EA041099B1 - SALTS OF PYRROLOTRIAZINE DERIVATIVES SUITABLE FOR USE AS TAM INHIBITORS - Google Patents

Description

Technical field

This disclosure provides the salt forms of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4yl)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-isobutyrylpiperidine-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, which will be useful as inhibitors of TAM kinases, as well as methods and intermediates related to them.

State of the art

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

The TAM subfamily consists of three RTKs including Tyro3, AXL and Mer ( HYPERLINK\l _ENREF_6\o Graham, 2014 #2585 Graham et al., 2014, Nature Reviews Cancer 14, 769-785; HYPERLINK \l _ENREF_13\o Linger, 2008 #2679 Linger et al., 2008, Advances in Cancer Research 100, 35-83). TAMkinases are characterized by an extracellular ligand-binding domain consisting of two immunoglobulin-like domains and two fibronectin type III domains. Two growth blocking 6 (GAS6) and protein S (PROS1) ligands have been identified for TAM kinases. GAS6 can bind to and activate all three TAM kinases, while PROS1 is a ligand for Mer and Tyro3 (Graham et al., 2014, Nature Reviews Cancer 14, 769-785).

AXL (also known as UFO, ARK, JTK11 and TYRO7) was originally identified as a transforming gene from the DNA of patients with chronic myelogenous leukemia (HYPERLINK\l_ENREF_16\o O'Bryan, 1991 #2856 O'Bryan et al., 1991, Mol Cell Biol 11, 5016-5031; HYPERLINK \l _ENREF_6 \o Graham, 2014 #2585 Graham et al., 2014, Nature Reviews Cancer 14, 769-785; HYPERLINK \l _ENREF_13 \o Linger, 2008 #2679 Linger et al. , 2008, Advances in Cancer Research 100, 35-83). GAS6 binds to AXL and induces subsequent autophosphorylation and activation of AXL tyrosine kinase. AXL activates several downstream signaling pathways including PI3K-Akt, Raf-MAPK, PLCPKC (Feneyrolles et al., 2014, Molecular Cancer Therapeutics 13, 2141-2148; HYPERLINK \l _ENREF_13 \o Linger, 2008 #2679 Linger et al., 2008, Advances in Cancer Research 100, 35-83).

MER (also known as MERTK, EYK, RYK, RP38, NYK, and TYRO12) was originally identified as a phosphoprotein from the lymphoblast expression library (Graham et al., 1995, Oncogene 10, 2349-2359; HYPERLINK\l _ENREF_6 \o Graham , 2014 #2585 Graham et al., 2014, Nature Reviews Cancer 14, 769-785; Both GAS6 and PROS1 can bind Mer and induce Mer kinase phosphorylation and activation (HYPERLINK \l _ENREF_10 \o Lew, 2014 #2592 Lew et al., 2014). Like AXL, MER activation also signals downstream signaling pathways, including PI3K-Akt and Raf-MAPK (HYPERLINK\l ENREF13\o Linger, 2008 #2679 Linger et al., 2008, Advances in Cancer Research 100, 35-83) .

TYRO3 (also known as DTK, SKY, RSE, BRT, TIF, ETK2) was originally identified in a NRP-based cloning study (HYPERLINK \l _ENREF_8 \o Lai, 1991 #3042 Lai et al., Neuron 6, 691-70, 1991; HYPERLINK \l _ENREF_6 \o Graham, 2014 #2585 Graham et al., 2014, Nature Reviews Cancer 14, 769-785; Linger et al., 2008, Advances in Cancer Research 100, 35-83). Both GAS6 and PROS1 ligands can bind to and activate TYRO3. Although the signaling pathways downstream of TYRO3 activation are the least understood among TAM RTKs, both 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.

Accordingly, there is a need for compounds and methods of using them to modulate TAM kinases in the treatment of cancer.

The essence of the invention

This application provides salts of a compound of formula I

which will be useful as a TAM inhibitor.

The present application further provides a maleic acid salt of a compound of formula I.

The present application further provides methods for preparing salts of a compound of formula I.

The present application provides salts of a compound of formula II:

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II which will be useful as a TAM inhibitor.

The present application further provides a hemisulphate salt of sulfuric acid of a compound of formula II.

The present application further provides a phosphoric acid salt of the compound of formula II.

The present application further provides a maleic acid salt of the compound of formula II.

The present application further provides a hydrochloric acid salt of the compound of formula II.

The present application further provides a salicylic acid salt of the compound of formula II.

The present application further provides a methanesulfonic acid salt (ie, mesylate) of a compound of formula II.

The present application further provides an ethanesulfonic acid salt (ie, esylate) of a compound of formula II.

The present application further provides methods for preparing salts of a compound of formula II.

This application further provides pharmaceutical compositions containing any of the salts of the compounds of formulas I and II.

The present application also provides methods for inhibiting TAM kinases, which methods include contacting the TAM kinases with any of the salts of the compounds of formulas I and II.

The present application also provides methods for inhibiting AXL and MER kinases, which methods include contacting the AXL or MER kinase with any of the salts of the compounds of formulas I and II.

The present application also provides methods for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of any of the salts of the compounds of formulas I and II.

Description of graphic materials

In FIG. 1 shows an X-ray powder diffraction pattern illustrative of the maleic acid salt of Compound I, Form I.

In FIG. 2 shows a DSC thermogram illustrative of the maleic acid salt of Compound I, Form I.

In FIG. 3 shows TGA data illustrative of the maleic acid salt of Compound I, Form I.

In FIG. 4 shows an X-ray powder diffraction pattern illustrative of the phosphoric acid salt of compound II.

In FIG. 5 shows a DSC thermogram illustrative of the phosphoric acid salt of compound II.

In FIG. 6 shows TGA data illustrative of the phosphoric acid salt of compound II.

In FIG. 7 shows an X-ray powder diffraction pattern illustrative of the maleic acid salt of compound II.

In FIG. 8 shows a DSC thermogram illustrative of the maleic acid salt of compound II.

In FIG. 9 shows TGA data illustrative of the maleic acid salt of compound II.

In FIG. 10 shows an X-ray powder diffraction pattern illustrative of the hemisulphate salt of sulfuric acid compound II.

In FIG. 11 shows a DSC thermogram illustrative of the hemisulphate salt of sulfuric acid compound II.

In FIG. 12 shows TGA data illustrative of the hemisulphate salt of sulfuric acid compound II.

In FIG. 13 shows an X-ray powder diffraction pattern illustrative of the hydrochloric acid salt of compound II.

- 2 041099

In FIG. 14 shows a DSC thermogram illustrative of the hydrochloric acid salt of compound II.

In FIG. 15 shows TGA data illustrative of the hydrochloric acid salt of compound II.

In FIG. 16 shows an X-ray powder diffraction pattern illustrative of the salicylic acid salt of Compound II.

In FIG. 17 shows a DSC thermogram illustrative of the salicylic acid salt of Compound II.

In FIG. 18 shows TGA data illustrative of the salicylic acid salt of Compound II.

In FIG. 19 shows an X-ray powder diffraction pattern illustrative of the methanesulfonic acid salt of compound II.

In FIG. 20 shows a DSC thermogram illustrative of the methanesulfonic acid salt of compound II.

In FIG. 21 shows TGA data illustrative of the methanesulfonic acid salt of compound II.

In FIG. 22 shows an X-ray powder diffraction pattern illustrative of the ethanesulfonic acid salt of compound II.

In FIG. 23 shows a DSC thermogram illustrative of the ethanesulfonic acid salt of compound II.

In FIG. 24 shows TGA data illustrative of the ethanesulfonic acid salt of compound II.

In FIG. 25 shows an X-ray powder diffraction pattern illustrative of the maleic acid salt of Compound I, Form II.

In FIG. 26 shows an X-ray powder diffraction pattern illustrative of the maleic acid salt of Compound I, Form III.

In FIG. 27 shows a DSC thermogram illustrative of the maleic acid salt of Compound I, Form III.

In FIG. 28 shows TGA data illustrative of the maleic acid salt of Compound I, Form III.

In FIG. 29 shows an X-ray powder diffraction pattern illustrative of the maleic acid salt of Compound I, Form IV.

In FIG. 30 shows a DSC thermogram illustrative of the maleic acid salt of Compound I, Form IV.

In FIG. 31 shows TGA data illustrative of the maleic acid salt of Compound I, Form IV.

In FIG. 32 shows an X-ray powder diffraction pattern illustrative of the maleic acid salt of Compound I, Form V.

In FIG. 33 shows a DSC thermogram illustrative of the maleic acid salt of Compound I, Form V.

In FIG. 34 shows TGA data illustrative of the maleic acid salt of Compound I, Form V.

Detailed description

Compounds and salts

This application provides salts of a compound of formula I:

I or their pharmaceutically acceptable hydrates and solvates, which will be useful as TAM inhibitors.

Accordingly, in some embodiments, the present application provides the maleic acid 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-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (herein also referred to as the maleate of the compound of formula I, the maleate of compound I or any variation thereof).

In some embodiments, the salt is a 1:1 stoichiometric ratio of K-(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.

Different forms of the same substance have different bulk properties, such as hygroscopicity, solubility, stability, and the like. Formulations with high melting points often have good thermodynamic stability, which is an advantage for extending the shelf life of solid form drug formulations. Forms with lower melting points are often less thermodynamically stable but have the advantage of increased water solubility, equivalent to increased drug bioavailability. Forms that are weakly hygroscopic are desirable due to their resistance to heat and moisture, and such forms are resistant to degradation during long-term storage.

The solid forms (eg, crystalline forms) described herein may have certain advantages, for example, they may have desirable properties such as ease of handling, ease of processing, storage stability, and ease of purification. Moreover, crystalline forms may be useful for improving pharmaceutical product performance such as dissolution profile, shelf life and bioavailability.

In some embodiments, the maleic acid salt of a compound of Formula I provided herein is crystalline.

As used herein, the term crystalline or crystalline form is intended to refer to a particular lattice configuration of a crystalline substance. Different crystalline forms of the same substance, as a rule, have different crystal lattices (for example, single cells), which are associated with different physical properties characteristic of each crystalline form. In some cases, different lattice configurations have different water or solvent content.

Various salt forms can be identified using solid state characterization techniques such as X-ray powder diffraction (XRPD). Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), etc. additionally help to identify the form, and also help to determine the stability and solvent/water content.

The powder X-ray diffraction pattern of reflections (peaks) is usually considered to be an imprint of a certain crystalline form. It is well known that the relative intensities of the XRPD peaks can vary greatly depending on, among other things, sample preparation technology, crystal size distribution, different filters used, sample loading procedure and the specific instrument used. In some cases, depending on the type of instrument or settings, new peaks may appear or existing ones may disappear. As used herein, the term peak refers to a reflection having a relative height/intensity of at least 4% of the maximum height/intensity. Furthermore, 2-theta: values can be affected by instrument type and other factors. Thus, peak designations such as those reported herein may vary within plus or minus 0.2° (2-theta:), and the terms essentially and about in the context of XRPD herein cover the above variations.

Likewise, temperatures in connection with DSC, TGA, or other thermal experiments may vary by about ±3°C depending on instrument, particular settings, sample preparation, etc. Accordingly, the crystal form shown herein, which is has a DSC thermogram essentially as shown in any of the figures, or the term about should be understood to include such variations.

In some embodiments, the salts and compounds described herein (eg, a compound of Formula I or a maleic acid salt of a compound of Formula I) are substantially isolated. Essentially isolated means that the salt or compound is at least partially or substantially separated from the environment in which it was formed or found. Partial separation may include, for example, a composition that contains a large amount of the salts described herein. Substantial separation may include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95% , at least about 97% or at least about 99% by weight of the salts described herein, or a salt thereof. Methods for isolating compounds and their salts are standard in the art.

The maleic acid salt of the compound of formula I can be obtained in various crystalline forms, including, for example, Form I, Form II, Form III, Form IV, or Form V.

Maleic acid salt of a compound of formula I, Form I:

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Provided herein are embodiments of (i)-(x) the crystalline form of Compound I of Formula I, referred to as Form I, as described in Examples 1 and 7 below.

(i) In some embodiments, the maleic acid salt of a compound of Formula I has at least one XRPD peak at 2-θ values selected from about 4.3°, about 8.4°, about 12.6°, about 13.2 ° and about 18.5°.

(ii) In some embodiments, the maleic acid salt of the compound of Formula I has at least two XRPD peaks at 2-θ values selected from about 4.3°, about 8.4°, about 12.6°, about 13.2 ° and about 18.5°.

(iii) In some embodiments, the maleic acid salt of the compound of Formula I has at least three XRPD peaks at 2-θ values selected from about 4.3°, about 8.4°, about 12.6°, about 13.2 ° and about 18.5°.

(iv) In some embodiments, the maleic acid salt of the compound of Formula I has at least four XRPD peaks at 2-θ values selected from about 4.3°, about 8.4°, about 12.6°, about 13.2 ° and about 18.5°.

(v) In some embodiments, the maleic acid salt of the compound of formula I contains the following XRPD peaks at 2-θ values: about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18, 5°.

(vi) In some embodiments, the maleic acid salt of the compound of formula I contains the following XRPD peaks at 2-θ values: about 4.3°, about 8.4°, and about 13.2°.

(vii) In some embodiments, the maleic acid salt of the compound of formula I has an XRPD profile substantially corresponding to that shown in FIG. 1.

(viii) In some embodiments, the implementation of the maleic acid salt of the compounds of formula I has a DSC thermogram having an endometrial peak at about 211°C.

(ix) In some embodiments, the maleic acid salt of the compound of formula I has a DSC thermogram substantially corresponding to that shown in FIG. 2.

(x) In some embodiments, the maleic acid salt of the compound of formula I has a TGA thermogram substantially corresponding to that shown in FIG. 3.

Maleic acid salt of the compound of formula I, form II:

Provided herein is a crystalline form of Compound I, referred to as Form II, which is described in Examples 16 and 17 below.

In some embodiments, Form II of the maleic acid salt of the compound of Formula I has at least one XRPD peak at 2θ values selected from about 3.8°, about 7.8°, about 23.5°, and about 26.0°.

In some embodiments, Form II of the maleic acid salt of the compound of Formula I has at least two XRPD peaks at 2-θ values selected from about 3.8°, about 7.8°, about 23.5°, and about 26.0° .

In some embodiments, Form II of the maleic acid salt of the compound of Formula I has at least three XRPD peaks at 2-θ values selected from about 3.8°, about 7.8°, about 23.5°, and about 26.0° .

In some embodiments, Form II of the maleic acid salt of the compound of formula I contains the following XRPD peaks at 2-θ values: about 3.8°, about 7.8°, about 23.5°, and about 26.0°.

In some embodiments, Form II of the maleic acid salt of the compound of Formula I contains the following XRPD peaks at 2-θ values: about 3.8°, about 7.8°, and about 23.5°.

In some embodiments, Form II of the maleic acid salt of the compound of Formula I has an XRPD profile substantially as shown in FIG. 25.

Maleic acid 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 in Examples 16 and 18 below.

In some embodiments, Form III of the maleic acid salt of the compound of Formula I has at least one XRPD peak at 2-θ values selected from about 3.8°, about 7.7°, about 12.1°, about 18.9° and about 20.6°.

In some embodiments, Form III of the maleic acid salt of the compound of Formula I has at least two XRPD peaks at 2-θ values selected from about 3.8°, about 7.7°, about 12.1°, about 18.9° and about 20.6°.

In some embodiments, Form III of the maleic acid salt of the compound of Formula I has at least three XRPD peaks at 2-θ values selected from about 3.8°, about 7.7°, about 12.1°, about 18.9° and about 20.6°.

In some embodiments, Form III of the maleic acid salt of the compound of Formula I has at least four XRPD peaks at 2-θ values selected from about 3.8°, about 7.7°, about 12.1°, about 18.9° and about 20.6°.

- 5 041099

In some embodiments, Form III of the maleic acid salt of a compound of Formula I contains the following XRPD peaks at 2-θ values: 3.8°, about 7.7°, about 12.1°, about 18.9°, and about

20.6°.

In some embodiments, Form III of the maleic acid salt of the compound of Formula I contains the following XRPD peaks at 2-θ values: about 3.8°, about 7.7°, about 12.1°, and about 18.9°.

In some embodiments, Form III of the maleic acid salt of the compound of Formula I has an XRPD profile substantially as shown in FIG. 26.

In some embodiments, Form III of the maleic acid salt of the compound of Formula I has a DSC thermogram having endometrial peaks at about 165.4°C and about 195.4°C. In some embodiments, Form III of the maleic acid salt of the compound of Formula I has a DSC thermogram having an endometrial peak at about 165.4°C. In some embodiments, Form III of the maleic acid salt of the compound of Formula I has a DSC thermogram having an endometrial peak at about 195.4°C.

In some embodiments, Form III of the maleic acid salt of the compound of Formula I has a DSC thermogram substantially corresponding to that shown in FIG. 27.

In some embodiments, Form III of the maleic acid salt of the compound of Formula I has a TGA thermogram substantially corresponding to that shown in FIG. 28.

Maleic acid salt of the compound of formula I, form IV:

Provided herein is a crystalline form of Compound I, referred to as Form IV, which is described in Examples 16 and 19 below.

In some embodiments, Form IV of the maleic acid salt of the compound of Formula I has at least one XRPD peak at 2-θ values selected from about 3.9°, about 4.6°, about 7.8°, about 9.1° and about 22.8°.

In some embodiments, Form IV of the maleic acid salt of the compound of Formula I has at least two XRPD peaks at 2-θ values selected from about 3.9°, about 4.6°, about 7.8°, about 9.1° and about 22.8°.

In some embodiments, Form IV of the maleic acid salt of the compound of Formula I has at least three XRPD peaks at 2-θ values selected from about 3.9°, about 4.6°, about 7.8°, about 9.1° and about 22.8°.

In some embodiments, Form IV of the maleic acid salt of the compound of Formula I has at least four XRPD peaks at 2-θ values selected from about 3.9°, about 4.6°, about 7.8°, about 9.1° and about 22.8°.

In some embodiments, Form IV of the maleic acid salt of the compound of Formula I contains the following XRPD peaks at 2-θ values: about 3.9°, about 4.6°, about 7.8°, about 9.1°, and about 22.8 °.

In some embodiments, Form IV of the maleic acid salt of the compound of Formula I contains the following XRPD peaks at 2-θ values: about 3.9°, about 4.6°, about 7.8°, and about 9.1°.

In some embodiments, Form IV of the maleic acid salt of the compound of Formula I has an XRPD profile substantially as shown in FIG. 29.

In some embodiments, Form IV of the maleic acid salt of the compound of Formula I has a DSC thermogram having endometrial peaks at about 152.1 and 202.6°C. In some embodiments, Form IV of the maleic acid salt of the compound of Formula I has a DSC thermogram having an endometrial peak at about 152.1°C. In some embodiments, Form IV of the maleic acid salt of the compound of Formula I has a DSC thermogram having an endometrial peak at about 202.6°C.

In some embodiments, Form IV of the maleic acid salt of the compound of Formula I has a DSC thermogram substantially corresponding to that shown in FIG. thirty.

In some embodiments, Form IV of the maleic acid salt of the compound of formula I has a TGA thermogram substantially corresponding to that shown in FIG. 31.

Maleic acid salt of a compound of formula I, Form V:

Provided herein is a crystalline form of Compound I, referred to as Form V, which is described in Examples 16 and 20 below.

In some embodiments, Form V of the maleic acid salt of the compound of Formula I has at least one XRPD peak at 2-θ values selected from about 4.1°, about 8.3°, about 8.8°, about 18.0° and about 27.3°.

In some embodiments, the maleic acid salt form V of the compound of formula I has at least two XRPD peaks at 2-θ values selected from about 4.1°, about 8.3°, about 8.8°, about 18.0° and about 27.3°.

In some embodiments, Form V of the maleic acid salt of the compound of Formula I has at least three XRPD peaks at 2-θ values selected from about 4.1°, about 8.3°, about

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8.8°, about 18.0° and about 27.3°.

In some embodiments, the maleic acid salt Form V of the compound of Formula I has at least four XRPD peaks at 2-θ values selected from about 4.1°, about 8.3°, about 8.8°, about 18.0° and about 27.3°.

In some embodiments, Form V of the maleic acid salt of a compound of formula I contains the following XRPD peaks at 2-θ values: about 4.1°, about 8.3°, about 8.8°, about 18.0°, and about 27.3 °.

In some embodiments, Form V of the maleic acid salt of the compound of Formula I contains the following XRPD peaks at 2-θ values: about 4.1°, about 8.3°, about 8.8°, and about 27.3°.

In some embodiments, the Form V maleic acid salt of the compound of Formula I has an XRPD profile substantially as shown in FIG. 32.

In some embodiments, Form V of the maleic acid salt of the compound of Formula I has a DSC thermogram having an endometrial peak at about 200.1°C.

In some embodiments, Form V of the maleic acid salt of the compound of Formula I has a DSC thermogram substantially corresponding to that shown in FIG. 33.

In some embodiments, Form V of the maleic acid salt of the compound of Formula I has a TGA thermogram substantially corresponding to that shown in FIG. 34.

The present application also provides salts of the compound of formula II

II or their pharmaceutically acceptable hydrates and solvates, which will be useful as TAM inhibitors.

Accordingly, in some embodiments, the present application provides a salt selected from N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,21][1,2,4] phosphoric acid salt triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide; maleic acid salts N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,21][1,2,4]triazin-5-yl)phenyl)-1-isopropyl- 2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide; hemisulfate salt of sulfuric acid N-(4-(4-amino-7-(1-isobutyrylpiperidin-4yl)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; hydrochloric acid salts N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,21][1,2,4]triazin-5-yl)phenyl)-1-isopropyl- 2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide; salts of salicylic acid N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,21][1,2,4]triazin-5-yl)phenyl)-1-isopropyl- 2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide; methanesulfonic acid salts N-(4-(4-amino-7-(1-isobutyrylpiperidin-4yl)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 and ethanesulfonic acid salts N-(4-(4-amino-7-(1-isobutyrylpiperidin-4yl)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, or its pharmaceutically acceptable solvates and hydrates.

In some embodiments, the present application provides a phosphoric acid salt N(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl )phenyl)-1-isopropyl-2,4dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (herein also referred to as the phosphate salt of the compound of formula II, the phosphate salt of compound II, or any variation thereof) .

In some embodiments, the salt is a 1:1 stoichiometric ratio of N-(4-(4-αmino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazine- 5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide to phosphoric acid.

In some embodiments, the implementation of the salt of phosphoric acid of the compounds of formula II is crystalline.

In some embodiments, the phosphoric acid salt of the compound of formula II is substantially isolated.

In some embodiments, the phosphoric acid salt of the compound of Formula II has at least one XRPD peak at 2-theta values selected from about 5.3°, about 9.1°, about 14.9°,

- 7 041099 about 15.8° and about 19.3°. In some embodiments, the phosphoric acid salt of the compound of Formula II has at least two XRPD peaks at 2-theta values selected from about 5.3°, about 9.1°, about 14.9°, about 15.8°, and about 19.3°. In some embodiments, the phosphoric acid salt of the compound of Formula II has at least three XRPD peaks at 2-theta values selected from about 5.3°, about 9.1°, about 14.9°, about 15.8°, and about 19.3°. In some embodiments, the phosphoric acid salt of the compound of Formula II has at least four XRPD peaks at 2-theta values selected from about 5.3°, about 9.1°, about 14.9°, about 15.8°, and about 19.3°. In some embodiments, the phosphoric acid salt of the compound of formula II contains the following XRPD peaks at 2-theta values: 5.3°, about 9.1°, about 14.9°, about 15.8°, and about 19.3°.

In some embodiments, the phosphoric acid salt of the compound of formula II has an XRPD profile substantially corresponding to that shown in FIG. 4.

In some embodiments, the implementation of the salt of phosphoric acid of the compounds of formula II has a DSC thermogram having an endometrial peak at about 257.2°C.

In some embodiments, the phosphoric acid salt of the compound of formula II has a DSC thermogram substantially corresponding to that shown in FIG. 5. In some embodiments, the phosphoric acid salt of the compound of formula II has a TGA thermogram substantially corresponding to that shown in FIG. 6.

In some embodiments, the present application provides the maleic acid salt N(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl )phenyl)-1-isopropyl-2,4dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (herein also referred to as the compound of formula II maleate, compound II maleate, or any variation thereof).

In some embodiments, the salt is 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide to maleic acid.

In some embodiments, the maleic acid salt of the compound of Formula II is crystalline.

In some embodiments, the maleic acid salt of the compound of Formula II is substantially isolated.

In some embodiments, the maleic acid salt of the compound of Formula II has at least one XRPD peak at 2-θ values selected from about 4.5°, about 6.5°, about 14.1°, about 24.0°, and about 28.2°. In some embodiments, the maleic acid salt of the compound of formula II has at least two XRPD peaks at 2-theta values selected from about 4.5°, about 6.5°, about 14.1°, about 24.0°, and about 28.2°. In some embodiments, the maleic acid salt of the compound of formula II has at least three XRPD peaks at 2-θ values selected from about 4.5°, about 6.5°, about 14.1°, about 24.0°, and about 28.2°. In some embodiments, the maleic acid salt of the compound of Formula II has at least four XRPD peaks at 2-θ values selected from about 4.5°, about 6.5°, about 14.1°, about 24.0°, and about 28.2°. In some embodiments, the maleic acid salt of the compound of formula II contains the following XRPD peaks at 2-θ values: about 4.5°, about 6.5°, about 14.1°, about 24.0°, and about 28.2°.

In some embodiments, the maleic acid salt of the compound of formula II has an XRPD profile substantially as shown in FIG. 7.

In some embodiments, the maleic acid salt of the compound of formula II has a DSC thermogram having an endometrial peak at about 194.8°C and/or about 239.7°C. In some embodiments, the maleic acid salt of the compound of formula II has a DSC thermogram substantially corresponding to that shown in FIG. 8. In some embodiments, the maleic acid salt of the compound of formula II has a TGA thermogram substantially corresponding to that shown in FIG. 9.

In some embodiments, the present application provides a sulfuric acid salt of N-(4(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl )phenyl)-1-isopropyl-2,4dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (herein also referred to as Compound II hemisulfate, Compound II hemisulfate, or any variation thereof).

In some embodiments, the salt is a 1:0.5 (i.e., 2:1) 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide to sulfuric acid.

In some embodiments, the implementation of the hemisulfate salt of sulfuric acid of the compounds of formula II is crystalline.

In some embodiments, the hemisulphate salt of sulfuric acid of the compound of formula II is substantially isolated.

In some embodiments, the hemisulphate salt of sulfuric acid of the compound of formula II has at least one XRPD peak at 2-theta values selected from about 5.3°, about 8.5°,

- 8 041099 about 15.3°, about 20.1° and about 24.9°. In some embodiments, the hemisulphate salt of sulfuric acid of a compound of formula II has at least two XRPD peaks at 2-θ values selected from about 5.3°, about 8.5°, about 15.3°, about 20.1°, and about 24.9°. In some embodiments, the hemisulphate salt of sulfuric acid of a compound of Formula II has at least three XRPD peaks at 2-θ values selected from about 5.3°, about 8.5°, about 15.3°, about 20.1°, and about 24.9°. In some embodiments, the hemisulphate salt of sulfuric acid of the compound of Formula II has at least four XRPD peaks at 2-θ values selected from about 5.3°, about 8.5°, about 15.3°, about 20.1°, and about 24.9°. In some embodiments, the hemisulphate salt of sulfuric acid of a compound of Formula II contains the following XRPD peaks at 2-θ values: about 5.3°, about 8.5°, about 15.3°, about 20.1°, and about 24.9° .

In some embodiments, the hemisulphate salt of sulfuric acid of the compound of formula II has an XRPD profile substantially as shown in FIG. 10.

In some embodiments, the hemisulphate salt of sulfuric acid of the compound of formula II has a DSC thermogram having an endometrial peak at about 289.4°C. In some embodiments, the hemisulphate salt of sulfuric acid of the compound of formula II has a DSC thermogram substantially corresponding to that shown in FIG. 11. In some embodiments, the hemisulphate salt of sulfuric acid of the compound of formula II has a TGA thermogram substantially corresponding to that shown in FIG. 12.

In some embodiments, the present application provides the hydrochloric acid salt N-(4(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl )phenyl)-1-isopropyl-2,4dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (herein also referred to as the hydrochloric acid salt of the compound of formula II, the hydrochloric acid salt of compound II, or any of its variation).

In some embodiments, the salt is 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide to hydrochloric acid.

In some embodiments, the hydrochloric acid salt of the compound of Formula II is crystalline.

In some embodiments, the hydrochloric acid salt of a compound of Formula II is substantially isolated.

In some embodiments, the hydrochloric acid salt of a compound of Formula II has at least one XRPD peak at 2-θ values selected from about 6.5°, about 9.7°, about 14.9°, about 21.5°, and about 23.9°. In some embodiments, the hydrochloric acid salt of a compound of formula II has at least two XRPD peaks at 2-θ values selected from about 6.5°, about 9.7°, about 14.9°, about 21.5°, and about 23.9°. In some embodiments, the hydrochloric acid salt of the compound of Formula II has at least three XRPD peaks at 2-θ values selected from about 6.5°, about 9.7°, about 14.9°, about 21.5°, and about 23.9°. In some embodiments, the hydrochloric acid salt of the compound of Formula II has at least four XRPD peaks at 2-θ values selected from about 6.5°, about 9.7°, about 14.9°, about 21.5°, and about 23.9°. In some embodiments, the hydrochloric acid salt of the compound of formula II contains the following XRPD peaks at 2-theta values: about 6.5°, about 9.7°, about 14.9°, about 21.5°, and about 23.9°.

In some embodiments, the hydrochloric acid salt of the compound of formula II has an XRPD profile substantially corresponding to that shown in FIG. 13.

In some embodiments, the hydrochloric acid salt of the compound of formula II has a DSC thermogram having an endometrial peak at about 190°C. In some embodiments, the hydrochloric acid salt of the compound of formula II has a DSC thermogram substantially corresponding to that shown in FIG. 14. In some embodiments, the hydrochloric acid salt of the compound of formula II has a TGA thermogram substantially corresponding to that shown in FIG. 15.

In some embodiments, the present application provides a salicylic acid salt N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazine-5 - yl)phenyl)-1-isopropyl 2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (herein also referred to as Compound II Salicylate, Compound II Salicylate, or any variation thereof).

In some embodiments, the salt is 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-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide to salicylic acid.

In some embodiments, the implementation of the salicylic acid salt of the compounds of formula II is crystalline.

In some embodiments, the salicylic acid salt of the compound of Formula II is substantially isolated.

- 9 041099

In some embodiments, the salicylic acid salt of the compound of Formula II has at least one XRPD peak at 2-θ values selected from about 7.3°, about 14.4°, about 15.7°, about 19.9°, and about 21.9°. In some embodiments, the salicylic acid salt of the compound of Formula II has at least two XRPD peaks at 2-θ values selected from about 7.3°, about 14.4°, about 15.7°, about 19.9°, and about 21.9°. In some embodiments, the salicylic acid salt of the compound of Formula II has at least three XRPD peaks at 2-θ values selected from about 7.3°, about 14.4°, about 15.7°, about 19.9°, and about 21.9°. In some embodiments, the salicylic acid salt of the compound of formula II has at least four XRPD peaks at 2-θ values selected from about 7.3°, about 14.4°, about 15.7°, about 19.9°, and about 21.9°. In some embodiments, the salicylic acid salt of the compound of formula II contains the following XRPD peaks at 2-θ values: about 7.3°, about 14.4°, about 15.7°, about 19.9°, and about 21.9°.

In some embodiments, the salicylic acid salt of the compound of formula II has an XRPD profile substantially corresponding to that shown in FIG. 16.

In some embodiments, the salicylic acid salt of the compound of formula II has a DSC thermogram having an endometrial peak at about 181.7°C, about 224.9°C, and/or 264.5°C. In some embodiments, the salicylic acid salt of the compound of formula II has a DSC thermogram substantially corresponding to that shown in FIG. 17. In some embodiments, the salicylic acid salt of the compound of formula II has a TGA thermogram substantially corresponding to that shown in FIG. 18.

In some embodiments, the present application provides a methanesulfonic acid salt of K-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazine-5 - yl)phenyl)-1isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (herein also referred to as formula II compound mesylate, compound II mesylate, or any variation thereof) .

In some embodiments, the salt is a 1:1 stoichiometric ratio of K-(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.

In some embodiments, the methanesulfonic acid salt of the compound of formula II is crystalline.

In some embodiments, the methanesulfonic acid salt of the compound of Formula II is substantially isolated.

In some embodiments, the methanesulfonic acid salt of the compound of Formula II has at least one XRPD peak at 2-θ values selected from about 5.0°, about 8.2°, about 13.2°, and about 16.9°. In some embodiments, the methanesulfonic acid salt of the compound of formula II has at least two XRPD peaks at 2-θ values selected from about 5.0°, about 8.2°, about 13.2°, and about 16.9°. In some embodiments, the methanesulfonic acid salt of the compound of Formula II has at least three XRPD peaks at 2-θ values selected from about 5.0°, about 8.2°, about 13.2°, and about 16.9°. In some embodiments, the methanesulfonic acid salt of the compound of formula II contains the following XRPD peaks at 2-θ values: about 5.0°, about 8.2°, about 13.2°, and about 16.9°.

In some embodiments, the methanesulfonic acid salt of the compound of formula II has an XRPD profile substantially as shown in FIG. 19.

In some embodiments, the methanesulfonic acid salt of the compound of Formula II has a DSC thermogram having an endometrial peak at about 174.8°C. In some embodiments, the methanesulfonic acid salt of the compound of formula II has a DSC thermogram substantially corresponding to that shown in FIG. 20. In some embodiments, the methanesulfonic acid salt of the compound of formula II has a TGA thermogram substantially corresponding to that shown in FIG. 21.

In some embodiments, the present application provides an ethanesulfonic acid salt of K-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazine-5 - yl)phenyl)-1isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (herein also referred to as esylate of the compound of formula II, esylate of compound II, or any variation thereof) .

In some embodiments, the salt is a 1:1 stoichiometric ratio of K-(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.

In some embodiments, the ethanesulfonic acid salt of the compound of Formula II is crystalline.

In some embodiments, the ethanesulfonic acid salt of the compound of Formula II is substantially isolated.

In some embodiments, the ethanesulfonic acid salt of the compound of formula II has at least one XRPD peak at 2-θ values selected from about 4.9°, about 7.6°, about 15.4°,

- 10 041099 about 16.8° and about 17.5°. In some embodiments, the ethanesulfonic acid salt of the compound of Formula II has at least two XRPD peaks at 2-θ values selected from about 4.9°, about 7.6°, about 15.4°, about 16.8°, and about 17.5°. In some embodiments, the ethanesulfonic acid salt of the compound of Formula II has at least three XRPD peaks at 2-θ values selected from about 4.9°, about 7.6°, about 15.4°, about 16.8°, and about 17.5°. In some embodiments, the ethanesulfonic acid salt of the compound of Formula II has at least four XRPD peaks at 2-θ values selected from about 4.9°, about 7.6°, about 15.4°, about 16.8°, and about 17.5°. In some embodiments, the ethanesulfonic acid salt of the compound of Formula II contains the following XRPD peaks at 2-θ values: about 4.9°, about 7.6°, about 15.4°, about 16.8°, and about 17.5°. In some embodiments, the ethanesulfonic acid salt of the compound of Formula II contains the following XRPD peaks at 2-θ values: about 4.9°, about 7.6°, about 15.4°, and about 17.5°.

In some embodiments, the ethanesulfonic acid salt of the compound of formula II has an XRPD profile substantially corresponding to that shown in FIG. 22.

In some embodiments, the ethanesulfonic acid salt of the compound of formula II has a DSC thermogram having an endometrial peak at about 187.7°C. In some embodiments, the esylate of the compound of formula II has a DSC thermogram substantially corresponding to that shown in FIG. 23. In some embodiments, the esylate of a compound of formula II has a TGA thermogram substantially corresponding to that shown in FIG. 24.

Ways

This application further provides a process for the preparation of a salt of formula I

I

Accordingly, the present document provides a process for preparing a salt which is a maleic acid salt of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2f][1,2,4]triazine -5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetraαhydropyrimidine-5carboxamide, which includes the introduction into the reaction of a compound of formula I with maleic acid to form said salt. The process for preparing the maleic acid salt of a compound of formula I is shown in Scheme 1 and described in Example 1.

In some embodiments, about 1 equivalent of maleic acid is used based on 1 equivalent of a compound of Formula I.

In some embodiments, said reaction of a compound of Formula I with maleic acid is performed in the presence of a solvent component.

In some embodiments, said solvent contains methanol.

In some embodiments, said solvent contains dichloromethane.

In some embodiments, said solvent contains methanol and dichloromethane.

In some embodiments, the method further comprises removing a substantial portion of the dichloromethane to precipitate said salt.

In some embodiments, the method further comprises removing a substantial portion of the dichloromethane to precipitate said salt.

In some embodiments, said method, prior to said reaction, further comprises providing a solution of a compound of Formula I in a solvent component.

In an additional embodiment, the solution is prepared by heating a suspension of the compound of formula I in the solvent component to a temperature of from about 45 to about 55°C.

In an additional embodiment, said method further comprises stirring said solution; and filtering said solution to obtain a filtrate before said addition to the reaction of the compound of formula I with maleic acid.

In a further embodiment, said method further comprises adding activated charcoal and silica gel to the solution after said step of heating said slurry to a temperature of about 45 to about 55°C to form a solution and before said step of stirring said solution.

- 11 041099

In some embodiments, the process for producing a salt of maleic acid No. -1-isopropyl-2,4-dioxo-3(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide comprises: adding a compound of formula I to a solvent component at room temperature to form a suspension ; heating said suspension to a temperature of about 45 to about 55° C. to form a solution; mixing said solution; filtering said solution to obtain a filtrate; adding maleic acid to said filtrate; and removing the solvent from said filtrate to precipitate said salt.

In some embodiments, said solvent contains methanol.

In some embodiments, said solvent contains dichloromethane.

In some embodiments, said solvent contains methanol and dichloromethane.

In some embodiments, said method further comprises adding activated charcoal to the solution after said step of heating said slurry to a temperature of about 45 to about 55°C to form a solution, and before said step of mixing said solution.

In some embodiments, said method further comprises adding silica gel to the solution after said step of heating said slurry to a temperature of about 45 to about 55°C to form a solution and before said step of mixing said solution.

In some embodiments, said method further comprises adding activated charcoal and silica gel to the solution after said step of heating said slurry to a temperature of about 45 to about 55° C. to form a solution, and before said step of stirring said solution.

Provided herein is a process for the preparation of Form II maleic acid salt N-(4-(4amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl )phenyl)-1-isopropyl-2,4dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide, which involves evaporating a saturated solution of the maleic acid salt of compound I in chloroform at temperature 25 ±1°С. A process for the preparation of Form II of the maleic acid salt of a compound of formula I can be found in Example 16, Table 1. 10.

Provided herein is a process for the preparation of Form III maleic acid salt N-(4-(4amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl )phenyl)-1-isopropyl-2,4dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide, which includes evaporation of a saturated solution of the maleic acid salt of compound I in 1, 4-dioxane at a temperature of 25 ± 1°C. A process for the preparation of Form III of the maleic acid salt of a compound of formula I can be found in Example 16, Table 1. 10.

Provided herein is a process for the preparation of N-(4-(4amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl maleic acid salt Form IV )phenyl)-1-isopropyl-2,4dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide, which involves evaporating a saturated solution of the maleic acid salt of compound I in n- BuOH at a temperature of 50±1°C. A process for the preparation of Form IV of the maleic acid salt of a compound of formula I can be found in Example 16, Table 1. 10.

Provided herein is a process for the preparation of Form V maleic acid salt N-(4-(4amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl )phenyl)-1-isopropyl-2,4dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide, which involves adding a saturated solution of the maleic acid salt of compound I in dichloromethane to heptane and stirring. A process for the preparation of Form V of the maleic acid salt of a compound of formula I can be found in Example 16, Table 1. 10.

The present application further provides a process for the preparation of a salt of formula II

II

Accordingly, the present document provides a method for preparing a salt which is N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-12 041099 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, which includes the introduction into the reaction of the compound of formula II with sulfuric acid to form said salt. Methods for preparing the hemisulphate salt of sulfuric acid of the compound of formula II can be found in example 2 and example 8, table. 2.

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

In some embodiments, the method includes: adding a compound of formula II to a solvent component to form a solution; adding sulfuric acid to said solution at room temperature; concentrating the solution to obtain a suspension; stirring the suspension at a temperature of from about 60 to about 70°C; and cooling the slurry to a temperature of about 15 to about 25° C. to precipitate said salt.

In some embodiments, the solvent component contains methanol.

In some embodiments, the solvent component comprises dichloromethane.

In some embodiments, the solvent component comprises methanol and dichloromethane.

In some embodiments, the implementation of sulfuric acid has a concentration of about 1M in water.

In some embodiments, the method further comprises preparing the sulfuric acid salt of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazine -5-yl)phenyl)-1isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The process for preparing the sulfuric acid salt of a compound of formula II is shown in Scheme 2 and described in Example 2.

In some embodiments, a process for preparing a salt that is a sulfuric acid salt of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4] triazin-5yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide, involves reacting a compound of formula II with about 1 eq. sulfuric acid based on 1 eq. compounds of formula II.

In some embodiments, a process for preparing a sulfuric acid salt of N-(4-(4-amino-7-(1isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl )-1-isopropyl-2,4-dioxo-3-phenyl1,2,3,4-tetrahydropyrimidine-5-carboxamide 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 about 50 to about 60°C; adding sulfuric acid to said solution; and removing the solvent to precipitate the sulfuric acid salt.

In some embodiments, the implementation of the first solvent contains methanol.

In some embodiments, sulfuric acid is added as a solution in water.

In some embodiments, the processes described above for preparing N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin- 5yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide includes the following steps: adding a salt of sulfuric acid N-(4-(4- amino-7-(1-isobutyrylpiperidin-4yl)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 the second solvent component to form a suspension; heating the suspension to a temperature of about 30 to about 40°C; mixing the suspension and collecting the resulting hemisulphate salt of sulfuric acid.

In some embodiments, the implementation of the second solvent component contains water.

The present document proposes a method for preparing the amorphous form of the hemisulfate salt of sulfuric acid N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin- 5-yl)phenyl)-1isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide. The process for preparing the amorphous form of the hemisulphate salt of sulfuric acid of the compound of formula II is shown in Scheme 1 and described in Example 2.

In some embodiments, the preparation of the amorphous form of the hemisulphate salt of sulfuric acid N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazine-5 -yl)phenyl)-1 isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide includes the following steps: adding hemisulphate salt of sulfuric acid N-(4-(4 -amino-7-(1isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl1, 2,3,4-tetrahydropyrimidine-5-carboxamide to the third solvent component at room temperature to form a solution; solution filtration; concentration of the filtrate; and drying the resulting solid to obtain an amorphous hemisulfate salt of sulfuric acid.

In some embodiments, the implementation of the third solvent component contains acetone and methanol.

The present document provides a method for preparing a salt which is a phosphoric acid salt of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4] triazin-5yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide, which comprises reacting a compound of formula II with phosphoric acid to form said salt. A method for preparing a phosphoric acid salt of a compound of formula II can be found in example 8, table. 2. In some embodiments, about 1.2 equivalents of phosphoric acid is used

- 13 041099 based on 1 equivalent of the compound of formula II.

Provided herein is a process for preparing a salt which is the maleic acid salt of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4] triazin-5yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide, which comprises reacting a compound of formula II with maleic acid to form said salt. A process for the preparation of a maleic acid salt of a compound of formula II can be found in Example 8, Table 1. 2. In some embodiments, about 1.5 eq. maleic acid is used on the basis of 1 eq. compounds of formula II.

Provided herein is a process for preparing a salt which is the hydrochloric acid 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, which includes the introduction of the reaction of the compound of formula II with hydrochloric acid to form the specified salt. A method for preparing a hydrochloric acid salt of a compound of formula II can be found in example 8, table. 2. In some embodiments, about 1.2 eq. hydrochloric acid is used on the basis of 1 eq. compounds of formula II.

Provided herein is a process for preparing a salt which is a salicylic acid salt of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4] triazin-5yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide, which comprises reacting a compound of formula II with salicylic acid to form said salt. A method for preparing a salicylic acid salt of a compound of formula II can be found in example 8, table. 2. In some embodiments, about 1.2 eq. salicylic acid is used on the basis of 1 eq. compounds of formula II.

The present document provides a process for preparing a salt which is a methanesulfonic acid salt of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4] triazin-5yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide, which comprises reacting a compound of formula II with methanesulfonic acid to form said salt. A method for preparing the methanesulfonic acid salt of the compound of formula II can be found in example 8, table. 2. In some embodiments, about 1 eq. methanesulfonic acid is used based on 1 eq. compounds of formula II.

Provided herein is a process for preparing a salt which is an ethanesulfonic acid salt of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4] triazin-5yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide, which comprises reacting a compound of formula II with ethanesulfonic acid to form said salt. A method for preparing the ethanesulfonic acid salt of the compound of formula II can be found in example 8, table. 2. In some embodiments, about 1 eq. ethanesulfonic acid is used based on 1 eq. compounds of formula II.

It should be understood that certain features of this disclosure, which are described in the context of separate embodiments for clarity, may also be presented in combination as a single embodiment (whereas the embodiments are intended to be combined as if written in multiple dependent forms). Conversely, various features of this disclosure, which for brevity are described in the context of one embodiment, may also be presented separately or in any suitable subcombination.

The salts and compounds of this disclosure may also include all isotopes and atoms that are present in intermediates or final salts or compounds. Isotopes include those atoms that have the same atomic number but different mass values. For example, isotopes of hydrogen include tritium and deuterium.

In some embodiments, the compounds or salts may occur together with other substances, such as water or solvents (eg, hydrates and solvates), or may be isolated.

In some embodiments, the compounds described herein, or salts thereof (eg, the maleic acid salt of a compound of formula I or the hemisulphate salt of sulfuric acid of a compound of formula II) are essentially isolated.

The phrase pharmaceutically acceptable is used herein to refer to those compounds, materials, compositions and/or dosage forms which, within the framework of rational medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction or other problem, or complications commensurate with a reasonable benefit/risk ratio.

As will be appreciated, the compounds provided herein, including their salts, can be prepared using known methods of organic synthesis and can be synthesized according to any of the many possible synthetic routes. The methods described herein can be controlled in accordance with any suitable method known in the art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (for example, 1H or 13C), infrared spectroscopy, or spectrophotometry (for example, UV in the visible range), or using chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC) or other related methods.

As used herein, the term "reacting" is known in the art and generally refers to bringing together chemical reactants in such a way that they interact at the molecular level to achieve chemical or physical transformation. In some embodiments, the introduction into the reaction includes two reactants, and one or more equivalents of the second reactant are used in relation to the first reactant. The reaction steps in the methods described herein can be carried out for a time and under conditions suitable to obtain the specified product.

The reactions in the methods described herein can be carried out in suitable solvents, which can be easily selected by a person skilled in the art of organic synthesis. Suitable solvents may be substantially unreactive with the starting materials (reagents), intermediates or products at the temperatures at which the reactions are carried out, for example temperatures that may range from the solvent's freezing point to the solvent's boiling point. This reaction can be carried out in a single solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents (or mixtures thereof) can be selected for the particular reaction step.

Suitable solvents may include halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachlorethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2trichloroethane, 1 ,1-dichloroethane, 2-chloropropane, 1,2-dichloroethane, 1,2-dibromoethane, hexafluorobenzene, 1,2,4trichlorobenzene, 1,2-dichlorobenzene, chlorobenzene, fluorobenzene, mixtures thereof, etc.

Suitable ether solvents include dimethoxymethane, tetrahydrofuran, 1,3dioxane, 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, tert methyl ether -butyl, mixtures thereof, and the like.

Suitable protic solvents may 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, isobutyl alcohol, tert-butyl alcohol, 2ethoxyethanol, diethylene glycol, 1-, 2- or 3-pentanol, neopentyl alcohol, tert-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol or glycerol.

Suitable aprotic solvents may include, by way of example and without limitation, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylαcetαamide (DMA), 1,3dimethyl-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.

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

The reactions in the methods described herein can be carried out at appropriate temperatures, which can be easily determined by a person skilled in the art. The reaction temperatures will depend on, for example, the melting and boiling points of the reactants and solvents, if present; reaction thermodynamics (eg, intense exothermic reactions may be carried out at lower temperatures); and reaction kinetics (eg, a high energy activation barrier may require elevated temperatures).

As used herein, the expressions ambient temperature and room temperature, or RT, are understood in the art and generally refer to temperature, such as the reaction temperature, which is approximately the same as the temperature of the reaction room, such as about 20 to about 30°C.

The reactions in the methods described herein can be carried out in air or in an inert atmosphere. In general, reactions containing reactants or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques well known to those skilled in the art.

Ways to use

Salts of the present invention (eg, salts of compounds of formulas I and II) can modulate or inhibit the activity of TAM kinases. For example, the compounds of the present invention can

- 15 041099 be used to inhibit TAM kinase activity in a cell or in an individual or patient in need of kinase inhibition by administering an inhibitory amount of a compound of the present invention to the cell, individual or patient.

In some embodiments, the salts of the present invention are selective for TAM kinases over one or more other kinases. In some embodiments, the compounds of the present invention are selective for TAM kinases over other kinases. In some embodiments, the selectivity is 2 times or more, 3 times or more, 5 times or more, 10 times or more, 25 times or more, 50 times or more, or 100 times or more.

The salts of the present invention may inhibit one or more of AXL, MER and TYRO3. In some embodiments, the salts are selective for one TAM kinase over another. Selective means that the compound binds to or inhibits a TAM kinase with greater affinity or activity, respectively, compared to a reference enzyme such as another TAM kinase. For example, salts can be AXL selective for MER and TYRO3, MER selective for AXL and TYRO3, or AXL and MER selective for TYRO3. In some embodiments, the salts inhibit all members of the TAM kinase family (eg, AXL, MER, and TYRO3). In some embodiments, the salts may be selective for AXL and MER for TYRO3 and other kinases. In some embodiments, provided herein is a method for inhibiting AXL and MER kinases, which comprises contacting AXL and MER kinases with a salt provided herein or a pharmaceutically acceptable salt thereof.

As inhibitors of TAM kinases, the compounds of the present invention are useful in the treatment of various diseases associated with abnormal expression or activity of TAM kinases. Salts of compounds (formulas I and II) which inhibit TAM kinases will be useful in providing a means of preventing growth or inducing apoptosis in tumors, in particular by inhibiting angiogenesis. Thus, the salts are expected to be useful in the treatment or prevention of proliferative diseases such as cancer. In particular, tumors with activating mutant receptor tyrosine kinases or upregulation of receptor tyrosine kinases may be particularly sensitive to such inhibitors.

In certain embodiments, the present invention provides a method of treating a TAM kinase mediated disease or disorder in a patient in need thereof, comprising the step of administering to said patient a salt as described herein (e.g., salts of compounds of formulas I and II), or its pharmaceutically acceptable compositions.

For example, the salts of the present invention are useful in the treatment of cancer. Examples of cancers include bladder cancer, breast cancer, cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, stomach cancer, head and neck cancer (e.g., cancer of the larynx, laryngopharynx, nasopharynx, oropharynx, lips, and mouth), kidney cancer, liver cancer (eg, hepatocellular carcinoma, cholangiocellular carcinoma), lung cancer (eg, adenocarcinoma, small cell lung cancer or non-small cell lung cancer, small cell and non-small cell cancer, bronchial carcinoma, bronchial adenoma, pleuropulmonary blastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (eg, exocrine pancreatic carcinoma), gastric cancer, thyroid cancer, cancer parathyroid cancer, skin cancer (eg, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer), and brain cancer (eg, astrocytoma, medulla loblastoma, ependymoma, neuroectodermal tumors, pineal tumors).

Other cancers amenable to treatment with the compounds of the present invention include bone cancer, intraocular cancers, gynecological cancers, endocrine system cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, pituitary cancer, triple negative cancer. breast cancer (TNBC) and environmentally induced cancers, including those induced by asbestos.

Additional examples of cancers 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 myelogenous leukemia, Hodgkin's or non-Hodgkin's lymphoma. lymphoma, myeloproliferative neoplasms (eg, polycythemia vera, essential thrombocythemia, and primary myelofibrosis), Waldenstrom's macroglobulinemia, hairy cell lymphoma, chronic myelogenous lymphoma, acute lymphoblastic lymphoma, AIDS-associated lymphomas, and Burkitt's lymphoma.

Other cancers treatable with the compounds of the present invention include ocular tumors, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, and osteosarcoma.

The salts of the present invention may also be useful in inhibiting tumor metastasis.

- 16 041099

In some embodiments, diseases and indications that are treatable with the compounds of the present invention include, without limitation, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary cancers, liver cancers, bone cancers. , cancers of the nervous system, gynecological cancers and cancers of the skin.

Examples of hematological cancers include varieties of lymphoma and leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (MLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MLZ), non-Hodgkin's lymphoma (including relapsed or refractory NHL), follicular lymphoma (FL), Hodgkin's lymphoma (HL), lymphoblastic lymphoma, myeloproliferative disorders (eg, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplastic syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T -cell lymphoma, peripheral T-cell lymphoma, Waldenström macroglobulinemia, hairy cell lymphoma, chronic myelogenous lymphoma and Burkitt's lymphoma.

Examples of sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

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

Examples of cancers of the gastrointestinal tract include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, pancreatic ulcerogenic adenoma, carcinoid tumors , vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colorectal cancer and bile duct cancer .

Examples of cancers of the genitourinary system include cancers of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], renal cell carcinoma), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, urothelial carcinoma), prostate (adenocarcinoma, sarcoma). ) and testicles (seminoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).

Examples of liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

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

Examples of cancers of the nervous system include cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, ostosis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoglioma, germinoma (pinealoma), glioblastoma, glioblastoma polymorphism, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors) and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma, Lhermitte-Duclos disease, central nervous system (CNS) neoplasm, primary CNS lymphoma, and axis tumor spine.

Examples of gynecological cancers include cancers of the uterus (endometrial carcinoma), cervical (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucosal cystadenocarcinoma, unclassified cancer), granulosa-thecal cell tumors, tumor from Sertoli-Leydig cells, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma) and fallopian tubes (carcinoma).

Examples of skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, mole dysplasia, lipoma, angioma, dermatofibroma, and keloids.

Examples of head and neck cancers include glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas, adenocarcinomas, oral cavity cancer, laryngeal cancer, nasopharyngeal cancer, nasal and paranasal sinus cancer, thyroid cancer, and parathyroid cancer.

In some embodiments, the present disclosure relates to a method of treating hepatocellular carcinoma in a patient in need thereof, the method comprising the step of administering to said patient a salt of a compound of formula I, or a salt of a compound of formula II, or a composition containing a salt of a compound of formula I, or a salt compounds of formula II.

In some embodiments, the present disclosure relates to a method of treating rhabdomyosarcoma, esophageal cancer, breast cancer, or head or neck cancer in a patient in need thereof, the method comprising the step of administering to said patient a salt of a compound of formula I, or a salt of a compound of formula II , or a composition containing a salt of a compound of formula I or a salt of a compound of formula II.

In some embodiments, the present disclosure relates to a method of treating a cancer, the cancer being selected from the group consisting of hepatocellular cancer, 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.

Targeting TAM receptor tyrosine kinases may provide a therapeutic approach to the treatment of viral diseases (T Shibata, et al. The Journal of Immunology, 2014, 192, 3569-3581). The present disclosure relates to a method for treating infections such as viral infections. The method includes 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 containing a salt of a compound of formula I or a salt of a compound of formula II.

Examples of viruses that cause infections treatable by the methods of the present invention include, without limitation, human immunodeficiency virus, human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, virus severe acute respiratory syndrome, Ebola virus, Marburg virus and measles virus. In some embodiments, viruses that cause infections treatable by the methods of the present invention include, without limitation, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV , Epstein-Barr virus), adenovirus, influenza virus, flaviviruses (for example: West Nile fever, Dengue fever, tick-borne viral encephalitis, yellow fever, Zika), echovirus, rhinovirus, Coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papilloma virus, molluscum virus, polio virus, rabies virus, JC virus, and tick-borne encephalitis virus.

In some embodiments, the present disclosure relates to a method for treating thrombosis (J.M.E.M. Cosemans et al. J. of Thrombosis and Haemostasis 2010, 8, 1797-1808 and A. AngelilloScherrer et al. J. Clin. Invest 2008, 118, 583-596) .

Combination Therapies

One or more additional pharmaceutical agents or treatments, such as, for example, antiviral agents, chemotherapeutic agents or other anticancer agents, immune enhancers, immunosuppressants, radiation therapy, antitumor and antiviral vaccines, cytokine therapy (for example, IL2, GM-CSF, etc.) e) and/or tyrosine kinase inhibitors may be used in combination with compounds of formula (I) or a compound as described herein for the treatment of TAM-associated diseases, disorders or conditions. The agents may be combined with the salts of the present invention (eg, salts of compounds of Formulas I and II) in a single dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms.

Suitable antiviral agents contemplated for use in combination with the salts of the present invention may include nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antivirals.

Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobukavir (BMS-180194); VSN-10652; emtricitabine [(-)-FTC]; beta-L-FD4 (also known as beta-E-O4C and called betaA-2',3'-dicleoxy-5-fluorocytidene); DAPD, ((-)-beta-O-2,6,-diaminopuridioxolane) and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradin (BHAR, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKS-442 (1-(ethoxy-methyl)-5-(1methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)pyrimidinedione) and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475). ); DMP-450;

BMS-2322623; ABT-378 and AG-1 549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuzid, and Yissum Project No. 11607.

Suitable agents for use in combination with the salts of the present application for the treatment of cancer include chemotherapeutic agents, targeted cancer therapies, immunotherapies, or radiation therapy. The salts of the present disclosure may be effective in combination with antihormonal drugs for the treatment of breast cancer and other tumors. Suitable examples are antiestrogen including, without limitation, tamoxifen and toremifene; aromatase inhibitors, including, without limitation, letrozole, anastrozole, and exemestane; adrenocorticosteroids (eg prednisone); progestins (eg megastrol acetate); and estrogen receptor antagonists (eg fulvestrant). Suitable antihormonal drugs used in the treatment of prostate cancer and other cancers may also be combined with the compounds of the present disclosure. Such drugs include antiandrogens including, but not limited to, flutamide, bicalutamide, and nilutamide; luteinizing hormone-releasing hormone (LHRH) analogs, including leuprolide, goserelin, triptorelin, and hystrelin; LHRH antagonists (eg degarelix); androgen receptor blockers (eg, enzalutamide); and agents that inhibit androgen production (eg, abiraterone).

The salts of the present invention can be combined together or sequentially with other anti-membrane receptor kinase agents, especially for patients who have developed primary or acquired resistance to targeted therapy. Such 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, and also against cancer-associated hybrid kinases such as Bcr-Abl and EML4-Alk. Anti-EGFR inhibitors include gefitinib and erlotinib, and anti-EGFR/Her2 inhibitors include, but are not limited to, dacomitinib, afatinib, lapitinib, and neratinib. Anti-EGFR antibodies include, but are not limited to, cetuximab, panitumumab, and necitumumab. c-Met inhibitors may be used in combination with TAM inhibitors. These include onartumzumab, tivantnib, and INC-280. Anti-FGFR agents include, without limitation, AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258, lucitanib, dovitinib, TAS-120, JNJ-42756493, and Debiol347. Anti-Trk agents include, without limitation, LOXO-101 and RXDX-101. Anti-Abl (or Bcr-Abl) agents include imatinib, dasatinib, nilotinib, and ponatinib, and anti-Alk (or EML4-ALK) agents include crizotinib.

Angiogenesis inhibitors may be effective in the treatment of certain tumors in combination with TAM inhibitors. These include antibodies to VEGF or VEGFR or VEGFR kinase inhibitors. Anti-VEGF antibodies or other therapeutic proteins include bevacizumab and aflibercept. VEGFR kinase inhibitors and other antiangiogenic inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

Activation of intracellular signaling pathways is frequently observed in cancers, and agents targeting components of these pathways have been combined with receptor-targeted agents to improve efficacy and reduce resistance. Examples of agents that can be combined with the compounds of the present invention include PI3KAKT-mTOR pathway inhibitors, Raf-MAPK pathway inhibitors, JAK-STAT pathway inhibitors, Pim kinase inhibitors, and inhibitors of chaperones and cell cycle progression.

Anti-Pi3 kinase agents include, but are not limited to, pilaralisib, idelicib, buparlisib, and IPI-549. In some embodiments, the PI3K inhibitor is selective for PI3K-alpha, PI3K-beta, PI3K-gamma, and PI3K-delta. mTOR inhibitors such as rapamycin, sirolimus, temsirolimus and everolimus can be combined with TAM kinase inhibitors. Other suitable examples include, without limitation, vemurafenib and dabrafenib (Raf inhibitors) as well as trametinib, selumetinib and GDC-0973 (MEK inhibitors). Inhibitors of one or more JAKs (eg, ruxolitinib, baricitinib, tofacitinib), Hsp90 (eg, tanespimycin), cyclin-dependent kinases (eg, palbociclib), PARP (eg, olaparib), and proteasomes (eg, bortezomib, carfilzomib) may also be combined with the compounds according to the present invention. In some embodiments, the JAK inhibitor is selective for JAK1 over JAK2 and JAK3. Anti-Pimkinase agents include, without limitation, LGH447, INCB053914, and SGI-1776.

Other suitable agents for use in combination with the salts of the present invention include combinations of chemotherapeutic agents such as platinum-based dual chemotherapy used to treat lung cancer and other solid tumors (cisplatin or carboplatin plus gemcitabine; cisplatin or carboplatin plus docetaxel ; cisplatin or carboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed), or gemcitabine plus albumin-stabilized paclitaxel (Abraxane®).

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

Other suitable agents for use in combination with the salts of the present invention include: dacarbazine (DTIC), optionally together with other chemotherapy drugs such as carmustine (BCNU) and cisplatin; Darmouth regimen, which consists of DTIC, BCNU, cisplatin, and tamoxifen; combination of cisplatin, vinblastine and DTIC or temozolomide. The compounds provided herein can also be combined with immunotherapy drugs, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF) inhibitors.

Suitable chemotherapeutic 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.

Suitable chemotherapeutic or other anticancer agents further include, for example, certain natural products and their derivatives (eg, vinca alkaloids, anticancer antibiotics, enzymes, lymphokines, and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin , epirubicin, idarubicin, ara-C, paclitaxel (TAXOL™), mithramycin, deoxycoformycin, mitomycin C, L-asparaginase, interferons (particularly IFN-a), etoposide and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrozole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; antineoplastic enzyme; topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur and hematopoietic growth factors.

Other anti-cancer agents include antibody-based therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4, 4-1BB, and PD1, or antibodies to cytokines (IL-10, TGF-β, etc.). .d.).

Other anti-cancer agents include CSF1R inhibitors (PLX3397, LY3022855, etc.) and CSF1R antibodies (IMC-CS4, RG7155, etc.).

Other anti-cancer agents include BET inhibitors (INCB054329, OTX015, CPI-0610, etc.), LSD1 inhibitors (GSK2979552, INCB059872, etc.), HDAC inhibitors (panobinostat, vorinostat, etc.), DNA methyltransferases (azacytidine and decitabine) and other epigenetic modulators.

Other anticancer agents include the Bcl2 inhibitor ABT-199 and other inhibitors of the Bcl-2 family of proteins.

Other anti-cancer agents include a TGF-beta receptor kinase inhibitor such as LY2157299.

Other anti-cancer agents include a BTK inhibitor such as ibrutinib.

Other anti-cancer agents include beta-catenin signaling inhibitors, notch signaling inhibitors, and hedgehog signaling inhibitors.

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

Other anti-cancer agents also include immune cell migration blocking agents such as chemokine receptor antagonists including CCR2 and CCR4.

Other anticancer agents also include agents that enhance the immune system, such as adjuvants or adaptive T cell transfer.

Cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses.

One or more additional immune checkpoint inhibitors can be used in combination with a salt as described herein to treat TAM-associated diseases, disorders or conditions. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD20, CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, 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 a checkpoint inhibitory 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 KTR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFR beta inhibitors.

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

In some embodiments, the immune checkpoint molecule inhibitor is a PD-1 inhibitor, 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.

In some embodiments, the immune checkpoint molecule inhibitor is a PD-L1 inhibitor, 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 cases, the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab).

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

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

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

In some embodiments, the immune checkpoint molecule inhibitor is an OX40 inhibitor, such as 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.

In some embodiments, the immune checkpoint molecule inhibitor is a CD20 inhibitor, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

Salts of the present invention can 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 TGFe receptor.

The salts of the present invention 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 the alkylating agent 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).

The salts of the present invention can be combined with another immunogenic agent such as cancer cells, purified tumor antigens (including recombinant proteins, peptides and carbohydrate molecules), cells and cells transfected with genes encoding immunostimulatory cytokines. Non-limiting examples of cancer vaccines that can be used include melanoma antigen peptides such as gp100, MAGE, Trp-2, MARTI and/or tyrosine kinase antigens, or tumor cells transfected to express the cytokine GM-CSF.

The salts of the present invention may be used in combination with a vaccination regimen for the treatment of cancer. In some embodiments, the tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins from viruses associated with human cancers, such as human papillomaviruses (HPV), hepatitis viruses (HBV and HCV), and Kaposi's sarcoma herpesvirus (KSHV). In some embodiments, the salts of the present invention may be used in combination with a tumor specific antigen, such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, the salts of the present invention can be combined with dendritic cell immunization to activate potent antitumor responses.

The salts of the present invention can be used in combination with bispecific macro-cyclic peptides that target effector cells expressing the Fc alpha or Fc gamma receptor to tumor cells. The salts of the present invention can also be combined with macrocyclic peptides that activate the host's immune response.

The salts of the present invention may be used in combination with arginase inhibitors such as CB-1158.

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

The salts of the present invention can be used in combination with bone marrow transplantation to treat various tumors of hematopoietic origin.

The salts of the present invention can be used as an anticoagulant alone or in combination with other anticoagulants, including, without limitation, apixaban, dabigatran, edoxaban, fondaparinux, heparin, rivaroxaban, and warfarin.

Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the conventional literature. For example, the administration of many chemotherapeutic agents is described in the Physicians' Desk Reference (PDR, eg, 1996 edition, Medical Economics Company, Montvale, NJ), the contents of which are incorporated herein by reference in their entirety.

Pharmaceutical formulations and dosage forms

When used as pharmaceuticals, the salts of the present invention may be administered as pharmaceutical compositions that refer to a combination of a compound provided herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. Such compositions may be prepared in a manner well known in the pharmaceutical art and may be administered in a variety of ways depending on whether topical or systemic treatment is desired and the area to be treated. Administration can be topical (including ophthalmic and mucosal, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal, and transdermal), ophthalmic, oral or parenteral. Ocular delivery methods may include topical administration (eye drops), subconjunctival, periocular, or intravitreal injection, or administration via a balloon catheter or ophthalmic inlays surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, eg intrathecal or intraventricular, administration. Parenteral administration may be in the form of a single bolus dose or, for example, may be carried out continuously by means of a perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Common pharmaceutical carriers, aqueous, powder or oily bases, thickeners, etc. may be necessary or desirable.

The present application also covers pharmaceutical compositions which contain, as an active ingredient, one or more salts as provided herein (eg salts of compounds of formulas I and II) in combination with one or more pharmaceutically acceptable carriers. In preparing the compositions of the present invention, the active ingredient is usually mixed with an excipient, diluted with an excipient, or enclosed in such a carrier in the form of, for example, a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, capsules, 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, soft and hard gelatin capsules, suppositories, sterile injectable solutions or sterile packaged powders.

When preparing a formulation, the active compound (or salt forms of the present invention) may be milled to provide an appropriate particle size before being combined 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 can be adjusted by milling to provide a substantially uniform distribution in the formulation, eg about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrops, and methylcellulose. The compositions may additionally contain lubricating agents such as talc, magnesium stearate and mineral oils; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners and flavors. Compositions of the present invention may be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient using procedures known in the art.

The compositions may be formulated as unit dosage forms, with each dosage form containing from about 5 to about 100 mg, more typically from about 10 to about 30 mg, of the active ingredient. The term unit dosage form corresponds to physically discrete units suitable as unit doses for humans and other mammals, each unit dosage form containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical excipient.

The active compound may be effective over a wide dosage range and is usually administered in a pharmaceutically effective amount. However, it should be understood that the amount of compound actually administered will generally be determined by the physician in light of relevant circumstances, including the condition being treated, the route of administration chosen, the particular compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like. .P.

To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid composition to give it a dosage form containing a homogeneous mixture of the compound of the present invention. When these compositions are referred to before they are formulated as homogeneous, the active ingredient is generally evenly distributed throughout the composition so that the composition can be easily divided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation is then divided into unit dosage forms of the type described above, containing, for example, from 0.1 to about 500 mg of the active ingredient of the present invention.

Tablets or pills of the present invention may be coated or otherwise mixed to provide a dosage form that provides the benefit of prolonged action. For example, a tablet or pill may contain an internal drug component and an external drug component, the latter serving as a shell for the former. The two components can be separated by an enteric layer that resists breakdown in the stomach and allows the inner component to pass intact into the duodenum or be delayed upon release. Various materials can be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

Liquid forms in which the salts and compositions of the present invention for oral or injectable administration may be incorporated include aqueous solutions, suitable flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut butter, as well as elixirs and similar pharmaceutical carriers.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by oral or nasal inhalation for local or systemic action. The compositions can be sprayed using inert gases. Nebulized solutions may be inhaled directly from a nebulization device, or the nebulization device may be attached to face masks or intermittent positive pressure breathing apparatus. Solution, suspension or powder compositions can be administered orally or nasally from devices that deliver the composition in an appropriate manner.

The amount of salts (eg, salts of compounds of Formulas I and II) or composition administered to a patient will vary depending on what is being administered, the purpose of administration such as prophylaxis or therapy, the condition of the patient, the route of administration, and the like. In therapeutic applications, the compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially relieve the symptoms of the disease and its complications. Effective doses will depend on the disease state being treated, as well as the judgment of the attending physician, depending on such factors as the severity of the disease, the age, weight and general condition of the patient, and the like.

Compositions administered to a subject may be in the form of the pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization methods or sterile

- 23 041099 filtered. Aqueous solutions may be packaged for use as is or lyophilized, the lyophilized preparation being combined with a sterile aqueous vehicle prior to administration. The pH of compound solutions is typically 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It will be appreciated that the use of certain excipients, carriers or stabilizers mentioned above will result in the formation of pharmaceutical salts.

The therapeutic dose of a compound or salt of the present invention may vary depending on, for example, the particular use for which the treatment is being carried out, the route of administration of the compound, the health and disease of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound or salt provided herein in a pharmaceutical composition may vary depending on a number of factors, including dose, chemical characteristics (eg, hydrophobicity), and route of administration. For example, the compounds or salts proposed herein can be provided in an aqueous physiological buffer solution containing 0.1-10% wt./about. compounds or salts for parenteral administration. Some typical dosage ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, dosage ranges are from about 0.01 to about 100 mg/kg of body weight per day. The dosage is likely to depend on variables such as the type and extent of progression of the disease or disorder, the general health of the individual patient, the relative biological potency of the compound chosen, the formulation of the excipient, and the route of administration. Effective doses can be extrapolated from dose-response curves obtained in laboratory or model animal systems.

The compounds or salts provided herein may also be formulated in combination with one or more additional active ingredients, which may contain any pharmaceutical agent such as antiviral agents, vaccines, antibodies, immune enhancers, immunosuppressants, anti-inflammatory agents, and the like. .

Sets

The present invention also includes pharmaceutical kits useful, for example, for the treatment or prevention of TAM-associated diseases or disorders, obesity, diabetes and other diseases referred to herein, these kits include one or more containers containing a pharmaceutical composition, containing a therapeutically effective amount of a salt (eg, salts of compounds of formulas I and II) proposed herein. If desired, such kits may further include one or more of the various standard pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be appreciated by those skilled in the art. Instructions in the form of inserts or labels containing the amount of components to be administered, directions for administration and/or directions for mixing the components may also be included in the kit.

Examples

The invention will be described in more detail using specific examples. The following examples are offered for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize a number of non-critical parameters that can be changed or modified to produce substantially identical results. The compounds of the examples were found to be inhibitors of TAM kinases, as described below.

General methods

Preparative LC-MS purifications of some of the resulting compounds were performed using Waters mass directed fractionation systems. Basic hardware settings, protocols and software controls for working with these systems have been described in detail in the literature. See, for example, Two-Pump At Column Dilution Configuration for Preparative LC-MS, K. Blom, J. Combi. Chem. 4, 295 (2002); Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification, K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003) and Preparative LC-MS Purification: Improved Compound Specific Method Optimization, K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The separated compounds were typically subjected to analytical liquid chromatography with mass spectrometry (LC-MS) to check their purity under the following conditions: Instrument: Agilent 1100 series, LC/MSD, column: Waters Sunfire™ C ₁₈ , particle size 5 µm, 2.1x5.0 mm, buffers: mobile phase A: 0.025% TFA in water and mobile phase B: acetonitrile; gradient from 2% to 80% B over 3 min with a flow rate of 2.0 ml/min.

Some of the resulting compounds were also separated on a preparative column by reverse phase high performance liquid chromatography (RP-HPLC) with MS detector or flash chromatography (silica gel) as indicated in the examples. Typical column parameters for reverse phase high performance liquid chromatography (RP-HPLC):

Purification at pH 2: Waters Sunfiree C ₁₈ column, particle size 5 µm, 19x100 mm, eluting with

- 24 041099 mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile; the flow rate was 30 ml/min, the separating gradient was optimized for each compound using the compound-specific method optimization protocol as described in the literature [cf. Preparative LCMS Purification: Improved Compound Specific Method Optimization, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate that was used for the 30x100 mm column was 60 ml/min.

Purification at pH 10: Waters XBridge C ₁₈ column, particle size 5 µm, 19x100 mm, eluting with mobile phase A: 0.15% NH4OH in water and mobile phase B: acetonitrile; the flow rate was 30 ml/min, the separating gradient was optimized for each compound using the compound-specific method optimization protocol as described in the literature [cf. Preparative LCMS Purification: Improved Compound Specific Method Optimization, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate that was used for the 30x100 mm column was 60 ml/min.

Example 1 Synthesis of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,21][1,2,4]triazin-5-yl)phenyl)-1-maleate isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5carboxamide (compound I maleate Form I)

Scheme 1.

Step 1: 5-bromo-7-(piperidin-4-yl)pyrrolo[1,2-1][1,2,4]triazin-4-amine dihydrochloride (compound 2)

tert-Butyl 4-(4-amino-5-bromopyrrolo[2,1-f][1,2, 4]triazin-7-yl)piperidine-1-carboxylate (compound 1, 880 g, 2.221 mol) in dichloromethane (DCM, 8.0 L) at room temperature. Hydrochloric acid in 2-propanol (5.8 N, 2.7 L, 15.66 mol, 7.05 eq.) was added to the suspension. 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 residue was dried on a filter under standard vacuum for 24 h to give 5-bromo-7-(piperidin-4-yl)pyrrolo[1,21][1,2,4]triazine-4-amine dihydrochloride (compound 2, 848 g, 103%) as a light brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 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-de) δ 150.34, 139.32, 138.92, 113.24, 109.67, 95.70, 43.06, 30.57, 26.89 ppm .; CnH^BrN (mol. w. 295.0), LC-MS (EI) m/e 296.0 (M ⁺ + H).

Step 2: 1-(4-(4-Amino-5-bromopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan1-one (compound 3).

5-bromo-7(piperidin-4-yl)pyrrolo[1,2-1][1,2,4] triazine-4-amine dihydrochloride (compound 2, 1300 g, 3.522 mol) in N-methylpiperidinone (NMP, 10 L) at room temperature. N,Ndiisopropylethylamine (1593 g, 12.3 mol) was added to the suspension. The mixture was cooled to 10° C. and then isobutyryl chloride (388 g, 3.645 mol) was charged. 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 the starting material. After completion of the reaction, the reaction mixture was filtered through a pad of celite. The resulting filtrate was cooled to 10° C., water (26 L) was gradually added to precipitate the product. The solids were collected by filtration and washed with water (12 L). The residue was dried on a filter under standard vacuum for 48 hours to give 1-(4-(4-amino-5-bromopyrrolo[1,2d[1,2,4]triazin-7-yl)piperidin-1-yl)- 2-methylpropan-1-one (compound 3, 1095 g, 85%) as light brown solid.

¹ H 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 C 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 BrN ₅ O (mol. w 365.09), LC-MS (EI) m/e 366.1 (M ⁺ + H).

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

A five-necked 22 L round-bottom flask equipped with a mechanical stirrer, heater, thermocouple, reflux condenser, nitrogen inlet and nitrogen outlet tubes was charged with 1-(4-(4-amino-5-bromopyrrolo[1,2-f][1,2, 4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one (compound 3, 700 g, 1.911 mol), 4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)aniline (compound 4, 502 g, 2.293 mol) and potassium carbonate (528 g, 3.822 mol) in 1-butanol (7.7 L) and water (1.4 L) at room temperature . Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 90 g, 115 mmol) at room temperature. The reaction mixture was degassed and refilled with nitrogen and then heated to 80°C. After 2 hours at 80° C., n-heptane (8 L) was added to the reaction mixture. The resulting suspension was cooled to room temperature. The solids were collected by filtration and washed with water (6 L). The residue was dried on a filter under standard vacuum for 72 h to give 1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[1,2d[1,2,4]triazin-7-yl)piperidine 1-yl)-2-methylpropan-1-one (compound 5, 648 g, 90%) as a brown solid.

¹ H NMR (500 MHz, DMSO-d ₆ ) 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 (n, 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 C 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 ₂ 1H _M N6O (mol. w 378.48), LCMS (EI) m/e 379.2 (M ⁺ + H).

Step 4: N-(4-(4-amino-7-(1-isobutyrspiperidin-4-x)pyrrolo[1,2-H1,2,4]triazin-5-yl)phenyl)1-isopropyl-2, 4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (compound I).

1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[1,2-£][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-(pyridine-2- yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid hydrochloride (compound 6, 801 g, 2.569 mol) in tetrahydrofuran (THF, 10 L) at room temperature. Triethylamine (NEt ₃ , 0.695 L, 4.988 mol) was added to the reaction mixture. After completion of the reaction, the reaction mixture was equally divided into two 22 L round bottom flasks. Water (8 L) was charged to each flask at room temperature. Solids were collected by filtration. The resulting wet residue was placed back into the 22 L round bottom flask. The flask was charged with THF (3.2 L) and water (10.5 L). The suspension was heated to 55°C and stirred at 55°C for two hours. The solids were collected by filtration at 30° C. and washed with water (8 L). The residue was dried on a filter under standard vacuum for 72 hours to give N-(4-(4-amino-7-(1isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazine-5 -yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (compound I, 1425 g, 90%) in in the form of a light brown solid.

¹ H 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) m .d.;

¹³ C 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-CH ₃ ), 20.07, 19.89 ppm; C34H37N9O4 (mol. w 635.73), LC-MS (EI) m/e 636.3 (M ⁺ + H).

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

- 26 041099

N-(4-(4-amino7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f ][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3 (pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide ( compound I, 1401 g, 2.204 mol) in methanol (MeOH, 10 L) and dichloromethane (DCM, 20 L) at room temperature. The suspension was heated to 50°C to obtain a solution. Activated carbon (70 g) and silica gel (70 g) were added to the solution. After stirring for 2 hours at 50° C., the mixture was filtered through a pad of celite. Maleic acid (269 g, 2.314 mol) was added to the filtrate. Most of the DXM was distilled at atmospheric pressure. The solids gradually precipitated out. The solids were collected by filtration at 18° C. and washed with MeOH (3 L). The residue was dried on a filter under standard vacuum for 72 h to give N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4] maleate triazin-5-yl)phenyl)-1isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (compound I maleate, 1425 g, 86% ) as an almost white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.83 (s, 1H), 8.71 (s, 1H), 8.65-8.63 (m, 1H), 8.06 (td, J=7.8, 1.9Hz, 1H), 7.95(s, 1H), 7.77(d, J=8.6Hz, 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 C 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 ; C34H37N9O4 (free base, mol wt 635.73), LC-MS (EI) m/e 636.3 (M ⁺ + H).

Example 2 Synthesis of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5yl)phenyl)-1-isopropyl -2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide hemisulfate (amorphous form) (compound II hemisulfate)

Scheme 2.

Step 1: 5-bromo-7-(piperidin-4-yl)pyrrolo[1,2-1][1,2,4]triazin-4-amine dihydrochloride (compound 2)

A five-necked round-bottom flask with a volume of 22 L, equipped with a mechanical stirrer, heater, thermocouple, reflux condenser, nitrogen inlet and nitrogen outlet tubes, was charged with tert-butyl 4-(4-amino-5-bromopyrrolo[2,1-f][1,2, 4]triazin-7-yl)piperidine-1-carboxylate (compound 1, 880 g, 2.221 mol) in dichloromethane (DCM, 8.0 L) at room temperature. Hydrochloric acid in 2-propanol (5.8 N, 2.7 L, 15.66 mol, 7.05 eq.) was added to the suspension. The mixture was heated to 35° C. for 4 hours. The reaction mixture was diluted with tert-butyl methyl ether (TBME, 4.5 L) and cooled to room temperature.

- 27 041099 temperature. The suspension was filtered and washed with TBME (2.0 L). The residue was dried on the filter in vacuo for 24 hours to give 5-bromo-7-(piperidin-4-yl)pyrrolo[1,2-H1,2,4]triazine-4-amine dihydrochloride (compound 2, 848 g, 103%) as a light brown solid.

1H 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 BrN ₅ (mol. w. 295.0), LC-MS (EI) m/e 296.0 (M ⁺ + H).

Step 2: 1-(4-(4-amino-5-bromopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan1-one (compound 3).

5-bromo-7(piperidin-4-yl)pyrrolo[1,2-^[1,2,4]triazine -4-amine dihydrochloride (compound 2, 1300 g, 3.522 mol) in N-methylpiperidinone (NMP, 10 L) at room temperature. N,Ndiisopropylethylamine (1593 g, 12.3 mol) was added to the suspension. The mixture was cooled to 10° C. and then 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 the starting material. After completion of the reaction, the reaction mixture was filtered through a pad of celite. The resulting filtrate was cooled to 10° C. and water (26 L) was gradually added to precipitate the product. The solids were collected by filtration and washed with water (12 L). The residue was dried on a filter in vacuo for 48 hours to give 1-(4-(4-amino-5-bromopyrrolo[1,2-^[1,2,4]triazin-7-yl)piperidin-1-yl)-2 -methylpropan-1-one (compound 3, 1095 g, 85%) as a light brown solid.

¹ H NMR (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 C 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 BrN ₅ O (mol. w 365.09), LC-MS (EI) m/e 366.1 (M ⁺ + H).

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

A five-necked 22 L round-bottom flask equipped with a mechanical stirrer, heater, thermocouple, reflux condenser, nitrogen inlet and nitrogen outlet tubes was charged with 1-(4-(4-amino-5-bromopyrrolo[1,2-f][1,2, 4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one (compound 3, 700 g, 1.911 mol), 4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)aniline (compound 4, 502 g, 2.293 mol) and potassium carbonate (528 g, 3.822 mol) in 1-butanol (7.7 L) and water (1.4 L) at room temperature . The mixture was treated 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) at room temperature. The reaction mixture was degassed and refilled with nitrogen and then heated to 80°C. After 2 hours at 80° C., the reaction mixture was diluted with n-heptane (8 L).

The resulting suspension was cooled to room temperature. The solids were collected by filtration and washed with water (6 L). The residue was dried on a filter in vacuo 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)-2methylpropan-1-one (compound 5, 648 g, 90%) as a brown solid.

1H NMR (500 MHz, DMSO-d ₆ ) 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 (n, 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 C 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 ₂ iH ₂ 6N6O (mol. w 378.48), LCMS (EI) m/e 379.2 (M ⁺ + H).

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).

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) at room temperature. The reaction mixture was treated in turn with triethylamine (NEt ₃ , 241 g, 2.378 mol) followed by 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). After completion of the reaction, water (8 L) was added to the reaction mixture at room temperature. Solids were collected by filtration. The resulting wet residue was placed back into the 22 L round bottom flask and suspended in THF (2.7 L) and water (5.4 L). The suspension was heated to 55°C and stirred at 55°C for 2 hours. The solids were collected by filtration after cooling to 30°C and washed with water (8 l). The residue was dried on a filter in vacuo for 2 days to give Na(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2f][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.

¹ H 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), 7.557.46 (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 C 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-CH ₃ ), 20.06, 19.89 ppm; C35H38N8O4 (mol. w 634.74), LC-MS (EI) m/e 635.3 (M ⁺ + H).

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 (sulfuric acid salt of compound II).

N-(4-(4-amino-7-(1isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1, 2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl1,2,3,4-tetrahydropyrimidine-5-carboxamide (compound II, 713 g, 1.123 mol) in methanol (MeOH, 5.6 L) at room temperature. The mixture was heated to 55° C. and treated with a solution of sulfuric acid (H ₂ SO ₄ , 116 g, 1.179 mol) in water (1 L). After stirring at 55° C. for 30 minutes, 2.8 liters of solvents were distilled under reduced pressure. The reaction mixture was cooled to room temperature. The resulting solids were collected by filtration and washed with MeOH (0.7 L). The residue was dried on a filter under vacuum for 2 days to give N-(4-(4-amino-7-(1isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazine-5- yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl1,2,3,4-tetrahydropyrimidine-5-carboxamide sulfate (sulfuric acid salt of compound II, 744 g, 90%) as a yellow solid .

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).

N-(4-(4-amino-7-(1isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1, 2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl1,2,3,4-tetrahydropyrimidine-5-carboxamide sulfate (compound II sulfuric acid salt, 729 g, 0.995 mol) in water (16 L) at room temperature. The suspension was heated to 35°C and stirred for 3 days. The solids were collected by filtration and washed with water (10 L). The wet residue was dried on the filter in vacuo to give N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2f][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.

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 form.

N-(4-(4-amino-7-(1-isobutyrylpiperidin-4yl)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) at room temperature. The solution was filtered through filter paper into a 3 L single necked round bottom flask. The filtrate was concentrated to remove most of the solvents under reduced pressure. The resulting foamy solid was dried in a vacuum oven at 50° C. under standard vacuum with a nitrogen purge to give N-(4-(4-amino7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][ 1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide hemisulfate (amorphous hemisulfate compound II, 38 g, 95%) as a light yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 11.01 (s, 1H), 8.68 (s, 1H), 8.07 (s, 1H), 7.80 (d, J=8.6 Hz, 2H), 7.557.45 (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;

- 29 041099 ¹³ C NMR (101 MHz, DMSOCH) 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; C35H38N8O4 (mol. w 634.74), LC-MS (EI) m/e

635.3 (M ⁺ + H); acid titration, sulfate: free base=0.50; elemental analysis for sulfur, calculated value 2.34%, observed value 2.29%.

Example 3 Alternative Synthesis of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,21][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.

Step 1: 1-isopropyl-2,4-dioxo-3-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)-1,2, 3,4-tetrahydropyrimidine-5-carboxamide (compound 8).

1-isopropyl-2,4-dioxo-3-phenyl1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (compound 7, 202 g, 0.736 mol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (169 g, 0.773 mol) in N,N-dimethylformamide (DMF, 1.2 k) at room temperature. To the mixture was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3tetramethylisouronium hexafluorophosphate(U) (HATU, 336 g, 0.884 mmol) at room temperature. Triethylamine (NEt ₃ , 97 g, 0.957 mol) was added to the mixture after cooling to an internal temperature below 15°C. The reaction mixture was then stirred at 15-25° C. for 4 hours. Water (1.2 L) was added slowly to precipitate the product. The solids were collected by filtration and washed with water (3x0.6 L). The residue was dried in a vacuum oven at 50°C with a gentle purge of nitrogen to give 1isopropyl-2,4-dioxo-3-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (compound 8, 363 g, 104%) as a white solid.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.99 (s, 1H), 8.65 (s, 1H), 7.68-7.63 (m, 4H), 7.53-7, 51 (m, 2H), 7.487.45 (m, 1H), 7.36 (dd, J=8.2, 1.2 Hz, 2H), 4.78 (hept, J=6.8 Hz, 1H ), 1.43 (d, J=6.8 Hz, 6H), 1.29 (s, 12H) ppm;

¹³ C NMR (150 MHz, DMSOCH) δ 163.24, 160.69, 150.46, 147.50, 141.32, 135.96, 135.83, 129.47, 129.09, 129.03, 124.09, 119.19, 105.10, 83.98, 50.89, 25.14, 21.18 ppm; C ₂₆ H ₃₀ HM ₃ O ₅ (mol. w 475.35), LC-MS (EI) m/e 476.3 (M + + H).

Stage 2: 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)

A five-necked round-bottom flask with a volume of 22 L, equipped with a mechanical stirrer, reflux condenser, thermocouple, heater, nitrogen inlet and nitrogen outlet tubes, was charged with tert-butyl 4-(4-amino-5-bromopyrrolo[2,1-f][1,2, 4]triazin-7-yl)piperidine-1-carboxylate (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-2yl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (compound 8, 735 g, 1.546 mol) and tribasic potassium phosphate (K ₃ PO ₄ , 597 g, 2.811 mol) in 1,4-dioxane (6.0 L) and water (1.1 L) at room temperature. The mixture was degassed and refilled with nitrogen. 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 to the reaction mixture. The reaction mixture was degassed, refilled with nitrogen and heated to 80°C. After 3 h stirring at 80° C., water (6.0 L) was added to the reaction mixture over 1 h. The resulting solids were collected by filtration at 20° C. and washed with water (2 x 3.0 L) and n-heptane (2 x 2.0 l). The residue was transferred back to a 22 L round bottom flask and suspended in ethyl acetate (EtOAc, 6.0 L) and methyl t-butyl ether (MTBE, 2.2 L) at room temperature. The suspension was heated to 55° C. and stirred for 2 hours. After the mixture was cooled to 20° C., the solids were collected by filtration and washed with MTBE (2 x 1.0 L). The residue was dried in a filter funnel under vacuum for 2 days to give tert-butyl 4-(4-amino-5-(4-(1isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine -5-carboxamido)phenyl)pyrrolo[1,2d[1,2,4]triazin-7-yl)piperidine-1-carboxylate (compound 9, 827 g, 85%) as a light brown solid.

¹ H 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, 1H), 2.89 (s, 2H), 1.99 (d, J=11.4 Hz, 2H), 1.56 (cd, J=12, 7, 4.1 Hz, 2H), 1.44 (d, J=6.8 Hz, 6H), 1.42 (s, 9H) ppm;

¹³ C 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; C ₃₆ H ₄₀ N ₈ O ₅ (mol. w 664.76), LC-MS (EI) m/e 665.3 (M ⁺ + H).

Step 3. N-(4-(4-amino-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl2, 4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide dihydrochloride (compound 10)

A five-necked 22 L round-bottom flask equipped with a mechanical stirrer, reflux condenser, thermocouple, heater, nitrogen inlet and nitrogen outlet tubes was loaded with 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-N1,2,4]triazin-7-yl)piperidine-1-carboxylate (compound 9, 737 g , 1.053 mol) in dichloromethane (DCM, 4.5 L) at room temperature. Hydrochloric acid in 2-propanol (5.8 N in IPA, 1.474 L, 8.549 mol, 8.12 eq) was added to the suspension. 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 solids were collected by filtration and washed with DCM (2 x 0.2 L). The residue was dried in a filter funnel under vacuum for 2 days to give 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 an acicular 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;

¹³ C 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; C31H32NO3 (mol. w 564.64), LC-MS (EI) m/e 565.3 (M ⁺ + H).

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).

N-(4-(4-amino-7-(piperidin-4yl)pyrrolo[1,2-f][1,2, 4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidin-5-carboxamide dihydrochloride (608 g, 0.954 mol) in dichloromethane (DCM , 17.6 L) at room temperature. Aqueous sodium hydroxide solution (NaOH, 1N, 3.815 L, 3.815 mol) was added to the 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. After completion of the reaction, the mixture was filtered through a pad of celite. The organic phase was separated, washed with water (2 x 2.5 L) and concentrated under reduced pressure. 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 solids were collected by filtration. The residue was dried on the filter in vacuo for 24 h to give N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin- 5-yl)phenyl)-1-isopropyl2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (compound II, 548 g, 91%) as light yellow solid .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.03 (s, 1H), 8.68 (s, 1H), 8.19 (s, 1H), 7.82 (d, J=8, 6 Hz, 2H), 7.557.46 (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 C 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-CH ₃ ), 20.06, 19.89 ppm; C ₃₅ H ₃₈ N ₈ O ₄ (mol. w 634.74), LC-MS (EI) m/e 635.3 (M ⁺ + H).

Example 4 Synthesis of tert-butyl 4-(4-amino-5-bromopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-31 041099 carboxylate (compound 1 of Schemes 1 and 2) Scheme 4.

Stage 1 Stage 2 Stage 3

13 14 1

Step 1: tert-Butyl 4-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5,6-dihydropyridine-1(2H)carboxylate (compound 13)

A 3 L round-bottom flask equipped with a mechanical stirrer, heater, thermocouple, reflux condenser, nitrogen inlet and nitrogen outlet tubes was charged with 7-bromopyrrolo[1,2-f][1,2,4]triazine-4-amine (compound 11, 100 g , 469 mmol) and tert-butyl 4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (compound 12, 174 g , 563 mmol) in 1,4-dioxane (876 ml) at room temperature. Potassium carbonate (130 g, 939 mmol) and water (218 g) were added in turn to the reaction flask. The mixture was degassed by vacuum and refilled with nitrogen three times. After adding tetrakis(triphenylphosphine)palladium (0) (Pd(PPh ₃ ) ₄ , 13.56 g, 11.7 mmol), the reaction mixture was degassed and refilled with nitrogen three times at room temperature. The reaction mixture was then heated to 85-90°C and stirred at that temperature for 16 hours. After completion of the reaction, water (900 ml) was added over 30 minutes while maintaining the internal temperature above 50°C. The mixture was cooled to room temperature. The solids gradually precipitated out. The solids were collected by filtration at 18°C and washed with water (2x250 ml) and methyl mpem-butyl ether (MTBE, 3x200 ml). The wet residue was placed back into the reaction flask and stirred in MTBE (750 ml) at 50° C. for 1 hour. Solids were collected by filtration at room temperature. The residue was dried in a vacuum oven at 50°C under vacuum with a nitrogen purge for 72 h to give tert-butyl 4-(4-aminopyrrolo[1,2f][1,2,4]triazin-7-yl)-5, 6-dihydropyridine-1(2H)-carboxylate (compound 13, 123.7 g, 84%) as a brown solid.

¹ H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.69 (s, 2H), 7.00 (s, 1H), 6.91 (d, J=4.6 Hz, 1H), 6.69 (d, J=4.5 Hz, 1H), 4.06 (s, 2H), 3.55 (t, J=5.5 Hz, 2H), 2.59 -2.52 (m, 2H), 1.43 (s, 9H) ppm; C16H21N5O2 (mol. w 315.37), LC-MS (EI) m/e 316.1 (M ⁺ + H).

Step 2: tert-Butyl 4-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (compound 14)

A 2 L flask was loaded with tert-butyl 4-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5,6dihydropyridine-1(2H)-carboxylate (compound 13, 50.0 g, 159 mmol) and platinum (IV) oxide (10.0 g, 44 mmol) in acetic acid (1000 ml) at room temperature. The flask was placed in a Parr mixer with 50 psi hydrogen gas. After 16 h the reaction mixture was filtered through a pad of celite (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 the MTBE solution to adjust the pH to 6-7. The solids were collected by filtration and washed with water (2x300 ml) and n-heptane (2x300 ml). The residue was dried in a vacuum oven at 50°C under vacuum with a nitrogen purge for 16 h to give tert-butyl 4-(4-aminopyrrolo[1,2-L][1,2,4]triazin-7-yl)piperidine -1 carboxylate (compound 14, 49.3 g, 98%) as a light brown solid.

¹ H NMR (500 MHz, DMSO-06) 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 (cd, J=12.6, 4.0 Hz, 2H), 1.42 (s, 9H ) ppm; C ₁₆ H ₂₃ N ₅ O ₂ (mol. w 317.39), LC-MS (EI) m/e 318.1 (M ⁺ + H).

Step 3: tert-Butyl 4-(4-amino-5-bromopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (compound 1)

A five-necked round-bottom flask with a volume of 22 L, equipped with a mechanical stirrer, thermocouple, reflux condenser, nitrogen inlet and nitrogen outlet tubes, was loaded with tert-butyl 4(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl )piperidine-1-carboxylate (compound 14, 730 g, 2.30 mol) in tetrahydrofuran (THF, 14.0 L) at room temperature. The mixture was cooled to 0-5°C. N-bromosuccinimide (NBS, 409 g, 2.30 mol) was added to the reaction mixture over 5 min while maintaining the internal temperature below 15°C. After 1 hour stirring at a temperature below 10° C., some solvents (9.0 L) were removed under reduced pressure. To the remaining solution was added a solution of sodium bicarbonate (140 g, 1.67 mol) in water (14.0 L) over 5 minutes. Solids precipitated out. Solid

- 32 041099 substances were collected by filtration and washed with water (7.0 l) and n-heptane (4 l). The wet residue was dried on a filter under standard vacuum for 48 h to give tert-butyl 4-(4-amino-5-bromopyrrolo[1,2Ni[1,2,4]triazin-7-yl)piperidine-1-carboxylate (compound 1 , 886 g, 97%) as a brown solid.

1H NMR (400 MHz, DMSO-d ₆ ) 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 (cd, J=12.8, 4, 1 Hz, 2H), 1.41 (s, 9H) ppm;

¹³ C NMR (101 MHz, DMSOL) 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; C16H22BrN5O2 (mol. w 395.10), LC-MS (EI) m/e 396.1 (M ⁺ + H).

Example 5 Synthesis of 1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (Compound 7 of Schemes 2 and 3)

Stage 1: diethyl 2-((3-phenylureido)methylene)malonate o o tJU g Utt

NH|1

H

To a mixture of diethyl(aminomethylene)malonate (6.0 g, 32 mmol) and phenylisocyanate (3.8 ml, 35 mmol) in 1,2-dichloroethane (20 ml) was added N,N-diisopropylethylamine (7.2 ml , 42 mmol). The reaction mixture was then stirred at 70°C overnight, cooled to RT, added Et ₂ O (50 ml) and stirred for another 30 min. The resulting solid was collected by filtration, washed with ether and dried to give the product as a white solid (4.88 g, 50%). LC-MS calculated for C ₁₅ H ₁₉ N ₂ O ₅ (M+H) ⁺ : m/z=307.1. Found: 307.2.

Stage 2: ethyl 2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate „γ.Ο n

A mixture of diethyl 2-((3-phenylureido)methylene)malonate from the previous step (4.88 g, 15.9 mmol) and 2.5 M NaOEt in EtOH (13 mL, 32 mmol) in EtOH (20 mL) was stirred at RT for 1 h. The resulting mixture was diluted with EtOAc, washed/acidified with 1 N citric acid, washed with water, brine, dried over Na ₂ SO ₄ and concentrated to give the crude product as a white solid, which was used directly on next stage (4.1 g, 99%). LC-MS calculated for C ₁₃ H ₁₃ N ₂ O ₄ (M+H) ⁺ : m/z=261.1. Found: 261.1.

Stage 3: ethyl 1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate O O eAW

A mixture of ethyl 2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate from the previous step (1.50 g, 5.76 mmol), isopropyl iodide (1.2 ml, 12 mmol) and Cs ₂ CO ₃ (5.6 g, 17 mmol) in DMF (20 ml) was stirred at 50°C for 5 h. The reaction mixture was then cooled to RT, diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated to give the crude product, which was used directly in the next step. LC-MS calculated for C16Hi9N2O ₄ (M+H) ⁺ : m/z=303.1. Found: 303.1.

Stage 4: 1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

A mixture of ethyl 1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate from the previous step (1.70 g, 5.62 mmol) in 4.0 M HCl in 1,4-dioxane (9.8 ml, 39 mmol) and water (2.1 ml) were stirred at 60° C. for 4 h, cooled to RT and water was added. The resulting solid was then collected by filtration (washed with water) to give the product as a white solid (1.1 g, 71%). LC-MS calculated for C ₁₄ H ₁₅ N ₂ O ₄ (M+H) ⁺ : m/z=275.1. Found: 275.1.

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

To a mixture of diethyl 2-(aminomethylene)malonate (3.0 g, 16.0 mmol) and 2-isocyanatopyridine (2.02 g, 16.8

- 33 041099 mmol) in 1,2-dichloroethane (9.0 ml) at RT was added Ν,N-diisopropylethylamine (3.6 ml, 20.8 mmol).

The reaction mixture was then stirred at 70° C. overnight, cooled to RT and purified directly by column chromatography (0% to 15% MeOH in CH ₂ Cl ₂ ) to give the product (3.18 g, 65%). LC-MS calculated for C ₁₄ H ₁₈ N ₃ O ₅ (M+H)+: m/z=308.1. Found: 308.1.

Stage 2: 1-isoprotyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

A mixture of diethyl 2-((3-(pyridin-2-yl)ureido)methylene)malonate (3.18 g, 10.4 mmol) and 2.5 M NaOEt in EtOH (6.2 ml, 15.5 mmol) in EtOH (25 ml) was stirred at RT for 3 h. The resulting mixture was diluted with EtOH and washed/acidified with a solution of 1 N citric acid (30 ml). The organic layer was separated and the aqueous layer was further extracted with CHCl ₃ /isopropyl alcohol 3:1 (30 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give the crude product, ethyl 2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate, which was used directly on the next stages. LC-MS calculated for C ₁₂ H ₁₂ N ₃ O ₄ (M+H)+: m/z=262.1. Found: 262.2.

Mixture of crude ethyl 2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate from the previous step, 2-iodopropane (2.06 ml, 20.7 mmol) and Cs ₂ CO ₃ (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 RT, diluted with CHCl ₃ /isopropyl alcohol 3:1 (75 ml), washed with water, brine, dried over Na ₂ SO ₄ and concentrated to give the crude product, ethyl 1-isopropyl2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine -5-carboxylate, which was used directly in the next step. LC-MS calculated for C ₁₅ H ₁₈ N ₃ O ₄ (M+H)+: m/z=304.1. Found: 304.1.

A mixture of crude ethyl 1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine5-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 hours, cooled to RT and concentrated. The resulting material was then purified by column chromatography (0% to 15% MeOH in CH2Cl2) to give the product as an off-white solid (1.50 g, 47% three steps). LC-MS calculated for C ₁₃ H ₁₄ N ₃ O ₄ (M+H) ⁺ : m/z=276.1. Found: 276.1.

Example 7 Description of the solid state characteristics of N-(4-(4-amino-7-(1isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl) maleate -1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (compound I maleate form I)

X-ray powder diffractometry (XRPD) of compound I maleate X-ray powder diffractometry (XRPD) was obtained using a Rigaku MiniFlex X-ray powder diffractometer (XRPD). The general experimental procedure for XRPD was as follows: (1) X-ray emission from copper at 1.054056 A with a K^ filter; (2) X-ray powder at 30 kV, 15 mA; and (3) a sample of the powder was dispersed on a sample holder with zero background. General measurement conditions for XRPD were as follows: Starting angle 3°; limit angle 45°; sampling 0.02° and scanning speed 2°/min. The powder x-ray diffraction pattern is shown in Fig. 1, and the XRPD data are presented in Table. 1.

- 34 041099

Table 1. XRPD Data: Maleate Compound of Formula I (Form I)

Differential Scanning Calorimetry (DSC) of Compound I Maleate (Form I)

DSC was obtained using a TA Instruments Model Q200 Differential Scanning Calorimetry instrument with autosampler. The parameters of the DSC device were as follows: 30-300°C at 10°C/min; aluminum sample dish with Tzero lid; flow of nitrogen gas at a rate of 50 ml/min. The DSC thermogram is shown in Fig. 2. The DSC thermogram revealed a major endothermic event at a decomposition onset temperature of 202.9°C with a peak temperature of 211.0°C, which is considered the melting and decomposition temperature of the compound.

Thermogravimetric Analysis (TGA) of Compound I Maleate (Form I)

TGA was performed using a thermogravimetric analyzer TA Instrument, model Q500. The general conditions of the TGA experiment were as follows: temperature ramp from 20°C to 600°C at 20°C/min; nitrogen purge, gas flow at 40 ml/min, followed by purge flow balance; sample purge flow at 60 ml/min; platinum crucible for the sample. The TGA thermogram is shown in Fig. 3. A weight loss of about 0.7% was observed at temperatures up to 150°C, it was believed that this was due to loss of moisture and residual solvents. The compound begins to decompose to a large extent at temperatures above 200°C.

Solubility of Compound I Maleate (Form I)

The solubility of the maleate compound I was measured at 25±1°C and at 50±1°C. General procedures for testing solubility at 25±1°C are as follows: 1) 3 ml of each solvent listed in table. 1A were added to separate vials; 2) compound I maleate was added to form a cloudy solution at 25°C; 3) another 15-20 mg of compound I maleate was added; 4) the mixture was stirred at 25±1°C for 48 hours; 5) the supernatant was filtered using a syringe filter; and 6) the saturated solution was diluted with MeOH and analyzed by HPLC. General procedures for testing solubility at 50±1°C are as follows: 1) 3 ml of each solvent listed in table. 1A were added to separate vials; 2) compound I maleate was added to form a cloudy solution at 50°C; 3) another 20-25 mg of compound I maleate was added; 4) the mixture was stirred at 50±1°C for 24 hours; 5) the supernatant was filtered using a heated syringe filter at 50±1°C; and 6) the saturated solution was diluted with MeOH and analyzed by HPLC. The results are summarized in table. 1A.

Table 1A

Recording Solvent Solubility at 25 °C (mg/ml) Solubility at 50 °C (mg/ml) 1 MeCN 0.28 0.68 2 Chloroform 6.12 13.74 3 dichloromethane 24.35 33.70 4 DMF >50 >50 5 1,4-dioxane 2.31 4.62 6 methanol 1.64 3.09

- 35 041099

7 2-methoxyethanol 5.96 14.75 8 mshk 0.43 0.74 9 Toluene 0.18 0.20 10 Geksan 0.00 0.00 AND ΤΓΦ 0.92 1.63 12 Acetone 1.68 3.05 13 n-ViON 0.21 1, Yu 14 MTVE 0.08 0.1 15 dmso >50 >50 16 EtOH 0.65 1.93 17 EtOAc 0.18 0.40 18 Ethyl formate 0.68 0.99 19 Heptane 0.00 0.00 20 IP Ac 0.27 0.33 21 1-propanol 0.44 1.31 22 IPA 0.16 0.68 23 Water 0.02 0.04 24 MEK 0.28 2.19 25 2% DXM/ 98% MeOH (v/v) 1.46 N/A 26 10% DXM/ 90% MeOH (v/v) 1.88 N/A 27 DXM/MeOH (2/1) >50 N/A

Other crystalline salts

Other crystalline salts of the compound of formula I, such as the HCl salt, monosulfate, hemisulfate, mesylate and besylate, have also been discovered and prepared.

Example 8 Preparation of N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,21][1,2,4]triazin-5-yl)phenyl)-1- salts isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (salts of compound II)

Salts of compound II were obtained in accordance with the procedures described in table. 2 below. These salts were analyzed by XRPD, DSC and TGA (see Examples 9-15).

table 2

Salt Procedures Phosphate 60.94 mg of the free base of compound II were combined with 2.4 ml of the mixture

- 36 041099

methanol/DCM (1:2) and stirred to obtain a clear solution. Phosphoric acid in IPA (0.115 ml, 0.115 mmol, 1.20 eq.) was added and the solution was stirred at room temperature for 5 hours. The solvent was concentrated to a total volume of about 1.0 ml to give a suspension which was stirred at 65°C for 120 min. The suspension was cooled to room temperature (20-21°C) and stirred for 2 hours. The suspension was filtered and washed with MTBE. The solid was dried at 43-45°C under vacuum overnight. Weight: 58.2 mg (82.7%). The stoichiometric ratio of salt between the free base of the compound II and phosphoric acid was determined by elemental analysis and % mass, using HPLC as 1:1. XRPD (see example 9, Fig. 4), DSC (example 9, Fig. 5) and TGA (example 9, Fig. 6) Maleate 51.74 mg of the free base of compound II was combined with 1.5 ml of DCM and 0.5 ml of MeOH and stirred to obtain a clear solution. Maleic acid (14.19 mg, 0.12 mmol, 1.50 eq) was added and the solution was stirred at room temperature for 2 hours. The solvent was concentrated at 43-44°C to a total volume of about 0.5 ml. The mixture was cooled to room temperature and stirred for 2 hours. 1.5 ml of IP A was added and the suspension was stirred for 2-3 minutes. The suspension was filtered and washed with MTBE. The solid was dried at 43-45°C under vacuum overnight. Weight: 56 mg (91.5%). The stoichiometric salt ratio between the free base of compound II and maleic acid was determined using Ή NMR as 1:1. XRPD (see example 10, Fig. 7), DSC (see example 10, Fig. 8) and TGA (see example 10, Fig. 9) hemisulfate 87.70 mg of compound II free base were combined with 2.4 ml of MeOH and 1.2 ml of DCM and stirred for 20 minutes. to obtain an almost clear solution. Sulfuric acid in water (0.083 ml, 0.083 mmol, 1M in water, 0.6 eq.) was added and the solution was stirred at room temperature for 2 minutes. to obtain a clear solution. The solution was further stirred for 30 minutes. and the solvent was then concentrated to a volume of about 1.1 ml with

- 37 041099

obtaining a suspension. The mixture was further stirred at 70°C for 1.0 hour and at 65°C for 1.0 hour. The suspension was cooled to room temperature (19-20°C) and stirred for 1 hour. The suspension was filtered and washed with MTBE. The solid was dried at 43-45°C under vacuum overnight. Weight: 75.74 mg (80.2%). The stoichiometric ratio of salt between the free base of compound II and sulfuric acid was determined using elemental analysis as 2:1. XRPD (see example 11, Fig. 10), DSC (see example 11, Fig. 11) and TGA (see example I, Fig. 12) Hydrochloride 76.25 mg of the free base of compound II was combined with 2.0 ml of a mixture of methanol/DCM (1:2) and stirred to obtain a clear solution. Hydrochloric acid in IPA (0.14 ml, 0.14 mmol, 1.17 eq.) was added and the solution was stirred at room temperature for 3 hours. 1.5 ml of IP A was added and then the solvent was concentrated to a volume of about 1.4 ml at 67-68°C to obtain a suspension. 0.8 ml of ethanol was added and the suspension was stirred at 76-78°C for 2 hours. The suspension was cooled to room temperature (19-20°C) and stirred for 1 hour. The suspension was filtered and washed with MTBE. The solid was dried at 43-45°C under vacuum overnight. Weight: 72 mg (89.30%). The stoichiometric ratio of salt between the free base of the compound II and hydrochloric acid was determined as 1:1 by % mass, using HPLC and elemental analysis. XRPD (see example 12, Fig. 13), DSC (see example 12, Fig. 14) and TGA (see example 12, Fig. 15) salicylate 60.94 mg of the free base of compound II was combined with 2.4 ml of a mixture of methanol/DCM (1:2) and stirred to obtain a clear solution. Salicylic acid (16.3 mg, 0.115 mmol, 1.20 eq.) was added and the solution was stirred at room temperature for 2 hours. The solvent was concentrated to a volume of about 1.0 ml. 0.8 ml IPA was added and the suspension was stirred at 65°C for 120 min. The suspension was cooled to room temperature (19-20°C) and stirred for 2 hours. The suspension was filtered and washed with MTBE. The solid was dried at 43-45°C under vacuum overnight. Weight: 55.7 mg (79.4%).

- 38 041099

The stoichiometric salt ratio between the free base of compound II and salicylic acid was determined using Ή NMR as 1:1. XRPD (see example 13, Fig. 16), DSC (see example 13, Fig. 17) and TGA (see example 13, Fig. 18) Mesylate The procedure for preparing the mesylate of compound II was similar to the procedure for preparing the phosphate salt. 1.2 ml of compound II free base (0.04 M, 30.47 mg, 0.048 mmol, 1.0 eq.) in DCM/MeOH (2:1) was combined with methanesulfonic acid (0.05 ml, 1 M in IP A, 1.04 eq.). The stoichiometric ratio of salt between the free base of compound II and methanesulfonic acid was determined using 1H NMR as 1:1. XRPD (see example 14, Fig. 19), DSC (see example 14, Fig. 20) and TGA (see example 14, Fig. 21) Ezilat The procedure for preparing the mesylate of compound II was similar to the procedure for preparing the phosphate salt. 1.2 ml of compound II free base (0.04 M, 30.47 mg, 0.048 mmol, 1.0 eq.) in DCM/MeOH (2:1) was combined with ethanesulfonic acid (0.10 ml, 0.5 M in IP A, 1.04 eq.). The stoichiometric ratio of salt between the free base of compound II and ethanesulfonic acid was determined using 1H NMR as 1:1. XRPD (see example 15, Fig. 22), DSC (see example 15, Fig. 23) and TGA (see example 15, Fig. 24)

Example 9 Description of the Phosphate Solid State Characteristics of Compound II

X-ray Powder Diffraction (XRPD) Studies for Compound II Phosphate

The phosphate salt of compound II was characterized by XRPD. The XRPD was obtained using an X-ray powder diffractometer (XRPD) Rigaku MiniFlex. The general experimental procedure for XRPD was as follows: (1) X-ray from copper at 1.054056 A with a Κβ filter; (2) X-ray powder at 30 kV, 15 mA; and (3) a sample of the powder was dispersed on a sample holder with zero background. General measurement conditions for XRPD were as follows: Starting angle 3°; limit angle 45°; sampling 0.02° and scanning speed 2°/min.

The powder X-ray diffraction pattern of the phosphate salt of compound II is shown in FIG. 4, and the XRPD data are presented in Table. 3.

- 39 041099

Table 3

Differential Scanning Calorimetry (DSC) Studies for Compound II Phosphate

The phosphate salt of compound II was characterized by DSC. DSC was obtained using a TA Instruments Model Q200 Differential Scanning Calorimetry instrument with autosampler. The DSC instrument parameters were as follows: 30-350°C at 10°C/min; aluminum sample dish with Tzero lid; flow of nitrogen gas at a rate of 50 ml/min.

The DSC thermogram of compound II phosphate is shown in FIG. 5. The DSC thermogram revealed a major endothermic event at a decomposition onset temperature of 252.6°C with a peak temperature of 257.2°C, which is considered the melting/decomposition temperature of the compound.

Thermogravimetric Analysis (TGA) Studies for Compound II Phosphate

The phosphate salt of compound II was characterized by TGA. TGA was performed using a thermogravimetric analyzer TA Instrument, model Q500. The general conditions of the TGA experiment were as follows: temperature ramp from 20 to 600°C at 20°C/min; nitrogen purge, gas flow at 40 ml/min, followed by purge flow balance; sample purge flow at 60 ml/min; platinum crucible for the sample.

The TGA thermogram of compound II phosphate is shown in FIG. 6. A weight loss of about 1.8% was observed at temperatures up to 200°C, it was believed that this was due to loss of moisture or residual solvents. A significant weight loss was observed at temperatures above 230°C, it was believed that this was due to the decomposition of the compound.

Example 10 Description of the Solid State Characteristics of Compound II Maleate

X-Ray Powder Diffraction (XRPD) Studies for Compound II Maleate

Compound II maleate was characterized by XRPD. The XRPD was obtained using an X-ray powder diffractometer (XRPD) Rigaku MiniFlex. The general experimental procedure for XRPD was as follows: (1) X-ray from copper at 1.054056 A with a Κβ filter; (2) X-ray powder at 30 kV, 15 mA; and (3) a sample of the powder was dispersed on a sample holder with zero background. General measurement conditions for XRPD were as follows: Starting angle 3°; limit angle 45°; sampling 0.02° and scanning speed 2°/min.

An X-ray powder diffraction pattern of compound II maleate is shown in FIG. 7, and the XRPD data are presented in Table. 4.

- 40 041099

Table 4

Differential Scanning Calorimetry (DSC) Studies for Compound II Maleate

Compound II maleate was characterized by DSC. DSC was obtained using a TA Installations model Q200 differential scanning calorimetry instrument with an autosampler. The parameters of the DSC device were as follows: 30-300°C at 10°C/min; aluminum sample dish with Tzero lid; flow of nitrogen gas at a rate of 50 ml/min.

The DSC thermogram of compound II maleate is shown in FIG. 8. The DSC thermogram revealed two main endothermic events, the first of which was observed at the decomposition onset temperature of 183.4°C with a peak temperature of 194.8°C, and the second at the decomposition onset temperature of 233.4°C with a peak temperature of 239.7 °C.

Thermogravimetric Analysis (TGA) Studies for Compound II Maleate

Compound II maleate was characterized by TGA. TGA was performed using a thermogravimetric analyzer TA Installation, model Q500. The general conditions of the TGA experiment were as follows: temperature ramp from 20 to 600°C at 20°C/min; nitrogen purge, gas flow at 40 ml/min, followed by purge flow balance; sample purge flow at 60 ml/min; platinum crucible for the sample.

The TGA thermogram of compound II maleate is shown in FIG. 9. A weight loss of about 1.8% was observed at temperatures up to 125°C, it was believed that this was due to loss of moisture or residual solvents. A significant weight loss was observed at temperatures above 175°C, it was believed that this was due to the decomposition of the compound.

Example 11 Description of the Solid State Characteristics of Compound II Hemisulphate

X-Ray Powder Diffraction (XRPD) Studies for Compound II Hemisulfate

Compound II hemisulfate was characterized by XRPD. The XRPD was obtained using an X-ray powder diffractometer (XRPD) Rigaku MiniFlex. The general experimental procedure for XRPD was as follows: (1) X-ray from copper at 1.054056 A with a Κβ filter; (2) X-ray powder at 30 kV, 15 mA; and (3) a sample of the powder was dispersed on a sample holder with zero background. General measurement conditions for XRPD were as follows: Starting angle 3°; limit angle 45°; sampling 0.02° and scanning speed 2°/min.

An X-ray powder diffraction pattern of compound II hemisulfate is shown in FIG. 10, and the XRPD data are presented in Table. 5.

- 41 041099

Table 5

Differential Scanning Calorimetry (DSC) Studies for Compound II Hemisulfate

The hemisulfate of compound II was characterized by DSC. DSC was obtained using a TA Instruments Model Q200 Differential Scanning Calorimetry instrument with autosampler. The DSC instrument parameters were as follows: 30-350°C at 10°C/min; aluminum sample dish with Tzero lid; flow of nitrogen gas at a rate of 50 ml/min.

The DSC thermogram of compound II hemisulfate is shown in FIG. 11. The DSC thermogram revealed a major endothermic event at a decomposition onset temperature of 283.8°C with a peak temperature of 289.4°C, which is considered the melting/decomposition temperature of the compound.

Thermogravimetric Analysis (TGA) Studies for Compound II Hemisulfate

Compound II hemisulfate was characterized by TGA. TGA was performed using a thermogravimetric analyzer TA Instrument, model Q500. The general conditions of the TGA experiment were as follows: temperature ramp from 20 to 600°C at 20°C/min; nitrogen purge, gas flow at 40 ml/min, followed by purge flow balance; sample purge flow at 60 ml/min; platinum crucible for the sample.

The TGA thermogram of compound II hemisulfate is shown in FIG. 12. A weight loss of about 1.5% was observed at temperatures up to 100°C, it was believed that this was due to loss of moisture or residual solvents. At various stages, a significant weight loss was observed at temperatures above 200°C, it was believed that this was due to the decomposition of the compound.

Example 12 Description of Solid State Characteristics of Compound II Hydrochloride X-Ray Powder Diffractometry (XRPD) Studies of Compound II Hydrochloride

Compound II hydrochloride was characterized by XRPD. The XRPD was obtained using an X-ray powder diffractometer (XRPD) Rigaku MiniFlex. The general experimental procedure for XRPD was as follows: (1) X-ray from copper at 1.054056 A with a Κβ filter; (2) X-ray powder at 30 kV, 15 mA; and (3) a sample of the powder was dispersed on a sample holder with zero background. General measurement conditions for XRPD were as follows: Starting angle 3°; limit angle 45°; sampling 0.02° and scanning speed 2°/min.

An X-ray powder diffraction pattern of compound II hydrochloride is shown in FIG. 13, and the XRPD data are presented in Table. 6.

- 42 041099

Table 6

2-theta: (°) Height N% 4.4 56 AND 2 6.5 502 100 9.7 141 28.1 10.3 99 19.7 13.1 37 7.4 13.9 78 15.5 14.9 96 19.1 16.5 84 16.7 17.0 40 8 18.9 83 16.5 19.7 73 14.5 20.9 54 10.8 21.5 169 33.7 21.8 114 22.7 23.9 130 25.9 25.1 37 7.4 25.7 38 7.6 27.4 50 10 29.1 44 8.8

Differential Scanning Calorimetry (DSC) Studies for Compound II Hydrochloride

Compound II hydrochloride was characterized by DSC. DSC was obtained using a TA Installations model Q200 differential scanning calorimetry instrument with an autosampler. The DSC instrument parameters were as follows: 30-300°C at 10°C/min; aluminum sample dish with Tzero lid; flow of nitrogen gas at a rate of 50 ml/min.

The DSC thermogram of compound II hydrochloride is shown in FIG. 14. The DSC thermogram revealed a major endothermic event at a decomposition onset temperature of 183.5°C with a peak temperature of 190.0°C, which is considered the melting/decomposition temperature of the compound.

Thermogravimetric Analysis (TGA) Studies for Compound II Hydrochloride

Compound II hydrochloride was characterized by TGA. TGA was performed using a thermogravimetric analyzer TA Installation, model Q500. The general conditions of the TGA experiment were as follows: temperature ramp from 20 to 600°C at 20°C/min; nitrogen purge, gas flow at 40 ml/min, followed by purge flow balance; sample purge flow at 60 ml/min; platinum crucible for the sample.

The TGA thermogram of compound II hydrochloride is shown in FIG. 15. A weight loss of about 5.9% was observed at temperatures up to 200°C, it was believed that this was due to loss of moisture or residual solvents. A significant weight loss was observed at temperatures above 200°C, it was believed that this was due to the decomposition of the compound.

Example 13 Description of the Solid State Characteristics of Compound II Salicylate

X-Ray Powder Diffraction (XRPD) Studies for Salicylate Compound II

Compound II salicylate was characterized by XRPD. The XRPD was obtained using an X-ray powder diffractometer (XRPD) Rigaku MiniFlex. The general experimental procedure for XRPD was as follows: (1) X-ray from copper at 1.054056 A with a Κβ filter; (2) X-ray powder at 30 kV, 15 mA; and (3) a sample of the powder was dispersed on a sample holder with zero background. General measurement conditions for XRPD were as follows: Starting angle 3°; limit angle 45°; sampling 0.02° and scanning speed 2°/min.

The powder X-ray diffraction pattern of compound II salicylate is shown in FIG. 16, and the XRPD data are presented in Table. 7.

- 43 041099

Table 7

Differential Scanning Calorimetry (DSC) Studies for Salicylate Compound II

Compound II salicylate was characterized by DSC. DSC was obtained using a TA Instruments Model Q200 Differential Scanning Calorimetry instrument with autosampler. The parameters of the DSC device were as follows: 30-300°C at 10°C/min; aluminum sample dish with Tzero lid; flow of nitrogen gas at a rate of 50 ml/min.

The DSC thermogram of compound II salicylate is shown in FIG. 17. The DSC thermogram revealed 3 main endothermic events: the first event was observed at a decomposition start temperature of 176.0°C with a peak temperature of 181.7°C, the second event was observed at a decomposition start temperature of 209.9°C with a peak temperature of 224.9°C C, and the third event - at a temperature of the beginning of decomposition of 254.7°C with a peak temperature of 264.5°C.

Thermogravimetric Analysis (TGA) Studies for Salicylate Compound II

Compound II salicylate was characterized by TGA. TGA was performed using a thermogravimetric analyzer TA Instrument, model Q500. The general conditions of the TGA experiment were as follows: temperature ramp from 20 to 600°C at 20°C/min; nitrogen purge, gas flow at 40 ml/min, followed by purge flow balance; sample purge flow at 60 ml/min; platinum crucible for the sample.

The TGA thermogram of compound II salicylate is shown in FIG. 18. In the first stage, a weight loss of about 8.1% was observed at temperatures up to 250°C. A significant weight loss was observed at temperatures above 300°C, it was believed that this was due to the decomposition of the compound.

Example 14 Description of the Solid State Characteristics of Compound II Mesylate

X-Ray Powder Diffraction (XRPD) Studies for Compound II Mesylate

Compound II mesylate was characterized by XRPD. The XRPD was obtained using an X-ray powder diffractometer (XRPD) Rigaku MiniFlex. The general experimental procedure for XRPD was as follows: (1) X-ray from copper at 1.054056 A with a Κβ filter; (2) X-ray powder at 30 kV, 15 mA and (3) a powder sample was dispersed on a sample holder with

- 44 041099 zero background. General measurement conditions for XRPD were as follows: starting angle 3°; limit angle 45°; sampling 0.02° and scanning speed 2°/min.

An X-ray powder diffraction pattern of compound II mesylate is shown in FIG. 19, and the data

XRPD are presented in table. 8.

Table 8

2-theta: (°) Height n% 5.0 106 23.7 8.2 447 100 13.2 76 17 16.9 141 31.5

Differential Scanning Calorimetry (DSC) Studies for Compound II Mesylate

Compound II mesylate was characterized by DSC. DSC was obtained using a TA Installations model Q200 differential scanning calorimetry instrument with an autosampler. The parameters of the DSC device were as follows: 30-300°C at 10°C/min; aluminum sample dish with Tzero lid; flow of nitrogen gas at a rate of 50 ml/min.

The DSC thermogram of compound II mesylate is shown in FIG. 20. The DSC thermogram revealed a major endothermic event at an onset temperature of 166.3°C with a peak temperature of 174.8°C, which is considered the melting/decomposition temperature of the compound.

Thermogravimetric Analysis (TGA) Studies for Compound II Mesylate

Compound II mesylate was characterized by TGA. TGA was performed using a thermogravimetric analyzer TA Instrument, model Q500. The general conditions of the TGA experiment were as follows: temperature ramp from 20 to 600°C at 20°C/min; nitrogen purge, gas flow at 40 ml/min, followed by purge flow balance; sample purge flow at 60 ml/min; platinum crucible for the sample.

The TGA thermogram of compound II mesylate is shown in FIG. 21. A weight loss of about 2.3% was observed at temperatures up to 100°C, it was believed that this was due to loss of moisture or residual solvents. Significant weight loss was observed at temperatures above 200°С; it was believed that this was due to the decomposition of the compound.

Example 15 Description of the solid state characteristics of Compound II esylate

X-ray powder diffractometry (XRPD) studies for compound II esylate

Compound II esylate was characterized by XRPD. The XRPD was obtained using an X-ray powder diffractometer (XRPD) Rigaku MiniFlex. The general experimental procedure for XRPD was as follows: (1) X-ray from copper at 1.054056 A with a Κβ filter; (2) X-ray powder at 30 kV, 15 mA; and (3) a sample of the powder was dispersed on a sample holder with zero background. General measurement conditions for XRPD were as follows: starting angle 3°; limit angle 45°; sampling 0.02° and scanning speed 2°/min.

An X-ray powder diffraction pattern of compound II esylate is shown in FIG. 22, and the XRPD data are presented in Table. 9.

Table 9

Differential Scanning Calorimetry (DSC) Studies for Esylate Compound II

The esylate of compound II was characterized by DSC. DSC was obtained using a TA Installations model Q200 differential scanning calorimetry instrument with an autosampler. The parameters of the DSC device were as follows: 30-300°C at 10°C/min; aluminum sample dish with Tzero lid; flow of nitrogen gas at a rate of 50 ml/min.

The DSC thermogram of compound II esylate is shown in FIG. 23. The DSC thermogram revealed a major endothermic event at a decomposition onset temperature of 180.4°C with a peak temperature of 187.7°C, which is considered the melting/decomposition temperature of the compound.

- 45 041099

Thermogravimetric Analysis (TGA) Studies for Esylate Compound II

The esylate of compound II was characterized by TGA. TGA was performed using a thermogravimetric analyzer TA Instrument, model Q500. The general conditions of the TGA experiment were as follows: temperature ramp from 20 to 600°C at 20°C/min; nitrogen purge, gas flow at 40 ml/min, followed by purge flow balance; sample purge flow at 60 ml/min; platinum crucible for the sample.

The TGA thermogram of compound II esylate is shown in FIG. 24. A weight loss of about 1.6% was observed at temperatures up to 100°C, it was believed that this was due to loss of moisture or residual solvents. A significant weight loss was observed at temperatures above 200°C, it was believed that this was due to the decomposition of the compound.

Example 16 Preparation of other crystalline forms of N-(4-(4-amino-7-(1isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl) maleate -1-isopropyl-2,4-dioxo-3(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (maleic acid salt of Compound I, Form II-V)

The experimental procedure for the formation of forms II, III, IV and V of the maleic acid salt of compound I is summarized in table. 10.

Table 10. Crystallization procedures for the formation of solid maleate forms of compound I

Procedure Form in solid state after drying at 45-46°C in vacuum for 8 hours.

About 3.5 ml of a saturated solution of compound I maleate in chloroform was evaporated in air without stirring at 25±1°C and the resulting solid was analyzed by XRPD as Form II. XRPD (see example 17, Fig. 25). Form II About 4.0 ml of a saturated solution of compound I maleate in 1,4-dioxane was evaporated in air without stirring at 25±1°C and the resulting solid was analyzed by XRPD as Form III. XRPD (see example 18, Fig. 26), DSC (see example 18, Fig. 27) and TGA (see example 18, Fig. 28) Form III About 10 ml of a saturated solution of compound I maleate in n-ViOH was evaporated in air without stirring at 50±1°C and the resulting solid was analyzed by XRPD as form IV. XRPD (see example 19, Fig. 29), DSC (see example 19, Fig. 30) and TGA (see example 19, Fig. 31) Form IV Reverse addition from DXM/hexane: 1 ml of a saturated maleate solution of compound I prepared in dichloromethane was added to 3.0 ml of heptane, followed by stirring to obtain a solid, which was analyzed by XRPD as form V. XRPD (see example 20, Fig. 32), DSC ( see example 20, Fig. 33) and TGA (see example 20, Fig. 34) Form V

Example 17 Description of the Solid State Characteristics of Compound I Maleate, Form II

X-Ray Powder Diffractometry (XRPD) of Compound I Maleate, Form II X-ray powder diffractometry (XRPD) was obtained using a Rigaku MiniFlex X-ray powder diffractometer (XRPD). The general experimental procedure for XRPD was as follows: (1) X-ray from copper at 1.054056 A with a Κβ filter; (2) X-ray powder at 30 kV, 15 mA; and (3) a sample of the powder was dispersed on a sample holder with zero background. General measurement conditions for XRPD were as follows: starting angle 3°; limit angle 45°; sampling 0.02° and scanning speed 46 041099 2°/min.

An X-ray powder diffraction pattern of Form II of the maleic acid salt of Compound I is shown in FIG. 25, and the XRPD data are presented in Table. eleven.

Table 11

Example 18 Description of the Solid State Characteristics of Compound I Maleate, Form III

X-ray powder diffractometry (XRPD) was obtained using an X-ray powder diffractometer (XRPD) Rigaku MiniFlex. The general experimental procedure for XRPD was as follows: (1) X-ray from copper at 1.054056 A with a Κβ filter; (2) X-ray powder at 30 kV, 15 mA; and (3) a sample of the powder was dispersed on a sample holder with zero background. General measurement conditions for XRPD were as follows: starting angle 3°; limit angle 45°; sampling 0.02° and scanning speed 2°/min.

An X-ray powder diffraction pattern of Form III of the maleic acid salt of Compound I is shown in FIG. 26, and the XRPD data are presented in Table. 12.

Table 12

2-theta: (°) Height N% 3.8 719 100 7.7 654 91 8.5 61 8.5 10.8 50 7 I,5 44 6.1 12.1 320 44.5 13.8 84 I,7 14.9 57 7.9 15.4 88 12.2 16.2 57 7.9 16.9 93 12.9 18.3 75 10.4 18.9 335 46.6 19.6 60 8.3 20.6 196 27.3 21.6 71 9.9 23.1 192 26.7 25.3 139 19.3 25.8 162 22.5 29.1 58 8.1 30.4 42 5.8 37.0 39 5.4

Differential Scanning Calorimetry (DSC) Studies for Maleic Acid Salt Form III of Compound I

Form III of the maleic acid salt of compound I was characterized by DSC. DSC was obtained using a TA Instruments Model Q200 Differential Scanning Calorimetry instrument with autosampler. The parameters of the DSC device were as follows: 30-300°C at 10°C/min; aluminum sample dish with Tzero lid; flow of nitrogen gas at a rate of 50 ml/min.

A DSC thermogram of form III of the maleic acid salt of compound I is shown in FIG. 27. The DSC thermogram revealed two endothermic events: the first event was observed at a decomposition start temperature of 143.9°C with a peak temperature of 165.4°C, and the second event was observed at a decomposition start temperature of 186.3°C with a peak temperature of 195.4°C .

- 47 041099

Thermogravimetric Analysis (TGA) Studies for the Maleic Acid Salt of Compound I, Form III

Form III of the maleic acid salt of compound I was characterized by TGA. TGA was performed using a thermogravimetric analyzer TA Instrument, model Q500. The general conditions of the TGA experiment were as follows: temperature ramp from 20 to 600°C at 20°C/min; nitrogen purge, gas flow at 40 ml/min, followed by purge flow balance; sample purge flow at 60 ml/min; platinum crucible for the sample.

A thermogram of TGA form III of the maleic acid salt of compound I is shown in FIG. 28.

Example 19 Description of the Solid State Characteristics of Compound I Maleate, Form IV

X-ray powder diffractometry (XRPD) was obtained using an X-ray powder diffractometer (XRPD) Rigaku MiniFlex. The general experimental procedure for XRPD was as follows: (1) X-ray from copper at 1.054056 A with a Κβ filter; (2) X-ray powder at 30 kV, 15 mA; and (3) a sample of the powder was dispersed on a sample holder with zero background. General measurement conditions for XRPD were as follows: starting angle 3°; limit angle 45°; sampling 0.02° and scanning speed 2°/min.

An X-ray powder diffraction pattern of Form IV of the maleic acid salt of Compound I is shown in FIG. 29, and the XRPD data are presented in Table. 13.

Table 13

2-theta: (°) Height N% 3.9 1181 100 4.6 276 23.4 6.2 109 9.2 7.8 699 59.2 8.5 81 6.9 9.1 237 20.1 Yu,1 31 2.6 I,6 61 5.2 12.2 96 8.1 13.6 106 9 16.1 63 5.3 16.6 34 2.9 18.2 thirty 2.5 18.7 61 5.2 19.3 65 5.5 20.2 37 3.1 20.5 42 3.6 21.8 87 7.4 22.8 188 15.9 23.3 77 6.5 25.6 43 3.6 26.8 29 2.5 27.4 46 3.9 36.8 29 2.5

Differential Scanning Calorimetry (DSC) Studies for the Maleic Acid Salt of Compound I, Form IV

Form IV of the maleic acid salt of compound I was characterized by DSC. DSC was obtained using a TA Installations model Q200 differential scanning calorimetry instrument with an autosampler. The DSC instrument parameters were as follows: 30-300°C at 10°C/min; aluminum sample dish with Tzero lid; flow of nitrogen gas at a rate of 50 ml/min.

A DSC thermogram of form IV of the maleic acid salt of compound I is shown in FIG. 30. The DSC thermogram revealed two endothermic events: the first event was observed at a decomposition start temperature of 145.7°C with a peak temperature of 152.1°C, and the second event was observed at a decomposition start temperature of 188.3°C with a peak temperature of 202.6°C .

Thermogravimetric Analysis (TGA) Studies for the Maleic Acid Salt of Compound I, Form IV

Form IV of the maleic acid salt of compound I was characterized by TGA. TGA was performed using a thermogravimetric analyzer TA Installation, model Q500. The general conditions of the TGA experiment were as follows: temperature ramp from 20 to 600°C at 20°C/min;

- 48 041099 nitrogen purge, gas flow at 40 ml/min, followed by purge flow balance;

sample purge flow at 60 ml/min; platinum crucible for the sample.

A thermogram of TGA form IV of the maleic acid salt of compound I is shown in FIG. 31.

Example 20 Description of Compound I, Form V Maleate Solid State Characteristics

X-ray powder diffractometry (XRPD) was obtained using an X-ray powder diffractometer (XRPD) Rigaku MiniFlex. The general experimental procedure for XRPD was as follows: (1) X-ray from copper at 1.054056 A with a Κβ filter; (2) X-ray powder at 30 kV, 15 mA; and (3) a sample of the powder was dispersed on a sample holder with zero background. General measurement conditions for XRPD were as follows: starting angle 3°; limit angle 45°; sampling 0.02° and scanning speed 2°/min.

An X-ray powder diffraction pattern of the Form V maleic acid salt of Compound I is shown in FIG. 32, and the XRPD data are presented in Table. 14.

Table 14

2-theta: (°) Height n% 4D 423 95.3 8.3 444 100 8.8 140 31.5 10.7 43 9.7 12.5 35 7.9 13.0 34 7.7 15.6 44 9.9 18.0 130 29.3 20.5 41 9.2 23.1 53 I,9 23.5 122 27.5 24.1 38 8.6 27.3 150 33.8 28.4 42 9.5 29.4 36 8.1 31.4 43 9.7 35.5 49 AND

Differential Scanning Calorimetry (DSC) Studies for the Maleic Acid Salt of Compound I, Form V

Form V of the maleic acid salt of compound I was characterized by DSC. DSC was obtained using a TA Instruments Model Q200 Differential Scanning Calorimetry instrument with autosampler. The parameters of the DSC device were as follows: 30-300°C at 10°C/min; aluminum sample dish with Tzero lid; flow of nitrogen gas at a rate of 50 ml/min.

A DSC thermogram of Form V of the maleic acid salt of Compound I is shown in FIG. 33. The DSC thermogram revealed an endothermic event at an onset temperature of 189.1°C with a peak temperature of 200.1°C.

Thermogravimetric Analysis (TGA) Studies for the Maleic Acid Salt of Compound I, Form V

Form V of the maleic acid salt of compound I was characterized by TGA. TGA was performed using a thermogravimetric analyzer TA Instrument, model Q500. The general conditions of the TGA experiment were as follows: temperature ramp from 20 to 600°C at 20°C/min; nitrogen purge, gas flow at 40 ml/min, followed by purge flow balance; sample purge flow at 60 ml/min; platinum crucible for the sample.

A thermogram of TGA form V of the maleic acid salt of compound I is shown in FIG. 34.

Example A.

Axl autophosphorylation assay

Axl autophosphorylation was performed by incubating recombinant Axl protein (Life Technologies, PV4275) in a buffer containing 50 mM Tris, pH 7.5, 0.2 mg/ml Axl, 5 mM ATP, 20 mM MgCl ₂ and 2 mM DTT at room temperature within 1 hour

TAM Enzymatic Analysis

The kinase assay buffer contained 50 mM HEPES, pH 7.5, 10 mM MgCl ₂ , 1 mM EGTA, 0.01% NP-40, and 2 mM DTT. 0.1 μl of test compounds dissolved in DMSO was transferred from the compound plates to white 384-well assay plates (Greiner LUMITRAC plates). The final concentration of DMSO was 1.25%. Enzyme solutions containing 5.1 nM phosphorus-Axl, or 0.0625

- 49,041,099 nM c-Mer (Carna Biosciences, 08-108) or 0.366 nM Tyro3 (Life Technologies, PR7480A) were prepared in assay buffer. A 1 mM stock solution of peptide substrate Biotin-EQEDEPEGDYFEWLE-amide SEQ ID NO: 1 (Quality Controlled Biochemicals, MA) dissolved in DMSO was diluted to 1 μM in assay buffer containing 2000 μM ATP. 4 µl of the enzyme solution (or assay buffer in the case of a blank enzyme) was added to the appropriate wells on each plate, and then 4 µl/well of the substrate solution was added to initiate the reaction. The plate was protected from light and incubated at room temperature for 60 min. The reaction was stopped by adding 4 µl of a detection solution containing 50 mM Tris-HCl, pH 7.8, 150 mM NaCl, 0.05% BSA, 45 mM EDTA, 180 nM SA-APC (Perkin Elmer, CR130-100) and 3 nM Eu-W1024 antiphosphotyrosine PY20 (Perkin Elmer, AD0067). The plate was incubated for 1 hour at room temperature and the HTRF (time-resolved homogeneous fluorescence) signal was measured using a PHERAstar FS plate reader (BMG labtech). Percent inhibition was calculated for each concentration and the IC ₅₀ value was obtained by curve fitting using GraphPad Prism software.

Compounds of formulas I and II have been found to be inhibitors of one or more of AXL, MER and TYRO3. The IC ₅₀ data for the trifluoroacetic acid salts of the compounds of formulas I and II are described in US Patent Application No. 15/469,975 and are presented in Table 1 below. 15. Symbol f denotes IC ₅₀ < 5 nM, symbol ff denotes IC ₅₀ > 5 nM but < 10 nM, and symbol fff denotes IC ₅₀ > 10 nM but < 100 nM.

Table 15

Compound IC50 Axl (nM) IC ₅₀ Meg (nM) IC ₅₀ Tygo3 (nM) Trifluoroacetic acid salt of compound I t t ttt Compound maleic acid salt I t t ttt Trifluoroacetic acid salt of compound II t t ttt Salt of sulfuric acid compound II t t ttt

Example B Creation of BAF3-AXL, BAF3-MER and BAF3-TYRO3 Cells and Cell Proliferation Analysis AXL, MER or TYRO3 cytoplasmic domain fused with dimerization sequence and HA tag cloned into pMSCV vector with puromycin resistance marker to generate three constructs (pMSCV-AXL, pMSCV-MER and pMSCV-TYRO3). BAF3 cells are individually transfected with these three constructs by electroporation. Select and characterize individual clones that are 113-independent and resistant to puromycin. Cells with stable expression of AXL, MER or TYRO3 are selected and designated as BAF3-AXL, BAF3-MER and BAF3-TYRO3 cells.

BAF3, BAF3-AXL, BAF3-MER or BAF3-TYRO3 cell lines are contained in RPMI1640 with 10% PBS (Gibco/Life Technologies, Carlsbad, CA). To measure the effect of test compounds on cell viability, 1000 cells/well are plated in 384-well tissue culture plates in growth medium with compound serial dilution or DMSO alone for 48 hours at 37°C with 5% CO ₂ , cell viability is measured using an ATP assay (CellTiter-Glo Assay, Promega) according to the manufacturer's procedure. Data is converted to percent inhibition relative to DMSO control and IC ₅₀ curves are fitted using GraphPad Prism software.

Example C. BaF3-AXL ELISA and BaF3-MER ELISA

BaF3-AXL or BaF3-MER cells are maintained in RPMI culture medium with 10% PBS and puromycin (1 μg/ml, Gibco/Life Technologies, Carlsbad, CA). To measure the effect of test compounds on phosphorus-AXL or phosphorus-MER, cells are plated (5 x 10 ⁴ cells/well) on a V-bottomed polypropylene plate (Greiner bio-one) in the presence or absence of test compounds diluted in culture medium. , and incubated for 1 h at 37°C with 5% CO ₂ . Cells are harvested by centrifugation and lysed in 110 μl of ice-cold lysis buffer (Cell Signaling) with protease and phosphatase inhibitors (Halts PI, Thermo Fisher) for 30 min on ice. The cell lysate is stored at -80°C for ELISA. ELISA plates are prepared by incubating a Costar plate with anti-HA antibody (1 μg/ml) for 1 hour at room temperature. The plates are washed and blocked with PBS with 3% BSA. The cell lysate is loaded onto an ELISA plate and incubated at 4° C. overnight. Plates are washed and incubated with Eu-W1024 LANCE (PY-20) phosphotyrosine antibody (Perkin Elmer) in DELFIA assay buffer (Perkin Elmer) for 1 h and read with Pherastar (BMG Labtech). The data is converted to percent inhibition relative to a DMSO control and the IC ₅₀ value is determined by fitting percent inhibition versus log inhibitor concentration using GraphPad Prism.

Example D Phospho-AXL H1299 ELISA

H1299 cells (ATCC), a human non-small cell lung cancer cell line expressing Axl,

- 50 041099 contained in culture medium RPMI with 10% PBS (Gibco/Life Technologies, Carlsbad, CA). To measure the effect of test compounds on phosphorus-AXL, cells were plated (30,000 cells/well) in 96-well tissue culture plates (Costar) and incubated overnight at 37°C with 5% CO2. Compounds are added at the appropriate concentration and incubated for 1 hour at 37° C. with 5% CO2. rhGas6 (R&D Systems, 6 µg/ml) is added to each well. The plates are incubated at 37°C with 5% CO2 for 15 minutes. Cells are harvested and lysed in 110 μl ice-cold lysis buffer (Cell Signaling) with protease and phosphatase inhibitors (Halts PI, Thermo Fisher). The lysate is incubated for 1 hour on ice and stored at -80°C for ELISA. ELISA plates are prepared by incubating a Costar plate with anti-HA antibody (1 μg/ml) for 1 hour at room temperature. The plates are washed and blocked with PBS with 3% BSA. The cell lysate is loaded onto ELISA plates and incubated at 4° C. overnight. Plates are washed and incubated with Eu-W1024 LANCE (PY-20) phosphotyrosine antibody (Perkin Elmer) in DELFIA assay buffer (Perkin Elmer) for 1 h and read with Pherastar (BMG Labtech). The data is converted to percent inhibition relative to a DMSO-based control and the IC ₅₀ value is determined by fitting percent inhibition versus log inhibitor concentration using GraphPad Prism.

Example E Phospho-AXL H1299 Whole Blood ELISA

H1299 cells (ATCC) are maintained in RPMI culture medium with 10% PBS (Gibco/Life Technologies, Carlsbad, CA). To measure the effect of test compounds on phospho-AXL in whole blood, cells were plated (30,000 cells/well) in 96-well tissue culture plates (Costar) and incubated overnight at 37° C. with 5% CO ₂ . Blood from healthy donors is mixed with test compounds for 1 hour. Culture medium is removed from H1299 cells and blood with compound is added to each well. After 1 hour incubation at 37° C. with 5% CO ₂ rh-Gas6 (4 μg/ml, R&D Systems) is added to each well. The plate is incubated at 37° C. with 5% CO ₂ for 15 minutes. Cells are washed with PBS and lysed in 110 μl ice-cold lysis buffer (Cell Signaling) with protease and phosphatase inhibitors (Halts PI, Thermo Fisher) for 1 hour on ice. The tablet is stored at -80°C for ELISA. ELISA plates are prepared by incubating a Costar plate with anti-HA antibody (1 μg/ml) for 1 hour at room temperature. The plates are washed and blocked with PBS with 3% BSA. The cell lysate is loaded onto an ELISA plate and incubated at 4° C. overnight. Plates are washed and incubated with Eu-W1024 LANCE (PY-20) phosphotyrosine antibody (Perkin Elmer) in DELFIA assay buffer (Perkin Elmer) for 1 h and read with Pherastar (BMG Labtech). The data is converted to percent inhibition relative to a DMSO control and the IC ₅₀ value is determined by fitting percent inhibition versus log inhibitor concentration using GraphPad Prism.

Example F Phospho-Akt G361 ELISA using Cell Insight

G361 cells (ATCC), a Mer-expressing human melanoma cell line, are maintained in RPMI culture medium with 10% PBS (Gibco/Life Technologies, Carlsbad, CA). To measure the effect of test compounds on the MER signaling pathway, cells were plated at 2x10 ⁴ cells/well in a volume of 100 μl on 96-well CellBind surface plates (Corning) and incubated overnight at 37° C. with 5% CO ₂ . 20 µl of test compounds at appropriate concentrations are added to the cells and incubated for 1 hour. rhGas6 (4 µg/ml, R&D Systems) is added to each well and incubated for 20 minutes. Cells are fixed by adding 50 μl of 4% paraformaldehyde (Electron Microscopy Sciences) in PBS (Corning) for 30 min at room temperature. The plates are washed and incubated with 50 μl of 0.2% Triton X-100 (Sigma) in PBS for 10 min at room temperature. The plates are washed and incubated with 100 µl blocking buffer (0.1% BSA in PBS) for 30 min. The plates are washed and incubated with rabbit monoclonal antibody phospho-AKT (Ser473) (D9E) (Cell Signaling) diluted in 0.1% BSA (1:300 dilution) at 4° C. overnight. The plates are washed and incubated with 50 µl of F(ab') fragment ² goat anti-rabbit IgG (H+L) Alexaflour 488 (Molecular Probes, 1:1000 dilution) and Hoechst 33342 (Thermo Fisher, 1:2000 dilution) in PBS at room temperature. temperature for 2 hours. The plates are washed with PBS and read using Cell Insight CX5 (Thermo Fisher).

Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to be within the scope of the appended claims. All references, including all patents, patent applications and publications cited in this application, are incorporated herein in their entirety by reference.

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Claims (60)

CLAIM 1. Salt which is the salt of maleic acid N(4-(4-amino-7-(1isobutyrylpiperidin-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. 2. A salt according to claim 1, which is a 1:1 stoichiometric ratio of N-(4-(4-amino-7-(1isobutyrylpiperidin-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. Salt according to claim 1, which is crystalline. 4. Salt according to claim 1, which is essentially isolated. 5. Salt according to claim 1, characterized by a DSC thermogram having an endometrial peak at about 211 °C. 6. A salt according to claim 1 having a DSC thermogram corresponding to that shown in FIG. 2. 7. A salt according to claim 1 having a TGA thermogram corresponding to that shown in FIG. 3. 8. A salt according to claim 1 having at least one XRPD peak at 2-θ values selected from about 4.3°, about 8.4°, about 12.6°, about 13.2° and about 18, 5°. 9. A salt according to claim 1 having at least two XRPD peaks at 2-θ values selected from about 4.3°, about 8.4°, about 12.6°, about 13.2° and about 18, 5°. 10. A salt according to claim 1 having at least three XRPD peaks at 2-θ values selected from about 4.3°, about 8.4°, about 12.6°, about 13.2° and about 18, 5°. 11. A salt according to claim 1, having at least four XRPD peaks at 2-θ values selected from about 4.3°, about 8.4°, about 12.6°, about 13.2°, and about 18, 5°. 12. A salt according to claim 1, containing the following XRPD peaks at 2-θ values: about 4.3°, about 8.4°, about 12.6°, about 13.2° and about 18.5°. 13. A salt according to claim 1 having an XRPD profile as shown in FIG. 1. 14. Salt which is the hemisulphate salt of sulfuric acid N-(4-(4-amino-7-(1isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl )phenyl)-1-isopropyl-2,4-dioxo-3-phenyl1,2,3,4-tetrahydropyrimidine-5-carboxamide. 15. Salt according to claim 14, which is a 1:0.5 stoichiometric ratio of N-(4-(4-amino7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2, 4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide to sulfuric acid. 16. Salt according to claim 14, which is crystalline. 17. Salt according to claim 14, which is essentially isolated. 18. Salt according to claim 14, characterized by a DSC thermogram having an endometrial peak at about 289.4°C. 19. A salt according to claim 14 having a DSC thermogram corresponding to that shown in FIG. eleven. 20. A salt according to claim 14 having a TGA thermogram corresponding to that shown in FIG. 12. 21. A salt according to claim 14, having at least one XRPD peak at 2-θ values selected from about 5.3°, about 8.5°, about 15.3°, about 20.1°, and about 24, 9°. 22. A salt according to claim 14, having at least two XRPD peaks at 2-θ values selected from about 5.3°, about 8.5°, about 15.3°, about 20.1°, and about 24, 9°. 23. A salt according to claim 14, having at least three XRPD peaks at 2-θ values selected from about 5.3°, about 8.5°, about 15.3°, about 20.1°, and about 24, 9°. 24. A salt according to claim 14, having at least four XRPD peaks at 2-θ values selected from about 5.3°, about 8.5°, about 15.3°, about 20.1°, and about 24, 9°. 25. A salt according to claim 14 containing the following XRPD peaks at 2-θ values: about 5.3°, about 8.5°, about 15.3°, about 20.1° and about 24.9°. 26. A salt according to claim 14 having an XRPD profile as shown in FIG. 10. 27. Salt selected from N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2f][1,2,4]triazin-5-yl)phenyl phosphoric acid salt )-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide; maleic acid salts N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2f] [1,2,4]triazin-5-yl)phenyl)-1-isopropyl- 2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide; hydrochloric acid salts N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin5-yl)phenyl)-1-isopropyl- 2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide; salicylic acid salts N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2f] [1,2,4]triazin-5-yl)phenyl)-1-isopropyl- 2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxy - 52 041099 mida; methanesulfonic acid salts N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2f] [1,2,4]triazin-5-yl)phenyl)-1-isopropyl- 2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide and ethanesulfonic acid salts N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[ 1,2f] [ 1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 28. A pharmaceutical composition containing a salt according to any one of claims 1 to 27 and a pharmaceutically acceptable carrier. 29. A method for inhibiting TAM kinases, said method comprising contacting TAM kinases with a salt according to any one of claims 1-27. 30. A method for inhibiting AXL and MER kinases, said method comprising contacting AXL and MER kinases with a salt according to any one of claims 1-27. 31. A method of treating cancer in a patient, said method comprising administering to the patient a therapeutically effective amount of salt according to any one of claims 1-27. 32. The method of claim 31 wherein the cancer is selected from hepatocellular cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, cancer lung, 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 myelogenous leukemia , Hodgkin's or non-Hodgkin's lymphoma, Waldenström's macroglobulinemia, hairy cell lymphoma, Burkitt's lymphoma, glioblastoma, melanoma, and rhabdomyosarcoma. 33. 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. The method of obtaining a salt according to claim 1, including the introduction into the reaction of the compounds of formula I with maleic acid to form said salt. 35. The method according to item 34, in which about 1 eq. maleic acid is used on the basis of 1 eq. compounds of formula I. 36. The method of claim 34, wherein said reaction of a compound of formula I with maleic acid is carried out in the presence of a solvent component. 37. The method of claim 36 wherein said solvent component comprises methanol. 38. The method of claim 36 wherein said solvent component comprises dichloromethane. 39. The method of claim 36 wherein said solvent component comprises methanol and dichloromethane. 40. The method of claim 39, wherein the method further comprises removing a substantial portion of the dichloromethane to precipitate said salt. 41. The method of claim 36, wherein said method, prior to said reaction, further comprises providing a solution of a compound of formula I in a solvent component. 42. The method of claim 41, wherein the solution is prepared by heating a suspension of the compound of formula I in the solvent component to a temperature of about 45 to about 55°C. 43. The method according to item 42, in which the specified method further includes stirring the specified solution; and filtering said solution to obtain a filtrate before said addition to the reaction of the compound of formula I with maleic acid. 44. The method of claim 43, wherein said method further comprises adding activated charcoal and silica gel to the solution after said step of heating said slurry to about 45 to about 55°C to form a solution and before said step of stirring said solution. 45. A method for producing a salt according to claim 14, which includes introducing a compound of formula II into the reaction - 53 041099 and, with sulfuric acid to form said salt. 46. The method according to item 45, in which about 0.6 eq. sulfuric acid is used on the basis of 1 eq. compounds of formula II. 47. The method according to item 45 or 46, which includes adding a compound of formula II to the solvent component to obtain a solution; adding sulfuric acid to said solution at room temperature; concentrating the solution to obtain a suspension; stirring the slurry at a temperature of about 60 to about 70°C; and cooling the slurry to a temperature of about 15 to about 25°C to precipitate said salt. 48. The method of claim 47 wherein the solvent component comprises methanol. 49. The method of claim 47 wherein the solvent component comprises dichloromethane. 50. The method of claim 47 wherein the solvent component comprises methanol and dichloromethane. 51. The method of claim 47, wherein the sulfuric acid is present at a concentration of about 1 M in water. 52. The method of claim 45, wherein the method comprises preparing a sulfuric acid salt of N-(4-(4amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2, 4]triazin-5-yl)phenyl)-1-uzopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 53. The method of claim 52, wherein the method for preparing the salt which is the sulfuric acid 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, involves the introduction of the compound into the reaction formula II with about 1 eq. sulfuric acid based on 1 eq. compounds of formula II. 54. The process according to claim 52 or 53, wherein the process for preparing the sulfuric acid salt N-(4-(4-amino-7-(1isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4 ]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl1,2,3,4-tetrahydropyrimidine-5-carboxamide involves adding a compound of formula II to the first solvent component at room temperature with obtaining a solution; heating the solution to a temperature of about 50 to about 60°C; adding sulfuric acid to said solution; and removing the solvent to precipitate the sulfuric acid salt. 55. The method of claim 54 wherein the first solvent comprises methanol. 56. The method of claim 54, wherein the sulfuric acid is added as a solution in water. 57. The method according to claim 52 or 53, further comprising the following steps: addition of sulfuric acid salt N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2f][1,2,4]truazin-5-ul)phenyl)-1-uzopronil -2,4-dioxo-3-phenyl-1,2,3,4-tetrahydronurimidine-5-carboxamide to the second solvent component to form a suspension; heating the suspension to a temperature of from about 30 to about 40°C; mixing the suspension and collecting the resulting hemisulphate salt of sulfuric acid. 58. The method of claim 57 wherein the second solvent component comprises water. 59. The method according to claim 57, further comprising obtaining an amorphous form of hemisulfate salt of sulfuric acid, and obtaining an amorphous form of hemisulfate salt of sulfuric acid includes the following steps: adding hemisulfate salt of sulfuric acid to the third solvent component at room temperature to obtain a solution; solution filtration; concentrating the filtrate and drying the resulting solid to obtain an amorphous hemisulfate salt of sulfuric acid. 60. The method of claim 59 wherein the third solvent component comprises acetone and methanol. -