, about 14.9°, about 15.8°, and about 19.3° as represented by 2θ. In some embodiments, the phosphate salt of the compound of Formula II comprises the following XRPD peaks, namely, about 5.3°, about 9.1°, about 14.9°, about 15.8°, and about 19.3°.

[0094] In some embodiments, the phosphate salt of the compound of Formula II has an XRPD profile substantially shown in Figure 4.

[0095] In some embodiments, the phosphate salt of the compound of Formula II has an endothermic peak at about 257.2 °C in the DSC curve. In some embodiments, the phosphate salt of the compound of Formula II has a DSC curve substantially shown in Figure 5. In some embodiments, the phosphate salt of the compound of Formula II has a TGA curve substantially shown in Figure 6.

[0096] In some embodiments, the present application provides 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide maleate (also referred to herein as the maleate salt of the compound of Formula II, the maleate salt of Compound II, Compound II maleate salt, or any variation thereof).

[0097] In some embodiments, the above salt is a salt with a stoichiometric ratio of 1:1 of maleic acid to 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide.

[0098] In some embodiments, the maleate salt of the compound of Formula II is crystalline.

[0099] In some embodiments, the maleate salt of the compound of Formula II is substantially isolated.

[0100] In some embodiments, the maleate salt of the compound of Formula II has at least one XRPD peak selected from about 4.5°, about 6.5°, about 14.1°, about 24.0°, and about 28.2° as represented by 2θ. In some embodiments, the maleate salt of the compound of Formula II has at least two XRPD peaks selected from about 4.5°, about 6.5°, about 14.1°, about 24.0°, and about 28.2° as represented by 2θ. In some embodiments, the maleate salt of the compound of Formula II has at least three XRPD peaks selected from about 4.5°, about 6.5°, about 14.1°, about 24.0°, and about 28.2° as represented by 2θ. In some embodiments, the maleate salt of the compound of Formula II has at least four XRPD peaks selected from about 4.5°, about 6.5°, about 14.1°, about 24.0°, and about 28.2° as represented by 2θ. In some embodiments, the maleate salt of the compound of Formula II comprises the following XRPD peaks, namely, about 4.5°, about 6.5°, about 14.1°, about 24.0°, and about 28.2° as represented by 2θ.

[0101] In some embodiments, the maleate salt of the compound of Formula II has an XRPD profile substantially shown in FIG. 7.

[0102] In some embodiments, the maleate salt of the compound of Formula II has an endothermic peak at about 194.8 °C and / or about 239.7 °C in the DSC curve. In some embodiments, the maleate salt of the compound of Formula II has a DSC curve substantially shown in FIG. 8. In some embodiments, the maleate salt of the compound of Formula II has a TGA curve substantially shown in FIG. 9.

[0103] In some embodiments, the present application provides 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide hemisulfate salt (also referred to herein as the hemi-sulfate salt of the compound of Formula II, the hemi-sulfate salt of Compound II, Compound II hemi-sulfate salt, or any variation thereof).

[0104] In some embodiments, the above salt is a salt with a stoichiometric ratio 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide to sulfuric acid of 1:0.5 (i.e., 2:1).

[0105] In some embodiments, the hemisulfate salt of the compound of Formula II is crystalline.

[0106] In some embodiments, the hemisulfate salt of the compound of Formula II is substantially isolated.

[0107] In some embodiments, the hemisulfate salt of the compound of formula II has at least one XRPD peak selected from about 5.3°, about 8.5°, about 15.3°, about 20.1°, and 24.9° as represented by 2θ. In some embodiments, the hemisulfate salt of the compound of formula II has at least two XRPD peaks selected from about 5.3°, about 8.5°, about 15.3°, about 20.1°, and 24.9° as represented by 2θ. In some embodiments, the hemisulfate salt of the compound of formula II has at least three XRPD peaks selected from about 5.3°, about 8.5°, about 15.3°, about 20.1°, and 24.9° as represented by 2θ. In some embodiments, the hemisulfate salt of the compound of formula II has at least four XRPD peaks selected from about 5.3°, about 8.5°, about 15.3°, about 20.1°, and 24.9° as represented by 2θ. In some embodiments, the hemisulfate salt of the compound of formula II comprises the following XRPD peaks, namely, about 5.3°, about 8.5°, about 15.3°, about 20.1°, and 24.9° as represented by 2θ.

[0108] In some embodiments, the hemisulfate salt of the compound of formula II has an XRPD profile substantially shown in FIG. 10.

[0109] In some embodiments, the hemisulfate salt of the compound of formula II has an endothermic peak at about 289.4 °C in the DSC curve. In some embodiments, the hemisulfate salt of the compound of formula II has a DSC curve substantially shown in FIG. 11. In some embodiments, the hemisulfate salt of the compound of formula II has a TGA curve substantially shown in FIG. 12.

[0110] In some embodiments, the present application provides 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide hydrochloride (also referred to herein as the hydrochloride salt of the compound of Formula II, the hydrochloride salt of Compound II, Compound II hydrochloride salt, or any variation thereof).

[0111] In some embodiments, the salt is a salt in which the stoichiometric ratio of hydrochloric acid to 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide is 1:1.

[0112] In some embodiments, the hydrochloride salt of the compound of Formula II is crystalline.

[0113] In some embodiments, the hydrochloride salt of the compound of Formula II is substantially isolated.

[0114] In some embodiments, the hydrochloride salt of the compound of Formula II has at least one XRPD peak selected from about 6.5°, about 9.7°, about 14.9°, about 21.5°, and about 23.9° as represented by 2θ. In some embodiments, the hydrochloride salt of the compound of Formula II has at least two XRPD peaks selected from about 5.3°, about 9.1°, about 14.9°, about 15.8°, and about 19.3° as represented by 2θ. In some embodiments, the hydrochloride salt of the compound of Formula II has at least three XRPD peaks selected from about 5.3°, about 9.1°, about 14.9°, about 15.8°, and about 19.3° as represented by 2θ. In some embodiments, the hydrochloride salt of the compound of Formula II has at least four XRPD peaks selected from about 5.3°, about 9.1°, about 14.9°, about 15.8°, and about 19.3° as represented by 2θ. In some embodiments, the hydrochloride salt of the compound of Formula II comprises the following XRPD peaks, namely, about 5.3°, about 9.1°, about 14.9°, about 15.8°, and about 19.3°.

[0115] In some embodiments, the XRPD profile of the hydrochloride salt of the compound of Formula II is substantially shown in FIG. 13.

[0116] In some embodiments, the hydrochloride salt of the compound of Formula II has an endothermic peak at about 190 °C in the DSC curve. In some embodiments, the DSC curve of the hydrochloride salt of the compound of Formula II is substantially shown in FIG. 14. In some embodiments, the TGA curve of the hydrochloride salt of the compound of Formula II is substantially shown in FIG. 15.

[0117] In some embodiments, the present application provides 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide salicylate (also referred to herein as the salicylate salt of the compound of Formula II, the salicylate salt of Compound II, the Compound II salicylate salt, or any variation thereof).

[0118] In some embodiments, the salt is a salt having a stoichiometric ratio of 1:1 of salicylic acid to 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide.

[0119] In some embodiments, the salicylate salt of the compound of Formula II is crystalline.

[0120] In some embodiments, the salicylate salt of the compound of Formula II is substantially isolated.

[0121] In some embodiments, the salicylate of the compound of formula II has at least one XRPD peak selected from about 7.3°, about 14.4°, about 15.7°, about 19.9°, and about 21.9° as represented by 2θ. In some embodiments, the salicylate of the compound of formula II has at least two XRPD peaks selected from about 7.3°, about 14.4°, about 15.7°, about 19.9°, and about 21.9° as represented by 2θ. In some embodiments, the salicylate of the compound of formula II has at least three XRPD peaks selected from about 7.3°, about 14.4°, about 15.7°, about 19.9°, and about 21.9° as represented by 2θ. In some embodiments, the salicylate of the compound of formula II has at least four XRPD peaks selected from about 7.3°, about 14.4°, about 15.7°, about 19.9°, and about 21.9° as represented by 2θ. In some embodiments, the salicylate of the compound of formula II comprises the following XRPD peaks, namely, about 7.3°, about 14.4°, about 15.7°, about 19.9°, and about 21.9° as represented by 2θ.

[0122] In some embodiments, the salicylate of the compound of formula II has an XRPD profile substantially shown in Figure 16.

[0123] In some embodiments, the salicylate of the compound of formula II has endothermic peaks at about 181.7 °C, about 224.9 °C, and / or 264.5 °C in the DSC curve. In some embodiments, the salicylate of the compound of formula II has a DSC curve substantially shown in Figure 17. In some embodiments, the salicylate of the compound of formula II has a TGA curve substantially shown in Figure 18.

[0124] In some embodiments, the present application provides 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamidomethanesulfonate (hereinafter also referred to as the mesylate salt of the compound of Formula II, the mesylate salt of Compound II, Compound II mesylate salt, or any variation thereof).

[0125] In some embodiments, the above salt is a salt with a stoichiometric ratio of 1:1 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide to methanesulfonic acid.

[0126] In some embodiments, the methanesulfonate salt of the compound of Formula II is crystalline.

[0127] In some embodiments, the methanesulfonate salt of the compound of Formula II is substantially isolated.

[0128] In some embodiments, the methanesulfonate salt of the compound of Formula II has at least one XRPD peak selected from about 5.0°, about 8.2°, about 13.2°, and about 16.9° as represented by 2θ. In some embodiments, the methanesulfonate salt of the compound of Formula II has at least two XRPD peaks selected from about 5.0°, about 8.2°, about 13.2°, and about 16.9° as represented by 2θ. In some embodiments, the methanesulfonate salt of the compound of Formula II has at least three XRPD peaks selected from about 5.0°, about 8.2°, about 13.2°, and about 16.9° as represented by 2θ. In some embodiments, the methanesulfonate salt of the compound of Formula II comprises the following XRPD peaks, namely, about 5.0°, about 8.2°, about 13.2°, and about 16.9° as represented by 2θ.

[0129] In some embodiments, the XRPD profile of the methanesulfonate salt of the compound of Formula II is substantially shown in Figure 19.

[0130] In some embodiments, the methanesulfonate salt of the compound of Formula II has an endothermic peak at about 174.8 °C in the DSC curve. In some embodiments, the DSC curve of the methanesulfonate salt of the compound of Formula II is substantially shown in Figure 20. In some embodiments, the TGA curve of the methanesulfonate salt of the compound of Formula II is substantially shown in Figure 21.

[0131] In some embodiments, the present application provides 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamidoethanesulfonate (also referred to herein as the esylate salt of the compound of Formula II, the esylate salt of Compound II, the Compound II esylate salt, or any variation thereof).

[0132] In some embodiments, the salt is a salt having a stoichiometric ratio of 1:1 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide to ethanesulfonic acid.

[0133] In some embodiments, the ethanesulfonate salt of the compound of Formula II is crystalline.

[0134] In some embodiments, the ethanesulfonate salt of the compound of Formula II is substantially isolated.

[0135] In some embodiments, the ethanesulfonate of the compound of Formula II has at least one XRPD peak selected from about 4.9°, about 7.6°, about 15.4°, about 16.8°, and about 17.5° as represented by 2θ. In some embodiments, the ethanesulfonate of the compound of Formula II has at least two XRPD peaks selected from about 4.9°, about 7.6°, about 15.4°, about 16.8°, and about 17.5° as represented by 2θ. In some embodiments, the ethanesulfonate of the compound of Formula II has at least three XRPD peaks selected from about 4.9°, about 7.6°, about 15.4°, about 16.8°, and about 17.5° as represented by 2θ. In some embodiments, the ethanesulfonate of the compound of Formula II has at least four XRPD peaks selected from about 4.9°, about 7.6°, about 15.4°, about 16.8°, and about 17.5° as represented by 2θ. In some embodiments, the ethanesulfonate of the compound of Formula II comprises the following XRPD peaks, namely, about 4.9°, about 7.6°, about 15.4°, about 16.8°, and about 17.5° as represented by 2θ. In some embodiments, the ethanesulfonate of the compound of Formula II comprises the following XRPD peaks, namely, about 4.9°, about 7.6°, about 15.4°, and about 17.5° as represented by 2θ.

[0136] In some embodiments, the XRPD profile of the ethanesulfonate of the compound of Formula II is substantially shown in Figure 22.

[0137] In some embodiments, the ethanesulfonate of the compound of Formula II has an endothermic peak at about 187.7 °C in the DSC curve. In some embodiments, the esylate of the compound of Formula II has a DSC curve substantially shown in Figure 23. In some embodiments, the esylate of the compound of Formula II has a TGA curve substantially shown in Figure 24.

[0138] Manufacturing method This application relates to Formula I:

Chemical formula

[0139] Accordingly, provided herein is a method for producing a salt which is 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, the method comprising reacting a compound of formula I with maleic acid to form the above salt. The method for producing the maleate salt of the compound of formula I is shown in Scheme 1 and described in Example 1.

[0140] In some embodiments, about 1 equivalent of maleic acid is used based on 1 equivalent of the compound of formula I.

[0141] In some embodiments, reacting the compound of formula I with maleic acid is carried out in the presence of a solvent component.

[0142] In some embodiments, the solvent component includes methanol.

[0143] In some embodiments, the solvent component includes dichloromethane.

[0144] In some embodiments, the solvent component includes methanol and dichloromethane.

[0145] In some embodiments, the production method further includes removing a substantial portion of dichloromethane to precipitate the above salt.

[0146] In some embodiments, the production method further includes removing a substantial portion of dichloromethane to precipitate the above salt.

[0147] In some embodiments, the manufacturing method further includes forming a solution of the compound of Formula I in a solvent component before the reacting.

[0148] In a further embodiment, the solution is formed by heating a slurry of the compound of Formula I in the solvent component to a temperature of about 45 °C to about 55 °C.

[0149] In a further embodiment, the manufacturing method further includes stirring the solution and filtering the solution to form a filtrate before reacting the compound of Formula I with maleic acid.

[0150] In a further embodiment, the manufacturing method further includes adding activated carbon and silica gel to the solution after the step of heating the slurry to a temperature of about 45 °C to about 55 °C to form a solution and before the step of stirring the solution.

[0151] In some embodiments, the method for manufacturing 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 comprises adding a compound of Formula I to a solvent component at room temperature to form a slurry, heating the slurry to a temperature of about 45 °C to about 55 °C to form a solution, stirring the solution, filtering the solution to obtain a filtrate, adding maleic acid to the filtrate, removing the solvent from the filtrate to precipitate the salt and.

[0152] In some embodiments, the solvent component includes methanol.

[0153] In some embodiments, the solvent component includes dichloromethane.

[0154] In some embodiments, the solvent component includes methanol and dichloromethane.

[0155] In some embodiments, the manufacturing method further includes adding activated carbon to the solution after the step of heating the slurry to a temperature of about 45°C to about 55°C to form a solution and before the step of stirring the solution.

[0156] In some embodiments, the manufacturing method further includes adding silica gel to the solution after the step of heating the slurry to a temperature of about 45°C to about 55°C to form a solution and before the step of stirring the solution.

[0157] In some embodiments, the manufacturing method further includes adding activated carbon and silica gel to the solution after the step of heating the slurry to a temperature of about 45°C to about 55°C to form a solution and before the step of stirring the solution.

[0158] Provided herein is a method for manufacturing form II 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, which includes distilling off a saturated chloroform solution of compound I maleate at 25 ± 1°C. The method for manufacturing form II of the maleate of the compound of formula I is described in Example 16, Table 10.

[0159] Disclosed herein is a method for preparing the maleate salt 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 in Form III, which comprises distilling off a saturated 1,4-dioxane solution of Compound I maleate at 25 ± 1 °C. The method for preparing the maleate salt of the compound of Formula I in Form III is described in Example 16, Table 10.

[0160] Disclosed herein is a method for preparing the maleate salt 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 in Form IV, which comprises distilling off a saturated n-BuOH solution of Compound I maleate at 50 ± 1 °C. The method for preparing the maleate salt of the compound of Formula I in Form IV is described in Example 16, Table 10.

[0161] Disclosed herein is a method for preparing the maleate salt 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 in Form V, which comprises adding a saturated dichloromethane solution of Compound I maleate to heptane and stirring. The method for preparing the maleate salt of the compound of Formula I in Form V is described in Example 16, Table 10.

[0162] This application further provides a method for preparing a salt of Formula II:

Chemical formula

[0163] Accordingly, provided herein is a method for producing a salt which is 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide hemisulfate, the method comprising reacting a compound of formula II with sulfuric acid to form the above salt. The method for producing the hemisulfate of the compound of formula II is described in Example 8, Table 2.

[0164] In some embodiments, about 0.6 equivalents of sulfuric acid are used based on 1 equivalent of the compound of formula II.

[0165] In some embodiments, the production method comprises adding the compound of formula II to a solvent component to form a solution, adding sulfuric acid to the above solution at room temperature, concentrating the above solution to form a slurry, stirring the above slurry at a temperature of about 60 °C to about 70 °C, cooling the above slurry to a temperature of about 15 °C to about 25 °C to precipitate the above salt and including.

[0166] In some embodiments, the solvent component includes methanol.

[0167] In some embodiments, the solvent component includes dichloromethane.

[0168] In some embodiments, the solvent component includes methanol and dichloromethane.

[0169] In some embodiments, the sulfuric acid is an aqueous solution of about 1 M.

[0170] In some embodiments, the manufacturing method further includes manufacturing 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide sulfate. The manufacturing method of the sulfate of the compound of Formula II is shown in Scheme 2 and described in Example 2.

[0171] In some embodiments, the manufacturing method of the salt which is 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide sulfate includes reacting the compound of Formula II with about 1 equivalent of sulfuric acid based on 1 equivalent of the compound of Formula II.

[0172] In some embodiments, the manufacturing method 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide sulfate includes adding the compound of Formula II to a first solvent component at room temperature to form a solution, heating the solution to a temperature of 50°C to 60°C, adding sulfuric acid to the solution, removing the solvent to precipitate the sulfate and.

[0173] In some embodiments, the first solvent component includes methanol.

[0174] In some embodiments, the sulfuric acid is added as an aqueous solution.

[0175] In some embodiments, the method for producing the hemisulfate salt 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide is as follows: adding the hemisulfate salt 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide to a second solvent component to form a slurry; heating the slurry to a temperature of about 30 °C to about 40 °C; stirring the slurry; collecting the resulting hemisulfate salt; and

[0176] In some embodiments, the second solvent component contains water.

[0177] Disclosed herein is a method for producing an amorphous form of the hemisulfate salt 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The method for producing the amorphous form of the hemisulfate salt of the compound of formula II is shown in Scheme 2 and described in Example 2.

[0178] In some embodiments, the method for producing the amorphous form of the hemisulfate salt 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide is as follows: Adding the above 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide hemisulfate to a third solvent component to form a solution; Filtering the above solution; Concentrating the filtrate; Drying the resulting solid to produce the above amorphous hemisulfate; and includes.

[0179] In some embodiments, the third solvent component includes acetone and methanol.

[0180] Disclosed herein is a method for producing a salt which is 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide phosphate, the method including reacting a compound of formula II with phosphoric acid to form the above salt. The method for producing the phosphate salt of the compound of formula II is described in Example 8, Table 2. In some embodiments, about 1.2 equivalents of phosphoric acid are used based on 1 equivalent of the compound of formula II.

[0181] Disclosed herein is a method for producing a salt which is 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide maleate, the method including reacting a compound of formula II with maleic acid to form the above salt. The method for producing the maleate salt of the compound of formula II is described in Example 8, Table 2. In some embodiments, about 1.5 equivalents of maleic acid are used based on 1 equivalent of the compound of formula II.

[0182] In this specification, there is provided a method for producing a salt which is 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide hydrochloride, the method including reacting a compound of formula II with hydrochloric acid to form the above salt. The method for producing the hydrochloride salt of the compound of formula II is described in Example 8, Table 2. In some embodiments, about 1.2 equivalents of hydrochloric acid are used based on 1 equivalent of the compound of formula II.

[0183] In this specification, there is provided a method for producing a salt which is 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide salicylate, the method including reacting a compound of formula II with salicylic acid to form the above salt. The method for producing the salicylate salt of the compound of formula II is described in Example 8, Table 2. In some embodiments, about 1.2 equivalents of salicylic acid are used based on 1 equivalent of the compound of formula II.

[0184] In this specification, there is provided a method for producing a salt which is 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide methanesulfonate, the method including reacting a compound of formula II with methanesulfonic acid to form the above salt. The method for producing the methanesulfonate salt of the compound of formula II is described in Example 8, Table 2. In some embodiments, about 1 equivalent of methanesulfonic acid is used based on 1 equivalent of the compound of formula II.

[0185] In the present specification, there is provided a method for producing a salt which is 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamidoethanesulfonate, the method including reacting a compound of formula II with ethanesulfonic acid to form the above salt. The method for producing the ethanesulfonate of the compound of formula II is described in Example 8, Table 2. In some embodiments, about 1 equivalent of methanesulfonic acid is used based on 1 equivalent of the compound of formula II.

[0186] Certain features of the present disclosure that are described in the context of separate embodiments for clarity may be presented in combination in a single embodiment (such an embodiment is also intended to be combined in the same manner as described in a multiple dependent form). Conversely, various features of the present disclosure that are described in the context of a single embodiment for brevity may be presented separately or in any and appropriate partial combination.

[0187] The salts and compounds of the present disclosure may also include all isotopes of atoms present in the intermediate or final salt or compound. Isotopes are atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen are tritium and deuterium.

[0188] In some embodiments, the above compound or salt may coexist with other substances such as water and solvents (e.g., hydrates and solvates), or may be isolated.

[0189] In some embodiments, the compounds described herein, or their salts (e.g., maleate of the compound of formula I or hemisulfate of the compound of formula II), are substantially isolated.

[0190] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, or other problems or complications, and that exhibit a reasonable benefit / risk ratio.

[0191] As can be seen from the above, the compounds (including their salts) provided herein can be produced using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes. The manufacturing methods described herein can be monitored according to any and appropriate methods known in the art. For example, the formation of the product can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, or spectrophotometry (e.g., UV-visible light), or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC), or other related techniques.

[0192] As used herein, the term "react" is used as understood in the art and generally refers to bringing the above chemical reactants into contact with each other in such a way that the chemical reactants interact at the molecular level to effect a chemical or physical transformation. In some embodiments, the above "react" involves two reactants, and an amount of at least 1 equivalent of the second reactant relative to the first reactant is used. The reaction steps of the manufacturing methods described herein can be carried out under suitable times and conditions suitable for producing the specified product.

[0193] The reaction of the manufacturing method described in this specification may be carried out in an appropriate solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent may be substantially non-reactive with the starting materials (reactants), intermediates, or products at a temperature at which the reaction is carried out, for example, a temperature within the range from the freezing temperature to the boiling temperature of the solvent. A given reaction may be carried out in one solvent or a mixture of two or more solvents. Depending on a specific reaction step, a solvent (or a mixture of solvents) suitable for the specific reaction step can be selected.

[0194] Examples of suitable solvents include halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, 1,2-dichloroethane, 1,2-dibromoethane, hexafluorobenzene, 1,2,4-trichlorobenzene, 1,2-dichlorobenzene, chlorobenzene, fluorobenzene, and mixtures thereof.

[0195] Examples of suitable ether solvents include dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, and mixtures thereof.

[0196] Suitable protic solvents include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neopentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerin.

[0197] Suitable aprotic solvents include, by way of example and without limitation, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide.

[0198] Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.

[0199] The reactions of the manufacturing methods described in this specification can be carried out at appropriate temperatures that can be easily determined by those skilled in the art. The reaction temperature can depend, for example, on the melting and boiling points of the reactants and solvents (if present), the thermodynamics of the reaction (e.g., a highly exothermic reaction may need to be carried out at a low temperature), and the kinetics of the reaction (e.g., a high activation energy barrier may require a high temperature).

[0200] In this specification, the expressions "ambient temperature" and "room temperature" or "rt" are understood in the art and generally refer to a temperature such as the approximate temperature of the room in which the reaction is carried out, for example, a temperature in the range of about 20°C to about 30°C.

[0201] The reactions of the manufacturing methods described in this specification can be carried out in air or under an inert atmosphere. Generally, a reaction involving a reactant or product that substantially reacts with air can be carried out using synthetic techniques well-known to those skilled in the art that are sensitive to air.

[0202] Method of Use The salts of the present disclosure (e.g., salts of the compounds of Formulas I and II) can modulate or inhibit the activity of TAM kinase. For example, using the compounds of the present disclosure, the activity of TAM kinase in a cell, or an individual or patient that requires inhibition of the kinase, can be inhibited by administering an inhibitory amount of the compounds of the present disclosure to the cell, individual, or patient.

[0203] In some embodiments, the salts of the present disclosure are selective for the TAM kinase over one or more other kinases. In some embodiments, the compounds of the present disclosure are selective for the TAM kinase over 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.

[0204] The salts of the present disclosure can inhibit one or more of AXL, MER, and TYRO3. In some embodiments, the salt is more selective for one TAM kinase than another TAM kinase. "Selective" means that the compound binds or inhibits the TAM kinase with higher affinity or with a higher ability than a reference enzyme such as another TAM kinase. For example, the salt may be selective for AXL over MER and TYRO3, or selective for MER over AXL and TYRO3, or selective for AXL and MER over TYRO3. In some embodiments, the salt inhibits all of the TAM family members (e.g., AXL, MER, and TYRO3). In some embodiments, the salt may be selective for AXL and MER over TYRO3 and other kinases. In some embodiments, provided herein is a method of inhibiting AXL and MER kinases, the method comprising contacting the AXL and MER kinases with a salt provided herein or a pharmaceutically acceptable salt thereof.

[0205] The compounds of the present disclosure are useful as TAM kinase inhibitors for the treatment of various diseases associated with abnormal expression or abnormal activity of the TAM kinase. The salts of the compounds (of Formulas I and II) that inhibit the TAM kinase are useful in providing a means to prevent growth or induce apoptosis in tumors, particularly by inhibiting angiogenesis. Therefore, it is expected that the salts will be found to be useful for the treatment or prevention of proliferative disorders such as cancer. In particular, tumors with mutants that activate receptor tyrosine kinases or with upregulation of receptor tyrosine kinases may be particularly sensitive to the inhibitors.

[0206] In certain embodiments, the present disclosure provides a method of treating a TAM kinase-mediated disease or disorder in a patient in need thereof, the method comprising administering to the patient a salt provided herein (e.g., a salt of a compound of Formula I and II), or a pharmaceutically acceptable composition thereof.

[0207] For example, the salts of the present disclosure are useful for 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, anal cancer, endometrial cancer, gastric cancer, head and neck cancer (e.g., cancer of the larynx, hypopharynx, nasopharynx, oropharynx, lip, and oral cavity), kidney cancer, liver cancer (e.g., hepatocellular carcinoma, cholangiocarcinoma), lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung cancer, small cell and 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), gastric cancer, thyroid cancer, parathyroid cancer, skin cancer (e.g., squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer), and brain cancer (e.g., astrocytoma, medulloblastoma, ependymoma, neuroectodermal tumor, pineal tumor).

[0208] Other cancers treatable by the compounds of the present disclosure include bone cancer, intraocular cancer, gynecological cancer, endocrine cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, pituitary cancer, triple negative breast cancer (TNBC), and environmentally induced cancers including cancers induced by asbestos.

[0209] 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 or non-Hodgkin lymphoma, myeloproliferative neoplasms (e.g., polycythemia vera, essential thrombocythemia, and primary myelofibrosis), Waldenström macroglobulinemia, hairy cell lymphoma, chronic myelogenous leukemia, acute lymphoblastic lymphoma, AIDS-related lymphoma, and Burkitt lymphoma.

[0210] Other cancers treatable by the compounds of the present disclosure include eye tumors, glioblastoma, melanoma, rhabdomyosarcoma, lymphoma, and osteosarcoma.

[0211] The salts of the present disclosure may also be useful in inhibiting tumor metastasis.

[0212] In some embodiments, diseases and indications treatable using the compounds of the present disclosure include, but are not limited to, blood cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0213] Exemplary blood cancers include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), non-Hodgkin lymphoma (NHL) (including relapsed or refractory NHL), follicular lymphoma (FL), Hodgkin lymphoma, lymphoblastic lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, Waldenström macroglobulinemia, hairy cell lymphoma, chronic myelomonocytic leukemia, and lymphomas and leukemias such as Burkitt lymphoma.

[0214] Exemplary sarcomas include chondrosarcoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxosarcoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, mesenchymoma, and teratoma.

[0215] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchial cancer (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) cancer, bronchial adenoma, chondroma perverted, and mesothelioma.

[0216] Exemplary digestive tract cancers include esophageal cancers (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancers (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancers (tubular adenocarcinoma, islet cell adenoma, glucagon-producing tumor, gastrin-producing tumor, carcinoid tumor, VIP-producing tumor), small intestine cancers (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancers (adenocarcinoma, urothelial adenoma, villous adenoma, hyperplastic polyp, leiomyoma), colorectal cancer, and bile duct cancer.

[0217] Exemplary urogenital tract cancers include kidney cancers (adenocarcinoma, Wilms tumor [nephroblastoma], renal cell carcinoma), bladder and urethral cancers (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, urothelial carcinoma), prostate cancers (adenocarcinoma, sarcoma), and testicular cancers (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma).

[0218] Exemplary liver cancers include hepatocellular tumors (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0219] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondral chondroma (osteochondroma), chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor.

[0220] Exemplary nervous system cancers include skull cancers (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges cancers (meningioma, meningiosarcoma, gliomatosis), brain cancers (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pinealoma], glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), and spinal cord cancers (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma, Lhermitte-Duclos disease, central nervous system (CNS) neoplasms, primary CNS lymphoma, and spinal cord tumors.

[0221] Exemplary gynecological cancers include cancers of the uterus (endometrial cancer), cervix (cervical cancer, pre-tumor cervical dysplasia), ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulosa cell tumor, Sertoli-Leydig cell tumor, undifferentiated embryonal cell tumor, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid rhabdomyosarcoma (fetal rhabdomyosarcoma)), and fallopian tubes (carcinoma).

[0222] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloid.

[0223] Exemplary head and neck cancers include glioblastoma, melanoma, rhabdomyosarcoma, lymphoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cancer, laryngeal cancer, nasopharyngeal cancer, nasal cancer and paranasal sinus cancer, thyroid cancer and parathyroid cancer.

[0224] 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 salt of a compound of formula I or a salt of a compound of formula II, or a composition comprising a salt of a compound of formula I or a salt of a compound of formula II.

[0225] 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 salt of a compound of formula I or a salt of a compound of formula II, or a composition comprising a salt of a compound of formula I or a salt of a compound of formula II.

[0226] In some embodiments, the present disclosure provides a method for treating cancer 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.

[0227] By targeting the TAM receptor tyrosine kinase, a therapeutic approach for treating viral diseases can be provided (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. This method comprises administering to a patient in need thereof a therapeutically effective amount of a salt of a compound of formula I or a salt of a compound of formula II, or a composition comprising a salt of a compound of formula I or a salt of a compound of formula II.

[0228] 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 virus; 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, examples of viruses that cause infectious diseases treatable by the methods of the present disclosure include hepatitis (type A, B, or C) virus, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus (e.g., West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, Zika virus), echovirus, rhinovirus, coxsackievirus, coronavirus, 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 arbovirus encephalitis virus, but are not limited to these.

[0229] In some embodiments, the present disclosure provides methods for treating thrombosis (J.M.E.M. 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).

[0230] Combination therapy For the treatment of TAM-related diseases, disorders, or illnesses, one or more additional pharmaceuticals or treatment methods, such as antiviral agents, chemotherapeutic agents or other anticancer agents, immunostimulants, immunosuppressants, radiation, antitumor and antiviral vaccines, cytokine therapy agents (e.g., IL-2, GM-CSF, etc.), and / or tyrosine kinase inhibitors, etc., may be used in combination with a compound of Formula I or a compound described herein. The above pharmaceuticals may be combined with the present salt (e.g., salts of the compounds of Formula I and II) in a single dosage form, or the above pharmaceuticals may be administered simultaneously or sequentially as separate dosage forms.

[0231] Suitable antiviral agents contemplated for combination with the salts of the present disclosure include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral drugs.

[0232] Examples of suitable NRTIs include zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (1592U89), adefovir dipivoxil [bis(POM)-PMEA], lobucavir (BMS-180194), BCH-10652, emtricitabine [(-)-FTC], β-L-FD4 (also called β-L-D4C, the name being β-L-2’,3’-dideoxy-5-fluorocytidine), DAPD ((-)-β-D-2,6-diaminopurine dioxolane), and rodenosine (FddA). General suitable NNRTIs include nevirapine (BI-RG-587), delavirdine (BHAP, U-90152), efavirenz (DMP-266), PNU-142721, AG-1549, MKC-442 (1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione), and (+)-calanolide A (NSC-675451) and B. General suitable protease inhibitors include saquinavir (Ro 31-8959), ritonavir (ABT-538), indinavir (MK-639), nelfinavir (AG-1343), amprenavir (141W94), lasinavir (BMS-234475), DMP-450, BMS-2322623, ABT-378, AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

[0233] Suitable agents for use in combination with the salts of the present application for the treatment of cancer include chemotherapeutic agents, targeted cancer therapy agents, immunotherapy agents, or radiation therapy. The salts of the present disclosure may be effective in combination with antihormonal agents for the treatment of breast cancer and other tumors. Suitable examples include, but are not limited to, antiestrogen agents including tamoxifen and toremifene; aromatase inhibitors including letrozole, anastrozole, and exemestane; adrenocortical steroids (e.g., prednisone); progestins (e.g., megestrol acetate); and estrogen receptor antagonists (e.g., fulvestrant). Suitable antihormonal agents used in the treatment of prostate cancer and other cancers may also be used in combination with the compounds of the present disclosure. These antihormonal agents include, but are not limited to, antiandrogens including flutamide, bicalutamide, and nilutamide; luteinizing hormone-releasing hormone (LHRH) analogs including leuprolide, goserelin, triptorelin, and histrelin; LHRH antagonists (e.g., degarelix); androgen receptor blockers (e.g., enzalutamide); and agents that inhibit androgen production (e.g., abiraterone).

[0234] The salts of the present disclosure may be used in combination with other agents against membrane receptor kinases, or sequentially in combination with other agents, particularly for patients with primary or acquired resistance to targeted therapies. These therapeutic agents include inhibitors or antibodies against EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, PDGFR, FGFR1, FGFR2, FGFR3, FGFR4, TrkA, TrkB, TrkC, ROS, c-Kit, or Flt-3, as well as cancer-related fusion protein kinases such as Bcr-Abl and EML4-Alk. Inhibitors against EGFR include gefitinib and erlotinib, and inhibitors against EGFR / Her2 include dacomitinib, afatinib, lapatinib, and neratinib, but are not limited thereto. Antibodies against the above EGFR include cetuximab, panitumumab, and necitumumab, but are not limited thereto. An inhibitor of c-Met may be used in combination with a TAM inhibitor. Inhibitors of c-Met include onartuzumab, crizotinib, and INC-280. Agents against FGFR include AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258, lucitanib, dovitinib, TAS-120, JNJ-42756493, and Debio 1347, but are not limited thereto. Agents against Trk include LOXO-101 and RXDX-101, but are not limited thereto. Agents against Abl (or Bcr-Abl) include imatinib, dasatinib, nilotinib, and ponatinib, and an agent against Alk (or EML4-ALK) includes crizotinib.

[0235] Angiogenesis inhibitors may be effective in some tumors when used in combination with TAM inhibitors. Examples of these angiogenesis inhibitors include antibodies against VEGF or VEGFR or kinase inhibitors of VEGFR. Examples of antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept. Examples of inhibitors of VEGFR kinase and other anti-angiogenesis inhibitors include sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib, but are not limited thereto.

[0236] In cancer, activation of intracellular signaling pathways frequently occurs, and drugs targeting components of these pathways have been combined with drugs targeting receptors to enhance efficacy and reduce resistance. Examples of drugs that can be combined with the compounds of the present disclosure include inhibitors of the PI3K-AKT-mTOR pathway, inhibitors of the Raf-MAPK pathway, inhibitors of the JAK-STAT pathway, inhibitors of Pim kinase, and inhibitors of protein chaperones and cell cycle progression.

[0237] Examples of agents against PI3 kinase include, but are not limited to, pilaralisib, idelalisib, buparlisib, and IPI-549. In some embodiments, the PI3K inhibitor is selective for PI3Kα, PI3Kβ, PI3Kγ, or PI3Kδ. Inhibitors of mTOR such as rapamycin, sirolimus, temsirolimus, and everolimus may be used in combination with the TAM kinase inhibitor. Other suitable examples include, but are not limited to, vemurafenib and dabrafenib (Raf inhibitors) and trametinib, selumetinib, and GDC-0973 (MEK inhibitors). One or more inhibitors of JAK (e.g., ruxolitinib, baricitinib, tofacitinib), inhibitors of Hsp90 (e.g., tanespimycin), inhibitors of cyclin-dependent kinases (e.g., palbociclib), inhibitors of PARP (e.g., olaparib), and inhibitors of proteasome (e.g., bortezomib, carfilzomib) may also be used in combination with the compounds of the present disclosure. In some embodiments, the JAK inhibitor is selective for JAK1 over JAK2 and JAK3. Examples of agents against Pim kinase include, but are not limited to, LGH447, INCB053914, and SGI-1776.

[0238] Other agents suitable for combination with the salts of the present disclosure include combinations of chemotherapeutic agents such as platinum-based combination agents used for lung cancer and other solid tumors (cisplatin or carboplatin + gemcitabine; cisplatin or carboplatin + docetaxel; cisplatin or carboplatin + paclitaxel; cisplatin or carboplatin + pemetrexed) or gemcitabine + paclitaxel conjugate particles (Abraxane®).

[0239] Suitable chemotherapeutic agents or other anticancer agents include, for example, alkylating agents (including, but not limited to, nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes) such as uracil mustard, chlorambucil, cyclophosphamide (Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0240] Other agents suitable for combination with the salts of the present disclosure include dacarbazine (DTIC), optionally in combination with other chemotherapeutic agents such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin, and tamoxifen; a combination of cisplatin, vinblastine, and DTIC; or temozolomide. The compounds provided herein may also be used in combination with immunotherapeutic agents including cytokines such as interferon α, interleukin 2, and tumor necrosis factor (TNF) inhibitors.

[0241] Suitable chemotherapeutic agents or other anticancer agents include, for example, antimetabolites (including, but not limited to, folic acid antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0242] Suitable chemotherapeutic agents or other anticancer agents include, for example, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (TAXOL (trademark)), mitomycin, deoxycoformycin, mitomycin C, L-asparaginase, interferon (especially IFN-α), etoposide, and teniposide and other specific natural products and their derivatives (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins).

[0243] Other cytotoxic agents include navelbine, CPT-11, anastrozole, letrozole, capecitabine, raloxifene, cyclophosphamide, ifosfamide, and droloxafine.

[0244] Cytotoxic agents such as epipodophyllotoxin; antitumor enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and hematopoietic growth factors are also suitable.

[0245] Other anticancer agents (plural possible) include antibody therapeutic agents such as trastuzumab (Herceptin), antibodies against costimulatory molecules such as CTLA-4, 4-1BB, and PD-1, or antibodies against cytokines (such as IL-10, TGF-β, etc.).

[0246] Other anticancer agents include CSF1R inhibitors (such as PLX3397, LY3022855, etc.) and CSF1R antibodies (such as IMC-CS4, RG7155, etc.).

[0247] Other anticancer agents include BET inhibitors (such as INCB054329, OTX015, CPI-0610, etc.), LSD1 inhibitors (such as GSK2979552, INCB059872, etc.), HDAC inhibitors (such as panobinostat, vorinostat, etc.), DNA methyltransferase inhibitors (azacitidine and decitabine), and other epigenetic modulators.

[0248] Other anticancer agents include the Bcl2 inhibitor ABT-199 and other Bcl-2 family protein inhibitors.

[0249] Other anticancer agents include TGFβ receptor kinase inhibitors such as LY2157299.

[0250] Other anticancer agents include BTK inhibitors such as ibrutinib.

[0251] Other anticancer agents include β-catenin pathway inhibitors, Notch pathway inhibitors, and Hedgehog pathway inhibitors.

[0252] Other anticancer agents include inhibitors of kinase-related cell proliferative disorders. These kinases include, but are not limited to, Aurora A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, Ephrin receptor kinase, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3, JNK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, Rsk, and SGK.

[0253] Other anticancer agents also include anticancer agents that block immune cell migration, such as antagonists for chemokine receptors including CCR2 and CCR4.

[0254] Other anticancer agents also include anticancer agents that enhance the immune system, such as adjuvants or adoptive T cell transfer.

[0255] Examples of anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses.

[0256] For the treatment of TAM-related diseases, disorders, or illnesses, one or more additional immune checkpoint inhibitors may be used in combination with the salts described herein. Exemplary immune checkpoint inhibitors include inhibitors of immune checkpoint molecules such as CD20, CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, CD96, TIGIT, and VISTA. In some embodiments, the salts provided herein may be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFRβ inhibitors.

[0257] In some embodiments, the inhibitor of the immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0258] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab, or PDR001. In some embodiments, the anti-PD1 antibody is pembrolizumab.

[0259] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab).

[0260] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

[0261] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525.

[0262] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of GITR, such as an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN01876, or MK-1248.

[0263] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of OX40, for example, an anti-OX40 antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600, or LAG525. In some embodiments, the OX40L fusion protein is MEDI6383.

[0264] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD20, for example, an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0265] The salts of the present disclosure may be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or the TGFβ receptor.

[0266] The salts of the present disclosure may be used in combination with one or more agents for the treatment of diseases such as cancer. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

[0267] The salts of the present disclosure may be used in combination with other immunogenic agents such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immunostimulatory cytokines. Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens such as peptides of gp100, MAGE antigens, Trp-2, MART1, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0268] The salts of the present disclosure may be used in combination with a vaccination protocol for the treatment of cancer. In some embodiments, the tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins derived from viruses associated with human cancers such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's sarcoma herpesvirus (KHSV). In some embodiments, the salts of the present disclosure may be used in combination with tumor-specific antigens such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, the salts of the present disclosure may be used in combination with dendritic cell immunization to activate a strong anti-tumor response.

[0269] The salts of the present disclosure may be used in combination with a bispecific macrocyclic peptide that targets Fcα or Fcγ receptor-expressing effector cells to tumor cells. Also, the salts of the present disclosure may be used in combination with a macrocyclic peptide that activates the immune responsiveness of the host.

[0270] The salts of the present disclosure may be used in combination with an arginase inhibitor, such as CB-1158.

[0271] The salts of the present disclosure may be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an inhibitor or IDO1, TDO, or arginase. Examples of IDO1 inhibitors include epacadostat and NGL919.

[0272] The salts of the present disclosure may be used in combination with bone marrow transplantation for the treatment of various hematopoietic-derived tumors.

[0273] The salts of the present disclosure may be used as a single agent as an anticoagulant, or in combination with other anticoagulants including, but not limited to, apixaban, dabigatran, edoxaban, fondaparinux, heparin, rivaroxaban, and warfarin.

[0274] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. Also, the administration of these chemotherapeutic agents is described in standard literature. For example, the administration of many of the above chemotherapeutic agents is described in the "Physicians’ Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if fully set forth.

[0275] Pharmaceutical Preparations and Dosage Forms The salts provided herein, when used as a medicament, may be administered in the form of a pharmaceutical composition which refers to a combination of a compound provided herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. These compositions can be manufactured by methods well-known in the pharmaceutical art and can be administered by various routes depending on whether local or systemic treatment is desired and on the area to be treated. Administration can be local administration (including intravitreal administration and administration to mucous membranes including intranasal, vaginal, and rectal delivery), pulmonary administration (e.g., by inhalation or insufflation of powder or aerosol, including by nebulizer; endotracheal administration, intranasal administration, epithelial administration, and transdermal administration), ophthalmic instillation, oral administration, or parenteral administration. Methods of intravitreal delivery can include local administration (ophthalmic instillation), subconjunctival, periocular, or intravitreal injection, or introduction by a balloon catheter or ophthalmic insert surgically placed in the conjunctival sac. Parental administration can include intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial administration, e.g., intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus injection or, for example, by continuous perfusion pump. Pharmaceutical compositions and formulations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, solutions, and powders. Conventional pharmaceutical carriers; aqueous, powder, or oily bases; thickening agents, etc. may be required or may be desirable.

[0276] This application also includes pharmaceutical compositions containing, as an active ingredient, one or more salts provided herein (e.g., salts of the compounds of Formulas I and II) in combination with one or more pharmaceutically acceptable carriers. In the manufacture of the compositions of the present disclosure, the active ingredient is generally mixed with, diluted by, or enclosed within such a carrier in the form of, for example, capsules, sachets, paper, or other containers. When the excipient serves as a diluent, the excipient may be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Accordingly, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, capsules of soft and hard gelatin, suppositories, sterile injectable solutions, and sterile packaged powders.

[0277] In the manufacture of the formulations, the active compound (or the salt form of the present disclosure) may be ground to an appropriate particle size before being mixed with other ingredients. If the active compound is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size may be adjusted, for example, to about 40 mesh by grinding so that the distribution in the formulation is substantially uniform.

[0278] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The above formulations may further contain lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweetening agents; and flavoring agents. After administering the compositions of the present disclosure to a patient using procedures known in the art, the compositions may be formulated to rapidly, continuously, or delayed release the active ingredient.

[0279] The composition may be formulated into unit dosage forms containing from about 5 to about 100 mg, more generally from about 10 to about 30 mg of the active ingredient per dosage unit. 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 the active substance calculated to produce the desired therapeutic effect, together with the appropriate pharmaceutical excipients.

[0280] The active compounds can be effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. However, it will be understood that the actual amount of the compound administered will usually be determined by a physician according to the relevant circumstances including the disease being treated, the selected route of administration, the actual compound being administered, the age, weight, and response to treatment of the individual patient, and the severity of the patient's symptoms.

[0281] Regarding the manufacture of solid compositions such as tablets, the above-mentioned main active ingredient is mixed with pharmaceutical excipients to form a solid pre-formulation composition containing a homogeneous mixture of the compounds of the present disclosure. When these pre-formulation compositions are called homogeneous, the active ingredient is generally uniformly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. Then, this solid pre-formulation composition is subdivided into unit dosage forms of the above type containing, for example, 0.1 to about 500 mg of the active ingredient of the present disclosure.

[0282] The tablets or pills of the present disclosure may be coated or formulated to provide a dosage form that gives the advantage of a long-lasting action. For example, the above tablets or pills may contain an inner administration component and an outer administration component, and the latter is in the form of a coating that covers the former. The two components may be separated by an enteric layer that functions so as to withstand disintegration in the stomach and allow the inner component to pass through intact into the duodenum or enable the release of the component to be delayed. Various materials can be used for such an enteric layer or coating, and such materials include many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0283] Liquid forms for oral or injectable administration that can contain the salts and compositions of the present disclosure include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as flavored emulsions containing elixirs and similar pharmaceutical vehicles.

[0284] Examples of the present composition for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The above liquid or solid compositions may contain appropriate pharmaceutically acceptable excipients as described above. In some embodiments, the present composition is administered via the oral or nasal respiratory route to obtain local or systemic effects. The composition of the solution may be sprayed by using an inert gas. The sprayed solution may be directly inhaled from the spraying device, or the spraying device may be connected to a face mask tent or an intermittent positive pressure respirator. The composition of the solution, suspension, or powder may be administered orally or nasally from a device for delivering the above preparation by an appropriate method.

[0285] The amount of the salt (e.g., the salt of the compounds of Formulas I and II) or composition administered to a patient will vary depending on the nature of the material being administered, the purpose of administration such as prophylaxis or treatment, the condition of the patient, the method of administration, and the like. In therapeutic use, a patient already suffering from a disease may be administered the composition in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dosage will depend on the judgment of the attending physician, which depends on factors such as the condition of the disease being treated, as well as the severity of the disease, the age, weight, and general condition of the patient.

[0286] The above composition administered to a patient may be in the form of the above pharmaceutical composition. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. The aqueous solution may be packaged for direct use or may be lyophilized, and the lyophilized preparation is mixed with a sterile aqueous carrier prior to administration. The pH of the formulation of the present compound is generally from 3 to 11, more preferably from 5 to 9, and most preferably from 7 to 8. It will be understood that the use of certain of the above excipients, carriers, or stabilizers may result in the formation of pharmaceutical salts.

[0287] The dosage in the treatment with the compounds or salts of the present disclosure may vary, for example, depending on the specific use for which the treatment is intended, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound or salt in the pharmaceutical composition provided herein may vary depending on many factors including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, in the case of parenteral administration, the compound or salt provided herein may be provided in a physiological buffered aqueous solution containing about 0.1 to about 10% w / v of the compound or salt. Some general dosage ranges are from about 1 μg / kg-body weight to about 1 g / kg-body weight per day. In some embodiments, the above dosage range is from about 0.01 mg / kg-body weight to about 100 mg / kg-body weight per day. The above dosages often depend on variables such as the type and degree of progression of the disease or disorder, the general health status of a particular patient, the relative biological effectiveness of the selected compound, the formulation of the excipient, and the route of its administration. The effective dosage can be extrapolated from the dose-response curve derived from in vitro tests or animal model test systems.

[0288] The compounds or salts provided herein can also be formulated in combination with one or more additional active ingredients including any medicaments such as antiviral agents, vaccines, antibodies, immunopotentiators, immunosuppressants, anti-inflammatory agents, and the like.

[0289] Kit The present disclosure also includes pharmaceutical kits useful for the treatment or prevention of, for example, TAM-related diseases or disorders, obesity, diabetes, and other diseases mentioned herein. The kit comprises one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a salt provided herein (e.g., salts of the compounds of Formulas I and II). As will be readily apparent to those skilled in the art, such kits may further comprise one or more of the various conventional pharmaceutical kit components, such as, for example, containers containing one or more pharmaceutically acceptable carriers, auxiliary containers, etc., as needed. The kit may also include instructions, as a package insert or label, indicating the dosage of the ingredient, instructions for administration, and / or instructions for mixing the ingredient.

Examples

[0290] The present invention will be described in more detail by specific examples. The following examples are presented for illustrative purposes and are not intended to limit the present invention in any form. Those skilled in the art will readily recognize various non-essential parameters that may be changed or modified and still produce substantially the same results. The compounds of the examples were found to be inhibitors of TAM kinase, as described below.

[0291] General methods Purification of some of the prepared compounds by preparative LC-MS was carried out on a preparative system based on Waters mass instructions. The basic equipment settings, protocols, and control software for the operation of these systems are described in detail in the literature. For example, see “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 usually subjected to analytical liquid chromatography-mass spectrometry (LCMS) under the following conditions for purity confirmation. The LCMS conditions are as follows: apparatus: Agilent 1100 series LC / MSD; column: Waters Sunfire™ C 18 Particle size 5 μm, 2.1×5.0 mm; mobile phase: A: 0.025% aqueous TFA solution, B: acetonitrile; gradient: B from 2% to 80% in 3 minutes, flow rate 2.0 mL / min.

[0292] Some of the prepared compounds were also separated on a preparative scale by reverse-phase high-performance liquid chromatography (RP-HPLC) equipped with an MS detector or flash chromatography (silica gel) as shown in the examples. The column conditions for general preparative reverse-phase high-performance liquid chromatography (RP-HPLC) are as follows. Purification at pH = 2: Waters Sunfire (TM) C 18 Column with a particle size of 5 μm, 19×100 mm, eluted with mobile phase A: 0.1% aqueous TFA (trifluoroacetic acid) and mobile phase B: acetonitrile; flow rate was 30 mL / min, and the separation gradient was optimized for each compound using the Compound Specific Method Optimization protocol 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)]. Usually, the flow rate used for a 30×100 mm column was 60 mL / min. Purification at pH = 10: Waters XBridge C 18 Column with a particle size of 5 μm, 19×100 mm, eluted with mobile phase A: 0.15% aqueous NH4OH and mobile phase B: acetonitrile; flow rate was 30 mL / min, and the separation gradient was optimized for each compound using the Compound Specific Method Optimization protocol 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)]. Usually, the flow rate used for a 30×100 mm column was 60 mL / min.

[0293] Example 1 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, Form I) Scheme 1 [Chemical formula] Step 1: 5-Bromo-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazine-4-amine dihydrochloride (Compound 2) Into a 22 L five-necked round-bottom flask equipped with a mechanical stirrer, a mantle heater, a thermocouple, a reflux condenser, a nitrogen inlet, and a nitrogen outlet, at room temperature, 4-(4-Amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl (Compound 1, 880 g, 2.221 mol) in dichloromethane (DCM, 8.0 L) was charged. To this suspension, a 2-propanol solution of hydrochloric acid (5.8 N, 2.7 L, 15.66 mol, 7.05 equivalents) was added. The mixture was heated to 35 °C. After 4 hours, the reaction mixture was diluted with tert-butyl methyl ether (TBME, 4.5 L). The resulting mixture was cooled to room temperature, filtered, and washed with TBME (2.0 L). The cake was dried on the filter under vacuum using shared facility equipment for 24 hours to obtain 5-bromo-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazine-4-amine dihydrochloride (Compound 2, 848 g, 103%) as a light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.53 - 9.29 (m, 3H), 8.23 (s, 1H), 6.91 (s, 1H), 3.38 (tt, J = 11.8, 3.6 Hz, 1H), 3.30 (d, J = 12.4 Hz, 2H), 3.00 (dtd, J = 12.8, 10.1, 2.6 Hz, 2H), 2.07 (dd, J = 14.1, 3.8 Hz, 2H), 1.97 - 1.87 (m, 2H) ppm; 13 C NMR (101 MHz, DMSO-d6) δ 150.34, 139.32, 138.92, 113.24, 109.67, 95.70, 43.06, 30.57, 26.89 ppm; C 11 H 14 BrN5 (MW 295.0), LCMS (EI) m / e 296.0 (M+ + H).

[0294] 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) Into a 22 L five-necked round-bottom flask equipped with a mechanical stirrer, a thermocouple, a reflux condenser, a nitrogen inlet, and a nitrogen outlet, at room temperature, 5-bromo-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazine-4-amine dihydrochloride (Compound 2, 1300 g, 3.522 mol) in N-methylpiperidinone (NMP, 10 L) was charged. To this suspension, N,N-diisopropylethylamine (1593 g, 12.3 mol) was added. The mixture was cooled to 10 °C, and then isobutyryl chloride (388 g, 3.645 mol) was introduced. The reaction mixture was stirred at room temperature and monitored by HPLC. Additional isobutyryl chloride (22.5 g, 0.211 mol) was added to consume all the starting materials. When the reaction was complete, 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 cake was dried on the filter under vacuum by shared facility equipment for 48 hours to obtain 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. 11H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 6.64 (s, 1H), 4.51 (d, J = 12.6 Hz, 1H), 4.01 (d, J = 13.2 Hz, 1H), 3.35 - 3.30 (m, 1H), 3.12 (t, J = 12.3 Hz, 1H), 2.91 - 2.84 (m, 1H), 2.64 (t, J = 12.1 Hz, 1H), 2.02 - 1.93 (m, 2H), 1.55 - 1.42 (m, 2H), 1.02 (d, J = 6.5 Hz, 3H), 1.00 (d, J = 6.5 Hz, 3H) ppm; 13 13C NMR (101 MHz, DMSO-d6) δ 174.50, 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, 19.87 ppm; C 15 H 20 BrN5O (MW 365.09), LCMS (EI) m / e 366.1 (M + + H).

[0295] 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) Into a 22 L five-neck round-bottom flask equipped with a mechanical stirrer, mantle heater, thermocouple, reflux condenser, nitrogen inlet, and nitrogen outlet, at room temperature, 1-butanol (7.7 L) and 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) were charged in water (1.4 L). To this mixture, at room temperature, 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) was added. The reaction mixture was degassed and refilled with nitrogen and 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 filtered off and washed with water (6 L). The cake was dried on the filter under vacuum using shared facility equipment for 72 hours to obtain 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. 11H NMR (500 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 6.43 (s, 1H), 5.24 (s, 2H), 4.53 (d, J = 12.6 Hz, 1H), 4.04 (d, J = 13.1 Hz, 1H), 3.38 (ddd, J = 11.8, 8.2, 3.8 Hz, 1H), 3.16 (t, J = 12.7 Hz, 1H), 2.87 (p, J = 6.7 Hz, 1H), 2.71 - 2.66 (m, 1H), 2.08 - 2.00 (m, 2H), 1.61 - 1.58 (m, 2H), 1.02 (d, J = 6.5 Hz, 3H), 1.00 (d, J = 6.5 Hz, 3H) ppm; 13 13C NMR (126 MHz, DMSO-d6) δ 174.51, 156.31, 148.51, 147.65, 133.98, 130.35, 122.57, 119.37, 114.57, 109.67, 108.85, 45.48, 41.81, 32.97, 31.50, 30.56, 29.50, 20.06, 19.89 ppm;C 21 H 26 N6O (MW 378.48), LCMS (EI) m / e 379.2 (M + + H).

[0296] 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) Into a 22 L five-necked round-bottom flask equipped with a mechanical stirrer, a thermocouple, a nitrogen inlet, and a nitrogen outlet, at room temperature, 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) were charged in tetrahydrofuran (THF, 10 L). Triethylamine (NEt3, 0.695 L, 4.988 mol) was added to this reaction mixture. When the reaction was complete, this reaction mixture was evenly divided into two 22 L round-bottom flasks. Water (8 L) was added to each flask at room temperature. The solid was filtered off. The obtained wet cake was returned to a 22 L round-bottom flask. THF (3.2 L) and water (10.5 L) were added to this flask. This slurry was heated to 55 °C and stirred at 55 °C for 2 hours. The solid was filtered off at 30 °C and washed with water (8 L). This cake was dried on a filter under vacuum using shared facility equipment for 72 hours to obtain 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, 1425 g, 90%) as a light brown solid. 11H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.71(s, 1H), 8.64 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 8.06 (td, J = 7.7, 1.9 Hz, 1H), 7.91 (s, 1H), 7.77 (d, J = 8.6 Hz, 2H), 7.60 - 7.53 (m, 2H), 7.43 (d, J = 8.6 Hz, 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, 12.3 Hz, 2H), 1.61 (q, J = 11.8 Hz, 1H), 1.55 - 1.47 (m, 1H), 1.44 (d, J = 6.8 Hz, 6H), 1.02 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H) ppm; 13 13C NMR (126 MHz, DMSO-d6) δ 174.51, 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, 125.09, 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, 19.89 ppm; 34 1H 37 C9H9N9O4 (MW 635.73), LCMS (EI) m / e 636.3 (M + + H).

[0297] 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, Form I) Into a 50 L reactor equipped with a mechanical stirrer, heating jacket, thermocouple, reflux condenser, nitrogen inlet, and nitrogen outlet, at room temperature, 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) was charged. This slurry was heated to 50 °C to form a solution. Activated carbon (70 g) and silica gel (70 g) were added to this solution. After stirring at 50 °C for 2 hours, this mixture was filtered through a Celite pad. Maleic acid (269 g, 2.314 mol) was added to the filtrate. Most of the DCM was distilled off under atmospheric pressure. Solids gradually precipitated. This solid was filtered off at 18 °C and washed with MeOH (3 L). This cake was dried on the filter under vacuum by shared facility equipment for 72 hours to obtain 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. 11H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.71 (s, 1H), 8.65 - 8.63 (m, 1H), 8.06 (td, J = 7.8, 1.9 Hz, 1H), 7.95 (s, 1H), 7.77 (d, J = 8.6 Hz, 2H), 7.58 - 7.55 (m, 2H), 7.44 (d, J = 8.5 Hz, 2H), 6.62 (s, 1H), 6.25 (s, 2H), 4.78 (hept, J = 6.7 Hz, 1H), 4.54 (d, J = 12.3 Hz, 1H), 4.06 (d, J = 12.5 Hz, 1H), 3.40 (tt, J = 11.6, 3.2 Hz, 1H), 3.20 (t, J = 12.3 Hz, 1H), 2.90 (hept, J = 6.6 Hz, 1H), 2.69 (t, J = 12.1 Hz, 1H), 2.09 -2.01 (m, 2H), 1.65 - 1.57 (m, 1H), 1.56 - 1.49 (m, 1H), 1.44 (d, J = 6.8 Hz, 6H), 1.02 (d, J = 5.5 Hz, 3H), 1.00 (d, J = 5.5 Hz, 3H) ppm; 13 13C NMR (101 MHz, DMSO) δ 174.52, 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, 130.22, 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, 19.89 ppm; 34 1H 37 C9H9N9O4 (Free base, MW 635.73), LCMS (EI) m / e 636.3 (M + + H).

[0298] Example 2 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide hemisulfate (amorphous) (Compound II hemisulfate) Scheme 2 [Chemical Structure] Step 1 5-Bromo-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine dihydrochloride (Compound 2) To a 22 L five-necked round-bottom flask equipped with a mechanical stirrer, mantle heater, thermocouple, reflux condenser, nitrogen inlet, and nitrogen outlet, 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl (Compound 1, 880 g, 2.221 mol) in dichloromethane (DCM, 8.0 L) was charged at room temperature. To this suspension, a 2-propanol solution of hydrochloric acid (5.8 N, 2.7 L, 15.66 mol, 7.05 equiv) was added. The mixture was heated at 35 °C for 4 h. The reaction mixture was diluted with tert-butyl methyl ether (TBME, 4.5 L) and cooled to room temperature. The slurry was filtered and washed with TBME (2.0 L). The cake was dried on the filter under vacuum using shared facility equipment for 24 h to obtain 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 (400 MHz, DMSO-d6) δ 9.53 - 9.29 (m, 3H), 8.23 (s, 1H), 6.91 (s, 1H), 3.38 (tt, J = 11.8, 3.6 Hz, 1H), 3.30 (d, J = 12.4 Hz, 2H), 3.00 (dtd, J = 12.8, 10.1, 2.6 Hz, 2H), 2.07 (dd, J = 14.1, 3.8 Hz, 2H), 1.97 - 1.87 (m, 2H) ppm; 1313C NMR (101 MHz, DMSO-d6) δ 150.34, 139.32, 138.92, 113.24, 109.67, 95.70, 43.06, 30.57, 26.89 ppm; C 11 H 14 BrN5 (MW 295.0), LCMS (EI) m / e 296.0 (M + + H).

[0299] 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) A 22 L five-necked round-bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser, nitrogen inlet, and nitrogen outlet was charged at room temperature with 5-bromo-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazine-4-amine dihydrochloride (Compound 2, 1300 g, 3.522 mol) in N-methylpiperidinone (NMP, 10 L). N,N-Diisopropylethylamine (1593 g, 12.3 mol) was added to this suspension. The mixture was cooled to 10 °C and treated with isobutyryl chloride (388 g, 3.645 mol). The reaction mixture was stirred while warming to room temperature and monitored by HPLC. Additional isobutyryl chloride (22.5 g, 0.211 mol) was added to consume all of the starting materials. When the reaction was complete, 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 filtered off and washed with water (12 L). The cake was dried under vacuum on the filter for 48 hours to obtain 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. 11H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 6.64 (s, 1H), 4.51 (d, J = 12.6 Hz, 1H), 4.01 (d, J = 13.2 Hz, 1H), 3.35 - 3.30 (m, 1H), 3.12 (t, J = 12.3 Hz, 1H), 2.91 - 2.84 (m, 1H), 2.64 (t, J = 12.1 Hz, 1H), 2.02 - 1.93 (m, 2H), 1.55 - 1.42 (m, 2H), 1.02 (d, J = 6.5 Hz, 3H), 1.00 (d, J = 6.5 Hz, 3H) ppm; 13 13C NMR (101 MHz, DMSO-d6) δ 174.50, 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, 19.87 ppm;C 15 H 20 BrN5O (MW 365.09), LCMS (EI) m / e 366.1 (M + + H).

[0300] 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) A 22 L five-neck round-bottom flask equipped with a mechanical stirrer, mantle heater, thermocouple, reflux condenser, nitrogen inlet, and nitrogen outlet was charged at room temperature with 1-butanol (7.7 L) and 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 water (1.4 L). The mixture was treated at room temperature with 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). The reaction mixture was degassed and refilled with nitrogen and then heated to 80 °C. After 2 h at 80 °C, the reaction mixture was diluted with n-heptane (8 L). The resulting slurry was cooled to room temperature. The solid was collected by filtration and washed with water (6 L). The cake was dried under vacuum on the filter for 72 h 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. 11H NMR (500 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 6.43 (s, 1H), 5.24 (s, 2H), 4.53 (d, J = 12.6 Hz, 1H), 4.04 (d, J = 13.1 Hz, 1H), 3.38 (ddd, J = 11.8, 8.2, 3.8 Hz, 1H), 3.16 (t, J = 12.7 Hz, 1H), 2.87 (p, J = 6.7 Hz, 1H), 2.71 - 2.66 (m, 1H), 2.08 - 2.00 (m, 2H), 1.61 - 1.58 (m, 2H), 1.02 (d, J = 6.5 Hz, 3H), 1.00 (d, J = 6.5 Hz, 3H) ppm; 13 13C NMR (126 MHz, DMSO-d6) δ 174.51, 156.31, 148.51, 147.65, 133.98, 130.35, 122.57, 119.37, 114.57, 109.67, 108.85, 45.48, 41.81, 32.97, 31.50, 30.56, 29.50, 20.06, 19.89 ppm;C 21 H 26 N6O (MW 378.48), LCMS (EI) m / e 379.2 (M + + H).

[0301] 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound II) A 22 L five-neck round-bottom flask equipped with a mechanical stirrer, a thermocouple, a nitrogen inlet, and a nitrogen outlet was charged at room temperature 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, 450 g, 1.189 mol), and 1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Compound 7, 342 g, 1.248 mol) in tetrahydrofuran (THF, 5 L). This reaction mixture was sequentially treated with triethylamine (NEt3, 241 g, 2.278 mol), then 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (HATU, 565 g, 1.486 mol). When the reaction was complete, water (8 L) was added to this reaction mixture at room temperature. The solid was collected by filtration. The obtained wet cake was returned to a 22 L round-bottom flask and slurried with THF (2.7 L) and water (5.4 L). This slurry was heated to 55 °C and stirred at 55 °C for 2 hours. After cooling to 30 °C, the solid was collected by filtration and washed with water (8 L). This cake was dried under vacuum on the filter for 2 days to obtain 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound II, 717 g, 95%) as a light brown solid. 11H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.68 (s, 1H), 8.19 (s, 1H), 7.82 (d, J = 8.6 Hz, 2H), 7.55 - 7.46 (m, 5H), 7.38 - 7.36 (m, 2H), 6.85 (s, 1H), 4.79 (hept, J = 6.8 Hz, 1H), 4.55 (d, J = 12.3 Hz, 1H), 4.08 (d, J = 12.9 Hz, 1H), 3.43 (tt, J = 11.8, 3.5 Hz, 1H), 3.21 (t, J = 12.4 Hz, 1H), 2.90 (hept, J = 6.7 Hz, 1H), 2.70 (t, J = 12.2 Hz, 1H), 2.02 (dd, J = 23.0, 13.5 Hz, 2H), 1.66 (q, J = 11.8, 11.3 Hz, 1H), 1.53 (q, J = 12.2, 11.7 Hz, 1H), 1.44 (d, J = 6.8 Hz, 6H), 1.03 (d, J = 7.0 Hz, 3H), 1.01 (d, J = 7.0 Hz, 3H) ppm; 13 13C NMR (126 MHz, DMSO-d6) δ 174.55, 163.26, 160.65, 152.60, 150.48, 147.46, 142.27, 138.14, 137.56, 135.87, 130.21, 129.89, 129.50, 129.12, 129.05, 122.72, 120.55, 111.00, 108.35, 105.10, 50.94, 45.35, 41.67, 32.98, 31.40, 30.50, 29.49, 21.19 (2 -CH3), 20.06, 19.89 ppm; 35 1H 38 N8O4(MW 634.74), LCMS (EI) m / e 635.3 (M + + H).

[0302] 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide sulfate (Compound II hydrochloride) Into a 22 L five-necked round-bottom flask equipped with a mechanical stirrer, a thermocouple, a nitrogen inlet, and a nitrogen outlet, at room temperature, 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound II, 713 g, 1.123 mol) in methanol (MeOH, 5.6 L) was charged. The mixture was heated to 55 °C and treated with an aqueous solution of sulfuric acid (H2SO4, 116 g, 1.179 mol) in water (1 L). After stirring at 55 °C for 30 minutes, 2.8 L of the solvent was distilled off under reduced pressure. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration and washed with MeOH (0.7 L). This cake was dried on the filter under vacuum for 2 days to obtain 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide sulfate (Compound II hydrochloride, 744 g, 90%) as a yellow solid.

[0303] Step 6 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide hemisulfate (Compound II hemisulfate) Into a 22 L five-necked round-bottom flask equipped with a mechanical stirrer, a thermocouple, a nitrogen inlet, and a nitrogen outlet, at room temperature, 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide sulfate (Compound II hydrochloride, 729 g, 0.995 mol) was charged in water (16 L). The slurry was heated to 35 °C and stirred for 3 days. The solid was filtered off and washed with water (10 L). The wet cake was dried on the filter under vacuum to obtain 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide hemisulfate (Compound II hemisulfate, 644 g, 95%) as an off-white solid.

[0304] Step 7 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide hemisulfate, amorphous In a 2 L round-bottomed flask, at room temperature, 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide hemisulfate (Compound II hemisulfate, 40 g, 58.5 mmol) in acetone (500 mL) and methanol (500 mL) was charged. This solution was filtered through filter paper and filtered into a 3 L round-bottomed flask. The filtrate was concentrated under reduced pressure to remove most of the solvent. The resulting foamy solid was dried in a vacuum oven at 50 °C under vacuum using shared facilities while sweeping with nitrogen to obtain 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide hemisulfate (amorphous hemisulfate of Compound II, 38 g, 95%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.68 (s, 1H), 8.07 (s, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.55 - 7.45 (m, 5H), 7.38 - 7.36 (m, 2H), 6.74 (s, 1H), 4.79 (hept, J = 6.8 Hz, 1H), 4.55 (d, J = 12.3 Hz, 1H), 4.07 (d, J = 13.0 Hz, 1H), 3.42 (tt, J = 11.8, 3.3 Hz, 1H), 3.24 - 3.18 (m, 1H), 2.91 (hept, J = 6.7 Hz, 1H), 2.70 (t, J = 12.0 Hz, 1H), 2.07 - 1.99 (m, 2H), 1.68 - 1.51 (m, 2H), 1.44 (d, J = 6.8 Hz, 6H), 1.03 (d, J = 7.0 Hz, 3H), 1.01 (d, J = 7.0 Hz, 3H) ppm; 1313C NMR (101 MHz, DMSO-d6) δ 174.55, 163.26, 160.65, 152.60, 150.48, 147.46, 142.28, 138.14, 137.56, 135.87, 130.21, 129.89, 129.50, 129.12, 129.05, 122.72, 120.55, 111.00, 108.35, 105.10, 50.94, 45.35, 41.67, 32.98, 31.40, 30.50, 29.49, 21.19 (2 -CH3), 20.06, 19.89 ppm; C 35 H 38 N8O4 (MW 634.74), LCMS (EI) m / e 635.3 (M + + H); Acid titration, sulfate: free base = 0.50; Elemental analysis of sulfur, calculated value 2.34%, measured value 2.29%.

[0305] Example 3 Separate 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound II) Scheme 3

Chemical Structure

[0306] Step 2 4-(4-Amino-5-(4-(1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenyl)pyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl (Compound 9) Into a 22 L five-necked round-bottom flask equipped with a mechanical stirrer, reflux condenser, thermocouple, mantle heater, nitrogen inlet, and nitrogen outlet, at room temperature, 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl (Compound 1, 557 g, 1.406 mol), 1-isopropyl-2,4-dioxo-3-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound 8, 735 g, 1.546 mol), and tripotassium phosphate (K3PO4, 597 g, 2.811 mol) were charged in 1,4-dioxane (6.0 L) and water (1.1 L). The mixture was degassed and refilled with a nitrogen atmosphere. To this reaction mixture, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (XPhos Pd G2, 77 g, 98 mmol) was added. The reaction mixture was degassed, refilled with a nitrogen atmosphere, and heated to 80 °C. After stirring at 80 °C for 3 hours, water (6.0 L) was added to this reaction mixture over 1 hour. The resulting solid was filtered off at 20 °C and washed with water (2 × 3.0 L) and n-heptane (2 × 2.0 L). This cake was returned to a 22 L round-bottom flask and slurried in ethyl acetate (EtOAc, 6.0 L) and methyl tert-butyl ether (MTBE, 2.2 L) at room temperature. The suspension was heated to 55 °C and stirred for 2 hours. After cooling this mixture to 20 °C, the solid was filtered off and washed with MTBE (2 × 1.0 L). This cake was dried under vacuum on a filter funnel for 2 days to give tert-butyl 4-(4-amino-5-(4-(1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenyl)pyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (Compound 9, 827 g, 85%) as a light brown solid. 11H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.67 (s, 1H), 7.90 (s, 1H), 7.78 (d, J = 8.6 Hz, 2H), 7.54 (t, J = 7.5 Hz, 2H), 7.48 - 7.46 (m, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.38 - 7.36 (m, 2H), 6.58 (s, 1H), 4.79 (hept, J = 6.7 Hz, 1H), 4.08 - 4.03 (m, 2H), 3.34 - 3.28 (m, 1 H), 2.89 (s, 2H), 1.99 (d, J = 11.4 Hz, 2H), 1.56 (qd, J = 12.7, 4.1 Hz, 2H), 1.44 (d, J = 6.8 Hz, 6H), 1.42 (s, 9H) ppm; 13 13C NMR (126 MHz, DMSO-d6) δ 163.25, 160.57, 156.20, 154.33, 150.49, 147.78, 147.40, 135.56, 135.89, 134.56, 131.20, 130.24, 129.49, 129.12, 129.03, 120.42, 117.99, 109.88, 109.35, 105.16, 79.08, 50.91, 43.90, 32.71, 30.54, 28.59, 21.11 ppm; 36 H 40 N8O5 (MW 664.76), LCMS (EI) m / e 665.3 (M + + H).

[0307] Step 3 N-(4-(4-Amino-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide dihydrochloride (Compound 10) To a 22 L five-necked round-bottom flask equipped with a mechanical stirrer, reflux condenser, thermocouple, mantle heater, nitrogen inlet, and nitrogen outlet, at room temperature, 4-(4-Amino-5-(4-(1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenyl)pyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl (Compound 9, 737 g, 1.053 mol) in dichloromethane (DCM, 4.5 L) was charged. To this suspension, a 2-propanol solution of hydrochloric acid (5.8 N IPA solution, 1.474 L, 8.549 mol, 8.12 eq) was added. The mixture was heated to 35 - 40 °C. After 3 hours at 35 - 40 °C, the reaction mixture was cooled to 15 °C. Water (0.4 L) was added and the mixture was stirred at 15 °C for 1 hour. The mixture was diluted with DCM (9.0 L). The solid was filtered off and washed with DCM (2 × 0.2 L). The cake was dried under vacuum on a filter funnel for 2 days to obtain N-(4-(4-Amino-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide dihydrochloride (630 g, 94%) as a needle-like solid. 1 H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.31 - 9.21 (m, 3H), 8.68 (s, 1H), 8.29 (s, 1H), 7.83 (d, J = 8.7 Hz, 2H), 7.55 - 7.46 (m, 5H), 7.38 - 7.37 (m, 2H), 6.80 (s, 1H), 4.83 (hept, J = 6.8 Hz, 1H), 3.50 (tt, J = 11.7, 3.4 Hz, 1H), 3.35 (d, J = 12.4 Hz, 2H), 3.08 (q, J = 12.5 Hz, 2H), 2.18 - 2.15 (m, 2H), 1.99 - 1.96 (m, 2H), 1.44 (d, J = 6.8 Hz, 6H) ppm; 1313C NMR (126 MHz, DMSO-d6) δ 163.26, 160.70, 150.47, 150.38, 147.52, 138.68, 138.59, 138.06, 135.86, 130.21, 129.50, 129.12, 129.05, 128.76, 126.12, 120.66, 111.81, 107.49, 105.09, 50.96, 43.19, 30.65, 27.07, 21.19 ppm; C 31 H 32 N8O3 (MW 564.64), LCMS (EI) m / e 565.3 (M + + H).

[0308] 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound II) In a 22 L five-necked round-bottom flask equipped with a mechanical stirrer, a thermocouple, a nitrogen inlet, and a nitrogen outlet, at room temperature, N-(4-(4-amino-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide dihydrochloride (608 g, 0.954 mol) was charged in dichloromethane (DCM, 17.6 L). An aqueous sodium hydroxide solution (NaOH, 1 N, 3.815 L, 3.815 mol) was added to this suspension. After stirring at room temperature for 1 hour, the mixture was cooled to 0 - 5 °C and treated with isobutyryl chloride (107 g, 1.001 mol). The reaction mixture was stirred at room temperature for 24 hours. When the reaction was complete, the mixture was filtered through a celite pad. The organic phase was separated, washed with water (2 × 2.5 L), and concentrated under reduced pressure. Dichloromethane (DCM, 2.4 L) and methyl tert-butyl ether (MTBE, 9.7 L) were added to the residue. The mixture was heated to 50 °C and stirred for 1 hour. After cooling to room temperature, the resulting solid was collected by filtration. This cake was dried under vacuum on the filter for 24 hours to obtain 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (Compound II, 548 g, 91%) as a pale yellow solid. 11H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.68 (s, 1H), 8.19 (s, 1H), 7.82 (d, J = 8.6 Hz, 2H), 7.55 - 7.46 (m, 5H), 7.38 - 7.36 (m, 2H), 6.85 (s, 1H), 4.79 (hept, J = 6.8 Hz, 1H), 4.55 (d, J = 12.3 Hz, 1H), 4.08 (d, J = 12.9 Hz, 1H), 3.43 (tt, J = 11.8, 3.5 Hz, 1H), 3.21 (t, J = 12.4 Hz, 1H), 2.90 (hept, J = 6.7 Hz, 1H), 2.70 (t, J = 12.2 Hz, 1H), 2.02 (dd, J = 23.0, 13.5 Hz, 2H), 1.66 (q, J = 11.8, 11.3 Hz, 1H), 1.53 (q, J = 12.2, 11.7 Hz, 1H), 1.44 (d, J = 6.8 Hz, 6H), 1.03 (d, J = 7.0 Hz, 3H), 1.01 (d, J = 7.0 Hz, 3H) ppm; 13 13C NMR (126 MHz, DMSO-d6) δ 174.55, 163.26, 160.65, 152.60, 150.48, 147.46, 142.27, 138.14, 137.56, 135.87, 130.21, 129.89, 129.50, 129.12, 129.05, 122.72, 120.55, 111.00, 108.35, 105.10, 50.94, 45.35, 41.67, 32.98, 31.40, 30.50, 29.49, 21.19 (2 -CH3), 20.06, 19.89 ppm; 35 1H 38 N8O4 (MW 634.74), LCMS (EI) m / e 635.3 (M + + H).

[0309] Example 4 Synthesis of tert-Butyl 4-(4-amino-5-bromopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (Compound 1 in Schemes 1 and 2) Scheme 4

Chemical formula

[0310] Step 2 4-(4-Aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl (Compound 14) Into a 2-L flask at room temperature, 4-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl (Compound 13, 50.0 g, 159 mmol) and platinum(IV) oxide (10.0 g, 44 mmol) in acetic acid (1000 mL) were charged. This flask was placed on a Parr Shaker in the presence of 50 psi of hydrogen gas. After 16 hours, 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 (about 50 g) in water (1200 mL) was added to this MTBE solution to adjust the pH value to 6 - 7. The solid was collected by filtration and washed with water (2 × 300 mL) and n-heptane (2 × 300 mL). This cake was dried in a vacuum oven at 50 °C for 16 hours while sweeping with nitrogen to obtain 4-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl (Compound 14, 49.3 g, 98%) as a light brown solid. 1 H NMR (500 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.59 (s, 2H), 6.81 (d, J = 4.4 Hz, 1H), 6.44 (d, J = 4.3 Hz, 1H), 4.05 (d, J = 11.3 Hz, 2H), 3.25 (tt, J = 11.8, 3.3 Hz, 1H), 2.88 (s, 2H), 1.95 (d, J = 11.9 Hz, 2H), 1.51 (qd, J = 12.6, 4.0 Hz, 2H), 1.42 (s, 9H) ppm;C 16 H 23N5O2 (MW 317.39), LCMS (EI) m / e 318.1 (M + + H).

[0311] Step 3 4-(4-Amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl (Compound 1) Into a 22 L five-necked round-bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser, nitrogen inlet, and nitrogen outlet, at room temperature, 4-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl (Compound 14, 730 g, 2.30 mol) in tetrahydrofuran (THF, 14.0 L) was charged. The mixture was cooled to 0 - 5 °C. While maintaining the internal temperature below 15 °C, N-bromosuccinimide (NBS, 409 g, 2.30 mol) was added to this reaction mixture over 5 minutes. After stirring at a temperature lower than 10 °C for 1 hour, a portion of the solvent (9.0 L) was removed under reduced pressure. To the remaining solution, an aqueous solution of sodium hydrogen carbonate (140 g, 1.67 mol) in water (14.0 L) was added over 5 minutes. A solid precipitated. This solid was collected by filtration and washed with water (7.0 L) and n-heptane (4 L). This wet cake was dried on a filter under vacuum using shared facility equipment for 48 hours to obtain 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl (Compound 1, 886 g, 97%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 6.66 (s, 1H), 4.04 (d, J = 11.0 Hz, 2H), 3.30 - 3.23 (m, 1H), 2.86 (br.s, 2H), 1.92 (d, J = 12.4 Hz, 2H), 1.50 (qd, J = 12.8, 4.1 Hz, 2H), 1.41 (s, 9H) ppm; 1313C NMR (101 MHz, DMSO-d6) δ 155.68, 154.29, 148.35, 135.37, 111.31, 110.68, 87.29, 79.10, 43.97, 32.63, 30.37, 28.58 ppm; C 16 H 22 BrN5O2 (MW 395.10), LCMS (EI) m / e 396.1 (M + + H).

[0312] Example 5 1-Isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Compound 7 of Schemes 2 and 3) Step 1 Diethyl 2-((3-phenylureido)methylene)malonate

Chem.

[0313] Step 2 Ethyl 2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate

Chem.

[0314] Step 3 Ethyl 1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate

Chem.

[0315] Step 4 1-Isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

Chem.

[0316] Example 6 Synthesis of 1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Compound 6 of Scheme 1) Step 1 Diethyl 2-((3-pyridin-2-ylureido)methylene)malonate

Chemical formula

[0317] Step 2 1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

Chemical formula

[0318] A mixture of ethyl 2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2.06 mL, 20.7 mmol) from the previous step and Cs2CO3 (10.1 g, 31.0 mmol) in DMF (35 mL) was stirred at 70 °C for 3 h. The reaction mixture was then cooled to room temperature, diluted with CHCl3 / isopropyl alcohol 3:1 (75 mL), washed with water, saturated brine, dried over Na2SO4 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. LCMS C 15 H 18 N3O4(M+H) + Calculated for: m / z = 304.1. Found: 304.1.

[0319] 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 4 M HCl in 1,4-dioxane (20 mL, 82 mmol) and water (5.0 mL) was stirred at 80 °C for 5 h, cooled to room temperature and concentrated. The resulting material was purified by column chromatography (0% - 15% MeOH in CH2Cl2) to give the product as a slightly yellowish solid (1.50 g, 47% over 3 steps). LCMS C 13 H 14 N3O4 (M+H) + Calculated for: m / z = 276.1. Found: 276.1.

[0320] 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, Form I) Powder X-ray Diffraction (XRPD) of Compound I Maleate Powder X-ray diffraction (XRPD) was obtained from a Rigaku MiniFlex X-ray Powder Diffractometer (XRPD). The general experimental procedure for XRPD was as follows. Namely, (1) X-ray radiation of 1.054056 Å from copper, K β filter used, (2) X-ray output 30 KV, 15 mA, (3) the sample powder was dispersed on a zero background sample holder. The general measurement conditions for XRPD were: start angle 3 degrees, end angle 45 degrees; sampling 0.02 degrees; scan speed 2 degrees / min. The XRPD pattern is shown in Figure 1 and the XRPD data are shown in Table 1.

Table 1

[0321] Differential Scanning Calorimetry (DSC) of Compound I Maleate (Form I) The DSC was obtained from a TA Instruments Differential Scanning Calorimetry, Model Q200 equipped with an automatic sample feeder. The DSC instrument conditions were as follows: namely, 30 to 300 °C at 10 °C / min; Tzero aluminum sample pans and lids; a nitrogen gas flow rate of 50 mL / min. The DSC curve is shown in Figure 2. From this DSC curve, a main endothermic event with an onset temperature of 202.9 °C and a peak temperature of 211.0 °C was revealed, which is considered to be the melting and decomposition temperature of the compound.

[0322] Thermogravimetric analysis (TGA) of Compound I maleate (Form I) The TGA was obtained from a TA Instrument Thermogravimetric Analyzer, Model Q500. The general experimental conditions for the TGA were: a temperature gradient of 20 °C to 600 °C at 20 °C / min; nitrogen purge, a gas flow rate of 40 mL / min and then equalizing the purge flow rate; a sample purge flow rate of 60 mL / min; and a platinum sample pan. The TGA curve is shown in Figure 3. A weight loss of approximately 0.7% was observed up to 150 °C, which was considered to be associated with the disappearance of moisture and residual solvents. This compound starts to decompose significantly above 200 °C.

[0323] Solubility of Compound I maleate (Form I) The solubility of Compound I maleate was measured at 25 ± 1 °C and 50 ± 1 °C. The general procedure for the solubility test at 25 ± 1 °C is as follows. That is, 1) 3 mL of each solvent listed in Table 1A was taken into individual vials, 2) Compound I maleate was added to form a turbid solution at 25 °C, 3) an additional 15 - 20 mg of Compound I maleate was added, 4) this mixture was stirred at 25 ± 1 °C for 48 hours, 5) the supernatant was filtered using a syringe filter, 6) this saturated solution was diluted with MeOH and analyzed by HPLC. The general procedure for the solubility test at 50 ± 1 °C is as follows. That is, 1) 3 mL of each solvent listed in Table 1A was taken into individual vials, 2) Compound I maleate was added to form a turbid solution at 50 °C, 3) an additional 20 - 25 mg of Compound I maleate was added, 4) this mixture was stirred at 50 ± 1 °C for 24 hours, 5) the supernatant was filtered using a syringe filter heated to 50 ± 1 °C, 6) this saturated solution was diluted with MeOH and analyzed by HPLC. The results are summarized in Table 1A. [Table 2]

[0324] Other crystalline salts Other crystalline salts of the compound of formula I, such as the HCl salt, monosulfate salt, hemisulfate salt, mesylate salt, and besylate salt, were found and prepared.

[0325] Example 8 Preparation of the salt 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (salt of Compound II) The salts of Compound II were prepared according to the procedure in Table 2 below. These salts were analyzed by XRPD, DSC, and TGA (see Examples 9 - 15). [Table 3-1] [Table 3-2]

[0326] Example 9 Solid State Characterization of Compound II Phosphate Examination of Compound II Phosphate by Powder X-ray Diffraction (XRPD) Compound II phosphate was characterized by XRPD. The XRPD was obtained from a Rigaku MiniFlex X-ray Powder Diffractometer (XRPD). The general experimental procedure for XRPD was as follows. That is, (1) X-ray radiation of 1.054056 Å derived from copper, K β filter used, (2) X-ray output 30 KV, 15 mA, (3) the sample powder was dispersed on a zero background sample holder. The general measurement conditions for XRPD were starting angle 3 degrees, ending angle 45 degrees; sampling 0.02 degrees; scanning speed 2 degrees / minute.

[0327] The XRPD pattern of Compound II phosphate is shown in Figure 4, and the XRPD data are shown in Table 3. [Table 4]

[0328] Examination of Compound II Phosphate by Differential Scanning Calorimetry (DSC) Compound II phosphate was characterized by DSC. The DSC was obtained from a TA Instruments Differential Scanning Calorimetry, Model Q200 equipped with an automatic sample feeder. The instrument conditions for DSC were as follows, that is, 30 - 350 °C at 10 °C / min; Tzero aluminum sample pan and lid; and a nitrogen gas flow rate of 50 mL / min.

[0329] The DSC curve of Compound II phosphate is shown in Figure 5. From this DSC curve, a main endothermic event with a starting temperature of 252.6 °C and a peak temperature of 257.2 °C was revealed, which is considered to be the melting / decomposition of the compound.

[0330] Study of Compound II Phosphate by Thermogravimetric Analysis (TGA) Compound II phosphate was characterized by TGA. TGA was obtained from a TA Instrument Thermogravimetric Analyzer, Model Q500. The general experimental conditions for TGA were as follows: a temperature gradient of 20°C / min from 20°C to 600°C; nitrogen purge, gas flow rate of 40 mL / min, and then equalizing the purge flow rate; sample purge flow rate of 60 mL / min; and a platinum sample pan.

[0331] The TGA curve of Compound II phosphate is shown in Figure 6. A weight loss of approximately 1.8% was observed up to 200°C, which was considered to be associated with the disappearance of moisture or residual solvent. A significant weight loss was observed above 230°C, which was considered to be associated with the decomposition of the compound.

[0332] Example 10 Solid-State Characterization of Compound II Maleate Study of Compound II Maleate by Powder X-Ray Diffraction (XRPD) Compound II maleate was characterized by XRPD. XRPD was obtained from a Rigaku MiniFlex X-ray Powder Diffractometer (XRPD). The general experimental procedure for XRPD was as follows. That is, (1) X-ray radiation of 1.054056 Å from copper, K β filter used, (2) X-ray output of 30 KV, 15 mA, and (3) the sample powder was dispersed on a zero-background sample holder. The general measurement conditions for XRPD were: start angle 3 degrees, end angle 45 degrees; sampling 0.02 degrees; scanning speed 2 degrees / min.

[0333] The XRPD pattern of Compound II maleate is shown in Figure 7, and the XRPD data are shown in Table 4.

Table 5

[0334] Study of Compound II Maleate by Differential Scanning Calorimetry (DSC) Compound II maleate was characterized by DSC. The DSC was obtained from a TA Instruments Differential Scanning Calorimetry, Model Q200 equipped with an automatic sample feeder. The instrument conditions for DSC were as follows: namely, from 30 to 300 °C at 10 °C / min; Tzero aluminum sample pans and lids; and a nitrogen gas flow rate of 50 mL / min.

[0335] The DSC curve of Compound II maleate is shown in Figure 8. From this DSC curve, two main endothermic events were revealed, where the onset temperature of the first event was 183.4 °C, the peak temperature was 194.8 °C, followed by the onset temperature of the second event being 233.4 °C and the peak temperature being 239.7 °C.

[0336] Examination of Compound II hemisulfate by thermogravimetric analysis (TGA) Compound II hemisulfate was characterized by TGA. The TGA was obtained from a TA Instrument Thermogravimetric Analyzer, Model Q500. The general experimental conditions for TGA were a temperature gradient of 20 °C / min from 20 °C to 600 °C; nitrogen purge, gas flow rate of 40 mL / min, then equilibrating the purge flow rate; sample purge flow rate of 60 mL / min; and platinum sample pans.

[0337] The TGA curve of Compound II hemisulfate is shown in Figure 9. A weight loss of approximately 1.8% was observed up to 125 °C, which was considered to be associated with the disappearance of moisture or residual solvent. A significant weight loss was observed above 175 °C, which was considered to be associated with the decomposition of the compound.

[0338] Example 11 Solid-state characterization of Compound II hemisulfate Examination of Compound II hemisulfate by powder X-ray diffraction (XRPD) Compound II hemisulfate was characterized by XRPD. The XRPD was obtained from a Rigaku MiniFlex X-ray Powder Diffractometer (XRPD). The general experimental procedure for XRPD was as follows. That is, (1) X-ray radiation of 1.054056 Å from copper, K β filter used, (2) X-ray output 30 KV, 15 mA, (3) the sample powder was dispersed on a zero-background sample holder. The general measurement conditions for XRPD were: start angle 3 degrees, end angle 45 degrees; sampling 0.02 degrees; scanning speed 2 degrees / minute.

[0339] The XRPD pattern of Compound II hemisulfate is shown in Figure 10, and the XRPD data are shown in Table 5.

Table 6

[0340] Examination of Compound II hemisulfate by differential scanning calorimetry (DSC) Compound II hemisulfate was characterized by DSC. The DSC was obtained from a TA Instruments Differential Scanning Calorimetry, Model Q200 equipped with an automatic sample feeder. The instrument conditions for DSC were as follows, that is, 30 to 350 °C at 10 °C / min; Tzero aluminum sample pan and lid; and a nitrogen gas flow rate of 50 mL / min.

[0341] The DSC curve of Compound II hemisulfate is shown in Figure 11. From this DSC curve, a main endothermic event with an onset temperature of 283.8 °C and a peak temperature of 289.4 °C was revealed, which is considered to be the melting / decomposition of the compound.

[0342] Examination of Compound II hemisulfate by thermogravimetric analysis (TGA) Compound II hemisulfate was characterized by TGA. The TGA was obtained from a TA Instrument Thermogravimetric Analyzer, Model Q500. The general experimental conditions for TGA were as follows: a temperature gradient of 20°C to 600°C at 20°C / min; nitrogen purge, gas flow rate of 40 mL / min, and then equalizing the purge flow rate; sample purge flow rate of 60 mL / min; and a platinum sample pan.

[0343] The TGA curve of Compound II hemisulfate is shown in Figure 12. A weight loss of approximately 1.5% was observed up to 100°C, which was considered to be associated with the disappearance of moisture or residual solvent. A significant weight loss was observed above 200°C, which was considered to be associated with the decomposition of the compound.

[0344] Example 12 Solid State Characterization of Compound II Hydrochloride Examination of Compound II Hydrochloride by Powder X-ray Diffraction (XRPD) Compound II hydrochloride was characterized by XRPD. The XRPD was obtained from a Rigaku MiniFlex X-ray Powder Diffractometer (XRPD). The general experimental procedure for XRPD was as follows. That is, (1) X-ray radiation of 1.054056 Å from copper, K β filter used, (2) X-ray output of 30 KV, 15 mA, (3) the sample powder was dispersed on a zero-background sample holder. The general measurement conditions for XRPD were: starting angle 3 degrees, ending angle 45 degrees; sampling 0.02 degrees; scanning speed 2 degrees / min.

[0345] The XRPD pattern of Compound II hydrochloride is shown in Figure 13, and the XRPD data are shown in Table 6.

Table 7

[0346] Examination of Compound II Hydrochloride by Differential Scanning Calorimetry (DSC) Compound II hydrochloride was characterized by DSC. The DSC was obtained from a TA Instruments Differential Scanning Calorimetry, Model Q200 equipped with an automatic sample feeder. The instrument conditions for DSC were as follows: namely, from 30 to 300 °C at 10 °C / min; Tzero aluminum sample pans and lids; and a nitrogen gas flow rate of 50 mL / min.

[0347] The DSC curve of Compound II hydrochloride is shown in Figure 14. From this DSC curve, a main endothermic event with an onset temperature of 183.5 °C and a peak temperature of 190.0 °C was revealed, which is considered to be the melting / decomposition of the compound.

[0348] Examination of Compound II hydrochloride by thermogravimetric analysis (TGA) Compound II hydrochloride was characterized by TGA. The TGA was obtained from a TA Instrument Thermogravimetric Analyzer, Model Q500. The general experimental conditions for TGA were a temperature gradient from 20 °C to 600 °C at 20 °C / min; nitrogen purge, gas flow rate of 40 mL / min, and then equalizing the purge flow rate; sample purge flow rate of 60 mL / min; and a platinum sample pan.

[0349] The TGA curve of Compound II hydrochloride is shown in Figure 15. A weight loss of approximately 5.9% was observed up to 200 °C, which was considered to be associated with the disappearance of moisture or residual solvent. A significant weight loss was observed above 200 °C, which was considered to be associated with the decomposition of the compound.

[0350] Example 13 Solid-state characterization of Compound II salicylate Examination of Compound II salicylate by powder X-ray diffraction (XRPD) Compound II salicylate was characterized by XRPD. The XRPD was obtained from a Rigaku MiniFlex X-ray Powder Diffractometer (XRPD). The general experimental procedure for XRPD was as follows. That is, (1) X-ray radiation of 1.054056 Å derived from copper, K β filter used, (2) X-ray output 30 KV, 15 mA, (3) the sample powder was dispersed on a zero-background sample holder. The general measurement conditions for XRPD were: starting angle 3 degrees, ending angle 45 degrees; sampling 0.02 degrees; scanning speed 2 degrees / minute.

[0351] The XRPD pattern of compound II salicylate is shown in Figure 16, and the XRPD data are shown in Table 7.

Table 8

[0352] Examination of compound II salicylate by differential scanning calorimetry (DSC) Compound II salicylate was characterized by DSC. The DSC was obtained from a TA Instruments Differential Scanning Calorimetry, Model Q200 equipped with an automatic sample feeder. The instrument conditions for DSC were as follows, that is, 30 - 300 °C at 10 °C / min; Tzero aluminum sample pan and lid; and a nitrogen gas flow rate of 50 mL / min.

[0353] The DSC curve of compound II salicylate is shown in Figure 17. Three main endothermic events were revealed by this DSC curve, that is, the first endothermic event with a starting temperature of 176.0 °C and a peak temperature of 181.7 °C, the second endothermic event with a starting temperature of 209.9 °C and a peak temperature of 224.9 °C, and the third endothermic event with a starting temperature of 254.7 °C and a peak temperature of 264.5 °C.

[0354] Examination of compound II salicylate by thermogravimetric analysis (TGA) Compound II salicylate was characterized by TGA. The TGA was obtained from a TA Instrument Thermogravimetric Analyzer, Model Q500. The general experimental conditions for TGA were as follows: a temperature gradient of 20°C to 600°C at 20°C / min; nitrogen purge, gas flow rate of 40 mL / min, and then equilibrating the purge flow rate; sample purge flow rate of 60 mL / min; and a platinum sample pan.

[0355] The TGA curve of Compound II salicylate is shown in Figure 18. In the first step, a weight loss of approximately 8.1% was observed up to 250°C. A significant weight loss was observed above 300°C, which was considered to be associated with the decomposition of the compound.

[0356] Example 14 Solid State Characterization of Compound II Mesylate Examination of Compound II Mesylate by Powder X-ray Diffraction (XRPD) Compound II mesylate was characterized by XRPD. The XRPD was obtained from a Rigaku MiniFlex X-ray Powder Diffractometer (XRPD). The general experimental procedure for XRPD was as follows. That is, (1) X-ray radiation of 1.054056 Å from copper, K β filter used, (2) X-ray output 30 KV, 15 mA, (3) the sample powder was dispersed on a zero-background sample holder. The general measurement conditions for XRPD were: start angle 3 degrees, end angle 45 degrees; sampling 0.02 degrees; scanning speed 2 degrees / min.

[0357] The XRPD pattern of Compound II mesylate is shown in Figure 19, and the XRPD data are shown in Table 8. [Table 9]

[0358] Examination of Compound II Mesylate by Differential Scanning Calorimetry (DSC) Compound II mesylate was characterized by DSC. The DSC was obtained from a TA Instruments Differential Scanning Calorimetry, Model Q200 equipped with an automatic sample feeder. The instrument conditions for DSC were as follows: namely, 30 - 300 °C at 10 °C / min; Tzero aluminum sample pan and lid; and a nitrogen gas flow rate of 50 mL / min.

[0359] The DSC curve of compound II mesylate is shown in Figure 20. From this DSC curve, a main endothermic event with an onset temperature of 166.3 °C and a peak temperature of 174.8 °C was revealed, which is considered to be the melting / decomposition of the compound.

[0360] Investigation of compound II mesylate by thermogravimetric analysis (TGA) Compound II mesylate was characterized by TGA. The TGA was obtained from a TA Instrument Thermogravimetric Analyzer, Model Q500. The general experimental conditions for TGA were a temperature gradient of 20 °C / min from 20 °C to 600 °C; nitrogen purge, gas flow rate of 40 mL / min, and then equilibrating the purge flow rate; sample purge flow rate of 60 mL / min; and a platinum sample pan.

[0361] The TGA curve of compound II mesylate is shown in Figure 21. A weight loss of approximately 2.3% was observed up to 100 °C, which was considered to be associated with the disappearance of moisture or residual solvent. A significant weight loss was observed above 200 °C, which was considered to be associated with the decomposition of the compound.

[0362] Example 15 Solid-state characterization of compound II esylate Investigation of compound II esylate by powder X-ray diffraction (XRPD) Compound II ethylate was characterized by XRPD. The XRPD was obtained from a Rigaku MiniFlex X-ray Powder Diffractometer (XRPD). The general experimental procedure for XRPD was as follows. That is, (1) X-ray radiation of 1.054056 Å from copper, K β filter used, (2) X-ray output 30 KV, 15 mA, (3) the sample powder was dispersed on a zero-background sample holder. The general measurement conditions for XRPD were: starting angle 3 degrees, ending angle 45 degrees; sampling 0.02 degrees; scanning speed 2 degrees / minute.

[0363] The XRPD pattern of Compound II ethylate is shown in Figure 22, and the XRPD data are shown in Table 9.

Table 10

[0364] Examination of Compound II ethylate by differential scanning calorimetry (DSC) Compound II ethylate was characterized by DSC. The DSC was obtained from a TA Instruments Differential Scanning Calorimetry, Model Q200 equipped with an automatic sample feeder. The instrument conditions for DSC were as follows, that is, 30 - 300 °C at 10 °C / min; Tzero aluminum sample pan and lid; and a nitrogen gas flow rate of 50 mL / min.

[0365] The DSC curve of Compound II ethylate is shown in Figure 23. From this DSC curve, a main endothermic event with a starting temperature of 180.4 °C and a peak temperature of 187.7 °C was revealed, which is considered to be the melting / decomposition of the compound.

[0366] Examination of Compound II ethylate by thermogravimetric analysis (TGA) The ethylate of Compound II was characterized by TGA. The TGA was obtained from a TA Instrument Thermogravimetric Analyzer, Model Q500. The general experimental conditions for the TGA were as follows: a temperature gradient of 20°C to 600°C at 20°C / min; nitrogen purge, a gas flow rate of 40 mL / min, and then equalizing the purge flow rate; a sample purge flow rate of 60 mL / min; and a platinum sample pan.

[0367] The TGA curve of the ethylate of Compound II is shown in Figure 24. A weight loss of approximately 1.6% was observed up to 100°C, which was considered to be associated with the disappearance of moisture or residual solvent. A significant weight loss was observed above 200°C, which was considered to be associated with the decomposition of the compound.

[0368] Example 16 Preparation of Other Crystal Forms (Compound I Maleate, Forms II - V) 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 The experimental procedures for the formation of Compound I Maleate Forms II, III, IV, and V are summarized in Table 10.

Table 11

[0369] Example 17 Solid-State Characterization of Compound I Maleate, Form II Powder X-ray Diffraction (XRPD) of Compound I Maleate, Form II Powder X-ray Diffraction (XRPD) was obtained from a Rigaku MiniFlex X-ray Powder Diffractometer (XRPD). The general experimental procedure for the XRPD was as follows. That is, (1) X-ray radiation of 1.054056 Å from copper, K βFilter used, (2) X-ray output 30 KV, 15 mA, (3) The sample powder was dispersed on a zero-background sample holder. The general measurement conditions for XRPD were: start angle 3 degrees, end angle 45 degrees; sampling 0.02 degrees; scanning speed 2 degrees / minute.

[0370] The XRPD pattern of Form II of Compound I maleate is shown in Figure 25, and the XRPD data are shown in Table 11.

Table 12

[0371] Example 18 Solid State Characterization of Compound I Maleate, Form III Powder X-ray diffraction (XRPD) was obtained from a Rigaku MiniFlex X-ray Powder Diffractometer (XRPD). The general experimental procedure for XRPD was as follows. That is, (1) X-ray radiation of 1.054056 Å derived from copper, K β Filter used, (2) X-ray output 30 KV, 15 mA, (3) The sample powder was dispersed on a zero-background sample holder. The general measurement conditions for XRPD were: start angle 3 degrees, end angle 45 degrees; sampling 0.02 degrees; scanning speed 2 degrees / minute.

[0372] The XRPD pattern of Form III of Compound I maleate is shown in Figure 26, and the XRPD data are shown in Table 12.

Table 13

[0373] Examination of Compound I Maleate, Form III by Differential Scanning Calorimetry (DSC) Form III of Compound I maleate was characterized by DSC. The DSC was obtained from a TA Instruments Differential Scanning Calorimetry, Model Q200 equipped with an automatic sample feeder. The instrument conditions for DSC were as follows: namely, from 30 to 300 °C at 10 °C / min; Tzero aluminum sample pan and lid; and a nitrogen gas flow rate of 50 mL / min.

[0374] The DSC curve of Compound I maleate, Form III, is shown in Figure 27. From this DSC curve, two endothermic events were revealed: namely, the first endothermic event with an onset temperature of 143.9 °C and a peak temperature of 165.4 °C, and the second endothermic event with an onset temperature of 186.3 °C and a peak temperature of 195.4 °C.

[0375] Examination of Compound I maleate, Form III, by thermogravimetric analysis (TGA) Form III of Compound I maleate was characterized by TGA. The TGA was obtained from a TA Instrument Thermogravimetric Analyzer, Model Q500. The general experimental conditions for TGA were a temperature gradient of 20 °C to 600 °C at 20 °C / min; nitrogen purge, gas flow rate of 40 mL / min, and then equilibration of the purge flow rate; sample purge flow rate of 60 mL / min; and a platinum sample pan.

[0376] The TGA curve of Compound I maleate, Form III, is shown in Figure 28.

[0377] Example 19 Solid-state characterization of Compound I maleate, Form IV Powder X-ray diffraction (XRPD) was obtained from a Rigaku MiniFlex X-ray Powder Diffractometer (XRPD). The general experimental procedure for XRPD was as follows: namely, (1) X-ray radiation of 1.054056 Å from copper, K βFilter was used, (2) X-ray output was 30 KV and 15 mA, and (3) the sample powder was dispersed on a zero-background sample holder. The general measurement conditions for XRPD were as follows: starting angle was 3 degrees, ending angle was 45 degrees; sampling was 0.02 degrees; scanning speed was 2 degrees / minute.

[0378] The XRPD pattern of Form IV of Compound I maleate is shown in Figure 29, and the XRPD data are shown in Table 13.

Table 14

[0379] Examination of Compound I maleate, Form IV, by differential scanning calorimetry (DSC) Form IV of Compound I maleate was characterized by DSC. The DSC was obtained from a TA Instruments Differential Scanning Calorimetry, Model Q200 equipped with an automatic sample feeder. The instrument conditions for DSC were as follows: from 30 to 300 °C at 10 °C / min; Tzero aluminum sample pan and lid; and a nitrogen gas flow rate of 50 mL / min.

[0380] The DSC curve of Compound I maleate, Form IV, is shown in Figure 30. From this DSC curve, two endothermic events were revealed, namely, the first endothermic event with a starting temperature of 145.7 °C and a peak temperature of 152.1 °C, and the second endothermic event with a starting temperature of 188.3 °C and a peak temperature of 202.6 °C.

[0381] Examination of Compound I maleate, Form IV, by thermogravimetric analysis (TGA) Form IV of Compound I maleate was characterized by TGA. The TGA was obtained from a TA Instrument Thermogravimetric Analyzer, Model Q500. The general experimental conditions for TGA were as follows: a temperature gradient of 20 °C / min from 20 °C to 600 °C; nitrogen purge, gas flow rate of 40 mL / min, and then equilibration of the purge flow rate; sample purge flow rate of 60 mL / min; and a platinum sample pan.

[0382] The TGA curve of Compound I maleate, Form IV, is shown in Figure 31.

[0383] Example 20 Solid State Characterization of Compound I Maleate, Form V Powder X-ray diffraction (XRPD) was obtained from a Rigaku MiniFlex X-ray Powder Diffractometer (XRPD). The general experimental procedure for XRPD was as follows. That is, (1) X-ray radiation of 1.054056 Å from copper, K β filter used, (2) X-ray output 30 KV, 15 mA, (3) the sample powder was dispersed on a zero-background sample holder. The general measurement conditions for XRPD were: starting angle 3 degrees, ending angle 45 degrees; sampling 0.02 degrees; scanning speed 2 degrees / minute.

[0384] The XRPD pattern of Compound I maleate, Form V, is shown in Figure 32, and the XRPD data are shown in Table 14. [Table 15]

[0385] Examination of Compound I Maleate, Form V, by Differential Scanning Calorimetry (DSC) Compound I maleate, Form V, was characterized by DSC. DSC was obtained from a TA Instruments Differential Scanning Calorimetry, Model Q200 equipped with an automatic sample feeder. The instrument conditions for DSC were as follows, that is, 10 °C / min from 30 to 300 °C; Tzero aluminum sample pan and lid; and a nitrogen gas flow rate of 50 mL / min.

[0386] The DSC curve of Compound I maleate, Form V, is shown in Figure 33. From this DSC curve, an endothermic event with a starting temperature of 189.1 °C and a peak temperature of 200.1 °C was revealed.

[0387] Examination of Compound I Maleate, Form V, by Thermogravimetric Analysis (TGA) Form V of Compound I maleate was characterized by TGA. The TGA was obtained from a TA Instrument Thermogravimetric Analyzer, Model Q500. The general experimental conditions for the TGA were a temperature gradient of 20°C to 600°C at 20°C / min; nitrogen purge, gas flow rate of 40 mL / min and then equilibration of the purge flow rate; sample purge flow rate of 60 mL / min; and a platinum sample pan.

[0388] The TGA curve of Compound I maleate, Form V is shown in Figure 34.

[0389] Example A Axl autophosphorylation assay Autophosphorylation of Axl was performed by incubating recombinant Axl protein (Life Technologies, PV4275) for 1 hour at room temperature 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.

[0390] 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. A 0.1 μl DMSO solution of the test compound was transferred from the compound plate to a white 384-well assay plate (Greiner LUMITRAC plate). The final concentration of DMSO was 1.25%. 5.1 nM phosphorylated Axl, or 0.0625 nM c-Mer (Carna Biosciences, 08-108), or 0.366 nM Tyro3 (Life Technologies, PR7480A) was prepared in the assay buffer. A 1 mM stock solution of the peptide substrate biotin-EQEDEPEGDYFEWLE-amide SEQ ID NO:1 (Quality Controlled Biochemicals, MA) was diluted to 1 μM in the assay buffer containing 2000 μM ATP. 4 μl of the enzyme solution (or assay buffer for the enzyme blank test) was added to the appropriate wells of each plate, and then 4 μl / well of the substrate solution was added to initiate the reaction. The plate was shielded from light and incubated at room temperature for 60 minutes. The reaction was stopped by adding 4 μl of the detection solution containing 50 mM Tris-HCl (pH 7.8), 150 mM NaCl, 0.05% BSA, 45 mM EDTA, 180 nM SA-APC (PerkinElmer, CR130-100), and 3 nM Eu-W1024 anti-phosphotyrosine PY20 (PerkinElmer, AD0067). The plate was incubated at room temperature for 1 hour, and the HTRF (homogeneous time-resolved fluorescence) signal was measured on a PHERAstar FS plate reader (BMG labtech). The percentage of inhibition was calculated for each concentration, and the IC 50 value was derived from curve fitting using GraphPad Prism software.

[0391] The compounds of Formulas I and II were found to be inhibitors of one or more of AXL, MER, and TYRO3. The IC 50The data is disclosed in U.S. Patent Application No. 15 / 469,975, and the data is shown in Table 15 below. The symbol "†" indicates an IC of ≦5 nM 50 and "††" indicates an IC that is >5 nM but ≦10 nM 50 and "†††" indicates an IC that is >10 nM but ≦100 nM 50 .

Table 16

[0392] Example B Generation and cell proliferation assay of BAF3-AXL, BAF3-MER, and BAF3-TYRO3 cells The cytoplasmic domains of AXL, MER, or TYRO3 fused with a dimerization sequence and an HA tag are cloned into a pMSCV vector with a puromycin resistance marker to generate three constructs (pMSCV-AXL, pMSCV-MER, and pMSCV-TYRO3). BAF3 cells are individually transfected with the above three constructs by electroporation. A single clone that is IL3-independent and puromycin-resistant is selected and characterized. Cells with stable expression of AXL, MER, or TYRO3 are selected and named BAF3-AXL, BAF3-MER, and BAF3-TYRO3 cells.

[0393] The BAF3, BAF3-AXL, BAF3-MER, or BAF3-TYRO3 cell lines are maintained in RPMI1640 (Gibco / Life Technologies, Carlsbad, CA) containing 10% FBS. To measure the effect of the test compound on cell viability, 1000 cells / well are seeded in a 384-well tissue culture plate in growth medium containing serial dilutions of the compound or DMSO only, incubated at 37 °C under 5% CO2 for 48 hours, and cell viability is measured by an ATP assay (CellTiter-Glo Assay, Promega) according to the manufacturer's procedure. The data is converted to the inhibition rate relative to the DMSO control, and the IC 50 curve is curve-fitted using GraphPad Prism software.

[0394] Example C BaF3-AXL ELISA and BaF3-MER ELISA Maintain BaF3-AXL or BaF3-MER cells in RPMI medium containing 10% FBS and puromycin (1 μg / ml, Gibco / Life Technologies, Carlsbad, CA). To measure the effect of the test compound on phosphorylated AXL or phosphorylated MER, seed the cells in a V-bottom polypropylene plate (Greiner bio-one) in the presence or absence of the test compound diluted in the medium (5×10 4 cells / well), and incubate at 37 °C for 1 hour under 5% CO2. Harvest the cells by centrifugation and lyse them on ice for 30 minutes in 110 μl of ice-cold lysis buffer (Cell Signaling) containing protease and phosphatase inhibitors (Halts PI, ThermoFisher). Store the cell lysates at -80 °C and perform ELISA. Prepare the ELISA plate by incubating a Costar plate with an anti-HA antibody (1 μg / ml) at room temperature for 1 hour. Wash this plate and block it with PBS containing 3% BSA. Add the cell lysates to the ELISA plate and incubate overnight at 4 °C. Wash this plate and incubate it with a LANCE Eu-W1024 anti-phosphotyrosine antibody (PY-20) (PerkinElmer) in DELFIA assay buffer (PerkinElmer) for 1 hour, and read it on a Pherastar (BMG Labtech). Convert the data to the inhibition rate relative to the DMSO control, and approximate the curve of the inhibition rate against the logarithm of the inhibitor concentration using GraphPad Prism to determine the IC 50 value.

[0395] Example D H1299 Phosphorylated AXL ELISA The H1299 cell line (ATCC), a human non-small cell lung cancer cell line that expresses Axl, is maintained in RPMI medium containing 10% FBS (Gibco / Life Technologies, Carlsbad, CA). To measure the effect of the test compound on phosphorylated AXL, the cells are seeded into 96-well tissue culture plates (Costar) (30,000 cells / well) and incubated overnight at 37 °C under 5% CO2. The appropriate concentration of the compound is added and incubated for 1 hour at 37 °C under 5% CO2. rhGas6 (R&D Systems, 6 μg / ml) is added to each well. The plates are incubated at 37 °C under 5% CO2 for 15 minutes. The cells are harvested and lysed in 110 μL of ice-cold lysis buffer (Cell Signaling) containing protease and phosphatase inhibitors (Halts PI, ThermoFisher). The lysate is incubated on ice for 1 hour, stored at -80 °C, and ELISA is performed. The ELISA plates are prepared by incubating Costar plates with anti-HA antibody (1 μg / ml) for 1 hour at room temperature. The plates are washed and blocked with PBS containing 3% BSA. The cell lysates are added to the ELISA plates and incubated overnight at 4 °C. The plates are washed and incubated with the LANCE Eu-W1024 anti-phosphotyrosine antibody (PY-20) (PerkinElmer) in DELFIA assay buffer (PerkinElmer) for 1 hour and read on a Pherastar (BMG Labtech). The data are converted to the inhibition rate relative to the DMSO control, and the IC 50 is determined by approximating the curve of the inhibition rate against the logarithm of the inhibitor concentration using GraphPad Prism.

[0396] Example E Whole Blood H1299 Phosphorylated AXL ELISA H1299 cells (ATCC) are maintained in RPMI medium (Gibco / Life Technologies, Carlsbad, CA) containing 10% FBS. To measure the effect of the test compound on phosphorylated AXL, the cells are seeded in a 96-well tissue culture plate (Costar) (30,000 cells / well) and incubated overnight at 37 °C under 5% CO2. Blood obtained from normal donors is mixed with the test compound for 1 hour. The medium is removed from the H1299 cells and the blood containing the compound is added to each well. After incubation at 37 °C under 5% CO2 for 1 hour, rh-Gas6 (4 μg / ml, R&D Systems) is added to each well. The plate is incubated at 37 °C under 5% CO2 for 15 minutes. The cells are harvested and lysed on ice for 1 hour in 110 μL of ice-cold lysis buffer (Cell Signaling) containing protease and phosphatase inhibitors (Halts PI, ThermoFisher). The plate is stored at -80 °C and ELISA is performed. The ELISA plate is prepared by incubating the Costar plate with anti-HA antibody (1 μg / ml) for 1 hour at room temperature. The plate is washed and blocked with PBS containing 3% BSA. The cell lysate is added to the ELISA plate and incubated overnight at 4 °C. The plate is washed and incubated with LANCE Eu-W1024 anti-phosphotyrosine antibody (PY-20) (PerkinElmer) in DELFIA assay buffer (PerkinElmer) for 1 hour and read on a Pherastar (BMG Labtech). The data are converted to the inhibition rate relative to the DMSO control, and the IC 50 is determined by approximating the curve of the inhibition rate against the logarithm of the inhibitor concentration using GraphPad Prism.

[0397] Example F G361 Phosphorylated Akt CellInsight ELISA The G361 cell line (ATCC), a human malignant melanoma cell line that expresses Mer, is maintained in RPMI medium (Gibco / Life Technologies, Carlsbad, CA) containing 10% FBS. To measure the effect of a test compound on the MER signaling pathway, the above cells are seeded in a 96-well CellBind surface plate (Corning) at 2×10 4 cells / well in a volume of 100 μL and incubated overnight at 37 °C under 5% CO2. 20 μL of the appropriate concentration of the test compound is added to the above cells and incubated for 1 hour. rhGas6 (4 μg / ml, R&D Systems) is added to each well and incubated for 20 minutes. The cells are fixed by adding 50 μL of a PBS (Corning) solution of 4% paraformaldehyde (Electron Microscopy Sciences) at room temperature for 30 minutes. The plate is washed and incubated with 50 μL of a PBS solution of 0.2% tritonX-100 (Sigma) at room temperature for 10 minutes. The plate is washed and incubated with 100 μL of blocking buffer (PBS solution of 0.1% BSA) for 30 minutes. The plate is washed and incubated overnight at 4 °C with phosphorylated AKT (Ser473) (D9E) rabbit mAb (Cell Signaling) diluted in 0.1% BSA (1:300 dilution). The plate is washed and incubated at room temperature for 2 hours with 50 μL of a PBS solution of Alexaflour 488 goat anti-rabbit IgG (H+L) F(ab’) 2 fragment (Molecular Probes, 1:1000 dilution) and Hoechst 33342 (ThermoFisher, 1:2000 dilution). The plate is washed with PBS and read on a CellInsight CX5 (ThermoFisher).

[0398] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to be included within the scope of the appended claims. Each cited reference, including all patents, patent applications, and publications cited in this application, is hereby incorporated by reference in its entirety into this specification.

Claims

1. A salt which is 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.

2. The salt of claim 1, which is a salt having a 1:1 stoichiometric ratio 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 to maleic acid.

3. The salt of claim 1 which is crystalline.

4. 2. The salt of claim 1 which is substantially isolated.

5. 2. The salt of claim 1, characterized by a DSC curve having an endothermic peak at about 211°C.

6. 2. The salt of claim 1, having a DSC curve substantially as shown in FIG.

7. 2. The salt of claim 1, having a TGA curve substantially as shown in FIG.

8. 2. The salt of claim 1 having at least one XRPD peak selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5° in terms of 2θ.

9. 2. The salt of claim 1 having at least two XRPD peaks selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5° in terms of 2θ.

10. 2. The salt of claim 1 having at least three XRPD peaks selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5° in terms of 2θ.

11. 2. The salt of claim 1 having at least four XRPD peaks, expressed in terms of 2-theta, selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5°.

12. 2. The salt of claim 1 having the following XRPD peaks, expressed in terms of 2θ: about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18.5°.

13. 2. The salt of claim 1, having an XRPD profile substantially as shown in FIG.

14. A salt which is 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide hemisulfate.

15. The salt of claim 14, wherein the stoichiometric ratio 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide to sulfuric acid is 1:0.

5.

16. The salt of claim 14 which is crystalline.

17. 15. The salt of claim 14 which is substantially isolated.

18. 15. The salt of claim 14, characterized by a DSC curve having an endothermic peak at about 289.4°C.

19. 15. The salt of claim 14, having a DSC curve substantially as shown in FIG.

20. 15. The salt of claim 14, having a TGA curve substantially as shown in FIG.

21. 15. The salt of claim 14 having at least one XRPD peak selected from about 5.3°, about 8.5°, about 15.3°, about 20.1°, and about 24.9° in terms of 2θ.

22. 15. The salt of claim 14 having at least two XRPD peaks selected from about 5.3°, about 8.5°, about 15.3°, about 20.1°, and about 24.9° in terms of 2θ.

23. 15. The salt of claim 14 having at least three XRPD peaks selected from about 5.3°, about 8.5°, about 15.3°, about 20.1°, and about 24.9° in terms of 2θ.

24. 15. The salt of claim 14 having at least four XRPD peaks, expressed in terms of 2θ, selected from about 5.3°, about 8.5°, about 15.3°, about 20.1°, and about 24.9°.

25. 15. The salt of claim 14, having the following XRPD peaks, expressed in terms of 2θ: about 5.3°, about 8.5°, about 15.3°, about 20.1°, and about 24.9°.

26. 15. The salt of claim 14, having an XRPD profile substantially as shown in FIG.

27. 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide phosphate, 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide maleate, 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide hydrochloride, 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide salicylate, 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide methanesulfonate, and 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide ethanesulfonate A salt selected from:

28. A pharmaceutical composition comprising the salt of any one of claims 1 to 27 and a pharma- ceutically acceptable carrier.

29. A method of inhibiting a TAM kinase, the method comprising contacting the TAM kinase with a salt according to any one of claims 1 to 27.

30. A method for inhibiting AXL and MER kinases, said method comprising contacting said AXL and MER kinases with a salt according to any one of claims 1 to 27.

31. A method of treating cancer in a patient, said method comprising administering to said patient a therapeutically effective amount of a salt according to any one of claims 1 to 27.

32. 32. The method of claim 31, 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.

33. 32. The method of claim 31, wherein the cancer is lung cancer, prostate cancer, colon cancer, breast cancer, melanoma, renal cell carcinoma, multiple myeloma, gastric cancer, or rhabdomyosarcoma.

34. A method for preparing the salt of claim 1, comprising the step of: 【Chemistry 1】 with maleic acid to form said salt.

35. 35. The method of claim 34, wherein about 1 equivalent of maleic acid is used based on 1 equivalent of the compound of formula I.

36. 35. The process of claim 34, wherein reacting the compound of formula I with maleic acid is carried out in the presence of a solvent component.

37. The process of claim 36 , wherein the solvent component comprises methanol.

38. The process of claim 36 , wherein the solvent component comprises dichloromethane.

39. 37. The process of claim 36, wherein the solvent component comprises methanol and dichloromethane.

40. 40. The process of claim 39, further comprising removing a substantial portion of the dichloromethane to precipitate the salt.

41. 37. The process of claim 36, further comprising forming a solution of the compound of formula I in a solvent component prior to said reacting.

42. 42. The process of claim 41, wherein the solution is formed by heating a slurry of the compound of Formula I in the solvent component to a temperature of about 45°C to about 55°C.

43. 43. The method of claim 42, further comprising agitating the solution and filtering the solution to form a filtrate prior to reacting the compound of formula I with maleic acid.

44. 44. The method of claim 43, further comprising adding activated carbon and silica gel to the solution after the step of heating the slurry to a temperature of about 45° C. to about 55° C. to form a solution and before the step of agitating the solution.

45. A method for preparing the salt of claim 14, comprising the step of: 【Chemistry 2】 with sulfuric acid to form said salt.

46. 46. ​​The method of claim 45, wherein about 0.6 equivalents of sulfuric acid are used based on 1 equivalent of the compound of formula II.

47. adding a compound of formula II to a solvent component to form a solution; adding sulfuric acid to the solution at room temperature; concentrating the solution to form a slurry; stirring the slurry at a temperature of about 60° C. to about 70° C.; cooling the slurry to a temperature of about 15° C. to about 25° C. to precipitate the salt; The method of claim 45 or 46, comprising:

48. 48. The process of claim 47, wherein the solvent component comprises methanol.

49. 48. The method of claim 47, wherein the solvent component comprises dichloromethane.

50. 48. The process of claim 47, wherein the solvent component comprises methanol and dichloromethane.

51. 48. The method of claim 47, wherein the sulfuric acid is about 1 M in water.

52. 46. ​​The process of claim 45, comprising producing 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide sulfate.

53. 53. The process of claim 52, wherein the process for preparing the salt 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide sulfate comprises reacting a compound of formula II with about 1 equivalent of sulfuric acid based on 1 equivalent of the compound of formula II.

54. The method for producing 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide sulfate comprises: adding a compound of formula II to a first solvent component at room temperature to form a solution; heating the solution to a temperature of 50° C. to 60° C.; adding sulfuric acid to the solution; removing the solvent to precipitate the sulfate salt; 54. The method of claim 52 or 53, comprising:

55. 55. The process of claim 54, wherein the first solvent comprises methanol.

56. 55. The method of claim 54, wherein the sulfuric acid is added as an aqueous solution.

57. adding the 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide sulfate to a second solvent component to form a slurry; heating the slurry to a temperature of about 30° C. to about 40° C.; agitating the slurry; collecting the hemisulfate produced; The method of claim 52 or 53, further comprising:

58. 58. The method of claim 57, wherein the second solvent component comprises water.

59. Producing an amorphous form of the hemisulfate salt, comprising: adding the hemisulfate salt to a third solvent component at room temperature to form a solution; filtering the solution; concentrating the filtrate; drying the resulting solid to produce the amorphous hemisulfate salt; 58. The method of claim 57, further comprising producing the hemisulfate salt comprising:

60. 60. The method of claim 59, wherein the third solvent component comprises acetone and methanol.

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