阅读说明：本技术 Mk2抑制剂的形式和组合物 (Forms and compositions of an MK2 inhibitor ) 是由 J·韩 L·黄 U·杰恩 Y·李 J·马罗那 K·莫尔特 C·帕巴 A·L·卢切尔曼 于 2018-03-15 设计创作，主要内容包括：本发明提供了MK2抑制剂的固体形式,其组合物,以及使用其的方法。(The present invention provides solid forms of an MK2 inhibitor, compositions thereof, and methods of using the same.)

1. A crystalline form of compound 1:

2. the crystalline form of claim 1, wherein compound 1 is unsolvated.

3. The crystalline form of claim 2, wherein the crystalline form is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 6.19 °, about 9.33 °, about 9.64 °, about 12.39 °, about 12.49 °, about 12.59 °, about 13.11 °, about 13.25 °, about 16.31 °, about 18.70 °, about 18.84 °, about 19.09 °, about 20.92 °, about 21.35 °, about 23.17 °, about 24.02 °, about 24.94 °, about 26.44 °, about 29.14 °, and about 30.04 ° 2 θ.

4. The crystalline form of claim 3, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having peaks, in terms of 2 θ, at about 9.33 °, about 9.64 °, and about 16.31 °.

5. The crystalline form of claim 3, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having peaks, in terms of ° 2 θ, at about 6.19 °, about 9.33 °, about 9.64 °, and about 16.31 °.

6. The crystalline form of claim 3, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having peaks, in terms of 2 θ, at about 6.19 °, about 9.33 °, about 9.64 °, about 16.31 °, and about 24.02 °.

7. The crystalline form of claim 3, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having peaks at about 9.64 °, about 12.39 °, about 12.49 °, about 12.59 °, about 13.11 °, about 13.25 °, about 16.31 °, about 18.70 °, about 18.84 °, about 19.09 °, about 20.92 °, about 21.35 °, about 23.17 °, about 24.02 °, about 24.94 °, about 26.44 °, about 29.14 °, and about 30.04 ° 2 θ.

8. The crystalline form of claim 1, wherein the crystalline form is a hydrate.

9. The crystalline form of claim 1, wherein the crystalline form is a solvate.

10. The crystalline form of claim 9, wherein the crystalline form is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 6.73 °, about 8.44 °, about 13.45 °, about 15.27 °, about 17.53 °, about 20.54 °, about 23.95 °, and about 24.49 ° 2 θ.

11. The crystalline form of claim 10, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having peaks, in terms of 2 Θ, at about 6.73 °, about 8.44 °, and about 23.95 °.

12. The crystalline form of claim 10, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having peaks, in terms of ° 2 Θ, at about 6.73 °, about 8.44 °, about 17.53 °, and about 23.95 °.

13. The crystalline form of claim 10, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having peaks, in terms of ° 2 Θ, at about 6.73 °, about 8.44 °, about 15.27 °, about 17.53 °, and about 23.95 °.

14. The crystalline form of claim 10, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having peaks, in terms of ° 2 Θ, at about 6.73 °, about 8.44 °, about 13.45 °, about 15.27 °, about 17.53 °, about 20.54 °, about 23.95 °, and about 24.49 °.

15. A complex comprising Compound 1 and a co-former X,

wherein X is selected from the group consisting of: t-aconitic acid, L-ascorbic acid, aspartic acid, benzoic acid, citric acid, gentisic acid, glutaric acid, 1-hydroxy-2-naphthoic acid, isethionic acid, ketoglutaric acid, L-lysine, maleic acid, malonic acid, methanesulfonic acid, naphthalene-1, 5-disulfonic acid, oxalic acid, phosphoric acid, saccharin, thiocyanic acid, p-toluenesulfonic acid and vanillin.

16. A composition comprising the crystalline form of any one of claims 1-14.

17. A composition comprising the complex of claim 15.

18. A method of inhibiting MK2 kinase or mutant activity thereof in a biological sample comprising the step of contacting the biological sample with the crystalline form of any one of claims 1-14 or the complex of claim 15.

19. A method of inhibiting MK2 kinase or mutant activity thereof in a patient comprising the step of administering to the patient the crystalline form of any one of claims 1-14, the complex of claim 15, or the composition of claim 16 or 17.

20. A method for treating an MK 2-mediated disease or disorder in a patient in need thereof, comprising the step of administering to the patient the crystalline form of any one of claims 1-14, the co-crystal of claim 15, or the composition of claim 16 or 17.

Technical Field

The present invention provides solid forms of compounds useful as inhibitors of MK2 kinase. The invention also provides pharmaceutically acceptable compositions comprising the solid forms of the invention, and methods of using the compositions in the treatment of various disorders.

Background

In recent years, the search for new therapeutic agents has been greatly facilitated by a better understanding of the structure of enzymes and other biomolecules associated with diseases. An important class of enzymes that has been the subject of extensive research is protein kinases.

Protein kinases constitute a large family of structurally related enzymes responsible for controlling various signal transduction processes within the cell. Protein kinases are thought to have evolved from a common ancestral gene due to conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. Kinases can be divided into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.).

Mitogen-activated protein kinase 2(MAPKAP K2 or MK2) mediates multiple p38 MAPK-dependent cellular responses. MK2 is an important intracellular regulator of the production of cytokines such as tumor necrosis factor alpha (TNF- α), interleukin 6(IL-6), and interferon gamma (IFN γ) associated with many acute and chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. MK2 resides in the nucleus of unstimulated cells, and upon stimulation, it translocates to the cytoplasm and phosphorylates and activates potato globulin (Tuberin) and HSP 27. MK2 is also implicated in heart failure, cerebral ischemic injury, modulation of stress resistance and the production of TNF- α (see Deak et al, EMBO.17: 4426-.

As mentioned above, many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, skeletal diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, alzheimer's disease and hormone-related diseases. Therefore, there remains a need to find protein kinase inhibitors useful as therapeutic agents.

Summary of The Invention

It has now been found that the novel solid forms of the present invention, and compositions thereof, are useful as inhibitors of one or more protein kinases and exhibit desirable properties. Generally, the salt forms, free base forms, and/or complex forms and pharmaceutically acceptable compositions thereof are useful for treating or lessening the severity of a variety of diseases or conditions, as detailed herein.

Brief Description of Drawings

Figure 1 depicts the XRPD pattern of compound 1 form a.

Figure 2 depicts the XRPD pattern of compound 1 form B.

Figure 3 depicts the XRPD pattern of compound 1 form C. .

Figure 4 depicts the XRPD pattern of compound 1 form D.

Figure 5 depicts the XRPD pattern of compound 1 form E.

Figure 6 depicts the XRPD pattern of compound 1 form F.

Figure 7 depicts the XRPD pattern of compound 1 form G.

Figure 8 depicts the XRPD pattern of compound 1 form H.

Figure 9 depicts the XRPD pattern of compound 1 form I.

Figure 10 depicts a comparison of the XRPD pattern of compound 1 form I obtained by recrystallization of compound 1 in THF/water (top) and the XRPD pattern of compound 1 form I obtained from a slurry of form H in water (bottom).

Figure 11 depicts the DSC thermogram for compound 1 form a.

Figure 12 depicts a DSC thermogram for compound 1 form B.

Figure 13 depicts a DSC thermogram for compound 1 form C.

Figure 14 depicts a DSC thermogram for compound 1 form D.

Figure 15 depicts a DSC thermogram for compound 1 form E.

Figure 16 depicts a DSC thermogram for compound 1 form F.

Figure 17 depicts a DSC thermogram for compound 1 form G.

Figure 18 depicts a DSC thermogram for compound 1 form H.

Figure 19 depicts a DSC thermogram of compound 1 form I obtained from a slurry of form H in water.

Figure 20 depicts the DSC thermogram of compound 1 form I obtained by recrystallization of compound 1 in THF/water.

Figure 21 depicts a TGA thermogram of compound 1 form a.

Figure 22 depicts a TGA thermogram of compound 1 form B.

Figure 23 depicts the TGA thermogram of compound 1 form C.

Figure 24 depicts a TGA thermogram of compound 1 form D.

Figure 25 depicts a TGA thermogram of compound 1 form E.

Figure 26 depicts a TGA thermogram of compound 1 form H.

Figure 27 depicts a TGA thermogram of compound 1 form I obtained from a slurry of form H in water.

Figure 28 depicts the TGA thermogram of compound 1 form I obtained by recrystallization of compound 1 in THF/water.

Figure 29 depicts a DVS isotherm plot of compound 1 form a.

Figure 30 depicts a DVS isotherm plot of compound 1 form C.

Figure 31 depicts a DVS isotherm plot of compound 1 form D.

Figure 32 depicts a DVS isotherm plot of compound 1 form E.

Figure 33 depicts a DVS isotherm plot of compound 1 form I.

FIG. 34 depicts Compound 1 form A¹H NMR spectrum.

FIG. 35 depicts Compound 1 form B¹H NMR spectrum.

FIG. 36 depicts Compound 1 form C¹H NMR spectrum.

FIG. 37 depicts Compound 1 form D¹H NMR spectrum.

FIG. 38 depicts Compound 1 form E¹H NMR spectrum.

FIG. 39 depicts Compound 1 form F¹H NMR spectrum.

FIG. 40 depicts Compound 1 form G¹H NMR spectrum.

FIG. 41 depicts Compound 1 form I obtained by recrystallization of Compound 1 in THF/water¹H NMR spectrum.

Figure 42 depicts a comparison of XRPD patterns of compound 1 form a (a) as such, (b) after DVS, (c) after compression at 2000psi, and (d) after heating at 190 ℃.

Figure 43 depicts a comparison of XRPD patterns of compound 1 form b (a) as such, (b) after compression at 2000psi, and (c) after heating at 190 ℃.

Figure 44 depicts a comparison of XRPD patterns of compound 1 form c (a) as such, (b) after DVS, (c) after compression at 2000psi, and (d) after heating at 190 ℃.

Figure 45 depicts a comparison of XRPD patterns of compound 1 form d (a) as such, (b) after compression at 2000psi, (c) after heating at 190 ℃, and (d) after DVS.

Figure 46 depicts a comparison of XRPD patterns of compound 1 form e (a) as such, (b) after compression at 2000psi, (c) after heating at 190 ℃, and (d) after DVS.

Figure 47 depicts a comparison of XRPD patterns of compound 1 form i obtained from a slurry of form H in water, (a) as such and (b) after DVS.

Fig. 48 is a schematic depicting interconversion between crystalline forms of compound 1.

Figure 49 depicts an XRPD pattern of a complex of compound 1 with t-aconitic acid.

Figure 50 depicts an XRPD pattern of a complex of compound 1 with L-ascorbic acid.

Figure 51 depicts an XRPD pattern of a complex of compound 1 and aspartic acid.

Figure 52 depicts an XRPD pattern of a complex of compound 1 and benzoic acid.

Figure 53 depicts an XRPD pattern of compound 1 complex with citric acid.

Figure 54 depicts an XRPD pattern of form 1 of compound 1 complex with gentisic acid.

Figure 55 depicts an XRPD pattern of form 2 of compound 1 complex with gentisic acid.

Figure 56 depicts an XRPD pattern of a complex of compound 1 with glutaric acid.

Figure 57 depicts an XRPD pattern of form 1 of compound 1 complexed with 1-hydroxy-2-naphthoic acid.

Figure 58 depicts an XRPD pattern of form 2 of compound 1 complexed with 1-hydroxy-2-naphthoic acid.

Figure 59 depicts an XRPD pattern of compound 1 complex with isethionic acid.

Figure 60 depicts an XRPD pattern of compound 1 complex with maleic acid.

Figure 61 depicts an XRPD pattern of a complex of compound 1 with ketoglutaric acid.

Figure 62 depicts an XRPD pattern of a complex of compound 1 and malonic acid.

Figure 63 depicts an XRPD pattern of compound 1 complex with methanesulfonic acid.

Figure 64 depicts an XRPD pattern of a complex of compound 1 with saccharin.

Figure 65 depicts an XRPD pattern of a complex of compound 1 and naphthalene-1, 5-disulfonic acid.

Figure 66 depicts an XRPD pattern of a complex of compound 1 with oxalic acid.

Figure 67 depicts an XRPD pattern of a complex of compound 1 and phosphoric acid.

Figure 68 depicts an XRPD pattern of compound 1 complex with p-toluenesulfonic acid.

Figure 69 depicts an XRPD pattern of a complex of compound 1 with thiocyanate.

Figure 70 depicts an XRPD pattern of a complex of compound 1 and vanillin.

Figure 71 depicts the overlap of XRPD patterns of compound 1 complex with L-ascorbic acid and compound 1 complex with L-lysine.

Figure 72 depicts the overlap of XRPD patterns of compound 1 complex with t-aconitic acid and form a.

Figure 73 depicts the overlap of XRPD patterns of the complex of compound 1 with aspartic acid and the coformer aspartic acid.

Figure 74 depicts the overlap of XRPD patterns of compound 1 complex with benzoic acid, form a, and co-former benzoic acid.

Figure 75 depicts the overlap of XRPD patterns of compound 1 complex with citric acid and co-former citric acid.

Figure 76 depicts the overlap of the XRPD patterns of compound 1 in form 1 complex with gentisic acid, compound 1 in form 2 complex with gentisic acid, and co-former gentisic acid.

Figure 77 depicts the overlap of XRPD patterns of the complex of compound 1 with glutaric acid and the coformer glutaric acid.

Figure 78 depicts the overlap of XRPD patterns of form 1 of compound 1 complex with 1-hydroxy-2-naphthoic acid and form 2 of compound 1 complex with 1-hydroxy-2-naphthoic acid.

Figure 79 depicts the overlap of XRPD patterns of compound 1 complex with isethionic acid and compound 1 complex with maleic acid.

Figure 80 depicts the overlap of XRPD patterns of the complex of compound 1 with ketoglutarate and the coformer ketoglutarate.

Figure 81 depicts the XRPD pattern overlap of compound 1 complex with malonic acid and form a.

Figure 82 depicts the overlap of XRPD patterns of compound 1 complex with methanesulfonic acid and compound 1 complex with saccharin.

Figure 83 depicts the overlap of XRPD patterns of compound 1 complex with naphthalene-1, 5-disulfonic acid and the unknown free base crystalline form.

Figure 84 depicts the overlap of XRPD patterns of the complex of compound 1 with oxalic acid and the coformer oxalic acid.

Figure 85 depicts the XRPD pattern overlap of compound 1 complex with phosphoric acid and form a.

Figure 86 depicts the overlap of XRPD patterns of compound 1 complex with thiocyanic acid and compound 1 complex with p-toluenesulfonic acid.

Figure 87 depicts the XRPD pattern overlap of compound 1 complex with vanillin as well as form a.

FIG. 88 depicts a complex of Compound 1 with maleic acid¹H NMR spectrum.

FIG. 89 depicts a complex of Compound 1 with saccharin¹H NMR spectrum.

Figure 90 depicts an XRPD pattern of compound 1 complex with maleic acid.

Figure 91 depicts an XRPD pattern of a complex of compound 1 with saccharin.

Detailed Description

General description of certain aspects of the invention:

PCT patent application PCT/US2015/050495 ("the' 463 application", the entire contents of which are incorporated herein by reference), filed on 16/9/2015 and published on 24/3/2016 as WO2016/044463, describes certain compounds that covalently and/or irreversibly inhibit MK2 activity. Such compounds include compound 1:

the compound 1((R) -3- ((2-chloro-5- (ethoxymethyl) pyrimidin-4-yl) oxy) -10-methyl-9, 10,11, 12-tetrahydro-8H- [1,4] diazepino [5',6':4,5] thieno [3,2-f ] quinolin-8-one) is designated compound I-82 in the '463 application and the synthesis of compound 1 is described in detail in example 82 therein.

Compound 1 is active (in enzymatic and cellular assays) in various assays and therapeutic models demonstrating covalent, irreversible inhibition of MK2 kinase. Notably, compound 1 was found to inhibit MK2 in Thp-1 human acute monocytic leukemia cells. Accordingly, compound 1 may be useful for treating one or more conditions associated with or mediated by the activity of MK2 kinase.

The crystalline form of compound 1 imparts or may impart properties such as improved water solubility, stability and ease of formulation compared to amorphous compound 1. Thus, the present invention provides several crystalline forms of compound 1.

According to one embodiment, the present invention provides compound 1 in amorphous form, crystalline form or a mixture thereof. Exemplary crystalline forms of compound 1 are described in more detail below.

In other embodiments, the present invention provides compound 1 substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of foreign matter. These extraneous materials may include starting materials, residual solvents, or any other impurities that may result from the preparation and/or isolation of compound 1. In certain embodiments, at least about 90% by weight of compound 1 is present. In certain embodiments, at least about 95% by weight of compound 1 is present. In other embodiments of the invention, at least about 99% by weight of compound 1 is present.

According to one embodiment, compound 1 is present in an amount of at least about 95, 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent, wherein the percentages are based on the total weight of the composition. According to another embodiment, compound 1 comprises no more than about 5.0 area% HPLC total organic impurities, in certain embodiments no more than about 3.0 area% HPLC total organic impurities, and in certain embodiments no more than about 1.5 area% HPLC total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 1 comprises no more than about 1.0 area% HPLC of any single impurity, no more than about 0.6 area% HPLC of any single impurity, and in certain embodiments, no more than about 0.5 area% HPLC of any single impurity, relative to the total area of the HPLC chromatogram.

The structures described for compound 1 are also intended to include all tautomeric forms of compound 1. In addition, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, other than by replacement of hydrogen by deuterium or tritium or by enrichment with hydrogen¹³C or¹⁴In addition to carbon substitution for C, compounds having the current structure are within the scope of the present invention.

A crystalline form of compound 1:

it has been found that compound 1 can exist in a variety of crystalline forms. The crystalline forms may be solvate, hydrate, and non-solvate forms of compound 1. The present invention contemplates all of these forms. In certain embodiments, the present invention provides compound 1 as a mixture of one or more crystalline forms.

As used herein, the term "polymorph" refers to different crystal structures (solvated or unsolvated forms) in which a compound can crystallize.

As used herein, the term "solvate" refers to a solid form (e.g., a channel solvate) having a stoichiometric or non-stoichiometric amount of solvent. For polymorphs, a solvent is incorporated into the crystal structure. Similarly, the term "hydrate" refers to a solid form having a stoichiometric or non-stoichiometric amount of water. For polymorphs, water will be incorporated into the crystal structure.

As used herein, the term "about" when used in reference to a ° 2 θ value refers to a specified value ± 0.3 ° 2 θ. In certain embodiments, "about" refers to ± 0.2 ° 2 θ or ± 0.1 ° 2 θ.

In certain embodiments, compound 1 is a crystalline solid. In other embodiments, compound 1 is a crystalline solid that is substantially free of amorphous compound 1. As used herein, the term "substantially free of amorphous compound 1" means that the compound does not contain a significant amount of amorphous compound 1. In certain embodiments, at least about 90% by weight of crystalline compound 1 is present, or at least about 95% by weight of crystalline compound 1 is present. In other embodiments of the invention, at least about 97%, 98%, or 99% by weight of crystalline compound 1 is present.

In certain embodiments, compound 1 is in a pure or unsolvated crystalline form, and thus does not incorporate any water or solvent in the crystal structure. It has been found that compound 1 can exist in at least three different pure (i.e., anhydrous) crystalline forms or polymorphs. In some embodiments, the present invention provides one anhydrous polymorphic (i.e., crystalline) form of compound 1, referred to herein as form a. In other embodiments, the present invention provides one anhydrous polymorphic (i.e., crystalline) form of compound 1, referred to herein as form B. In other embodiments, the present invention provides one anhydrous polymorphic (i.e., crystalline) form of compound 1, referred to herein as form D.

It has been found that compound 1 can exist in at least two different hydrate crystal forms or polymorphs. In some embodiments, the present invention provides one hydrate polymorphic (i.e., crystalline) form of compound 1, referred to herein as form C. In other embodiments, the present invention provides one hydrate polymorphic (i.e., crystalline) form of compound 1, referred to herein as form E.

Compound 1 may also exist in at least four different solvate crystal forms or polymorphs. In some embodiments, the present invention provides one solvate polymorphic (i.e., crystalline) form of compound 1, referred to herein as form F. In some embodiments, the present invention provides one solvate polymorphic (i.e., crystalline) form of compound 1, referred to herein as form G. In some embodiments, the present invention provides one solvate polymorphic (i.e., crystalline) form of compound 1, referred to herein as form H. In some embodiments, the present invention provides one solvate polymorphic (i.e., crystalline) form of compound 1, referred to herein as form I. In some embodiments, the present invention provides a mixture of multiple polymorphic (i.e., crystalline) forms of compound 1. For example, in some embodiments, the present invention provides a mixture of form a of compound 1 and one or more forms selected from form B, form C, form D, form E, form F, form G, form H and form I.

In certain embodiments, the present invention provides form a of compound 1. According to one embodiment, form a of compound 1 is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 6.19 °, about 9.33 °, about 9.64 °, about 12.39 °, about 12.49 °, about 12.59 °, about 13.11 °, about 13.25 °, about 16.31 °, about 18.70 °, about 18.84 °, about 19.09 °, about 20.92 °, about 21.35 °, about 23.17 °, about 24.02 °, about 24.94 °, about 26.44 °, about 29.14 °, and about 30.04 ° 2 θ.

In some embodiments, form a of compound 1 is characterized by a powder X-ray diffraction pattern having peaks at about 9.33 °, about 9.64 °, and about 16.31 ° 2 Θ. In some embodiments, form a of compound 1 is characterized by a powder X-ray diffraction pattern having peaks at about 6.19 °, about 9.33 °, about 9.64 °, and about 16.31 ° 2 Θ. In some embodiments, form a of compound 1 is characterized by a powder X-ray diffraction pattern having peaks at about 6.19 °, about 9.33 °, about 9.64 °, about 16.31 °, and about 24.02 ° 2 Θ. In one exemplary embodiment, form a of compound 1 is characterized by its X-ray powder diffraction pattern having substantially all of the peaks at the following positions:

in certain embodiments, the present invention provides form B of compound 1. According to one embodiment, form B of compound 1 is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 6.19 °, about 7.04 °, about 9.30 °, about 9.58 °, about 9.64 °, about 12.54 °, about 18.69 °, about 19.33 °, about 21.34 °, about 27.52 °, and about 29.18 ° 2 θ.

In some embodiments, form B of compound 1 is characterized by a powder X-ray diffraction pattern having peaks at about 7.04 °, about 12.54 °, and about 21.34 ° 2 Θ. In some embodiments, form B of compound 1 is characterized by a powder X-ray diffraction pattern having peaks at about 6.19 °, about 7.04 °, about 12.54 °, and about 21.34 ° 2 Θ. In one exemplary embodiment, form B of compound 1 is characterized by its X-ray powder diffraction pattern having substantially all of the peaks at the following positions:

in certain embodiments, the present invention provides form C of compound 1. According to one embodiment, form C of compound 1 is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 7.03 °, about 13.54 °, about 13.91 °, about 14.13 °, about 21.25 °, about 21.51 °, about 24.73 °, and 25.77 ° 2 θ.

In some embodiments, form C of compound 1 is characterized by a powder X-ray diffraction pattern having peaks at about 7.03 °, about 13.54 °, about 13.91 °, and about 14.13 ° 2 Θ. In some embodiments, form C of compound 1 is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 7.03 °, about 13.54 °, about 13.91 °, about 14.13 °, and about 25.77 ° 2 θ. In one exemplary embodiment, form C of compound 1 is characterized by its X-ray powder diffraction pattern having substantially all of the peaks at the following positions:

in certain embodiments, the present invention provides form D of compound 1. According to one embodiment, form D of compound 1 is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 4.89 °, about 6.01 °, about 6.10 °, about 9.83 °, about 12.06 °, about 20.55 °, about 20.98 °, about 25.75 °, and about 26.42 ° 2 θ.

In some embodiments, form D of compound 1 is characterized by a powder X-ray diffraction pattern having peaks at about 4.89 °, about 6.01 °, and about 9.83 ° 2 Θ. In some embodiments, form D of compound 1 is characterized by a powder X-ray diffraction pattern having peaks at about 4.89 °, about 6.01 °, about 9.83 °, about 25.75 °, and about 26.42 ° 2 Θ. In one exemplary embodiment, form D of compound 1 is characterized by its X-ray powder diffraction pattern having substantially all of the peaks at the following positions:

in certain embodiments, the present invention provides form E of compound 1. According to one embodiment, form E of compound 1 is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 6.80 °, about 7.13 °, about 9.95 °, about 15.48 °, about 15.64 °, and about 21.44 ° 2 θ. In some embodiments, form E of compound 1 is characterized by a powder X-ray diffraction pattern having peaks at about 6.80 ° and about 7.13 ° 2 Θ. In one exemplary embodiment, form E of compound 1 is characterized by its X-ray powder diffraction pattern having substantially all of the peaks at the following positions:

in certain embodiments, the present invention provides form F of compound 1. According to one embodiment, form F of compound 1 is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 7.11 °, about 8.92 °, about 10.41 °, about 10.68 °, about 11.00 °, about 13.70 °, about 22.11 °, and about 23.73 ° 2 θ. In some embodiments, form F of compound 1 is characterized by a powder X-ray diffraction pattern having peaks at about 7.11 °, about 8.92 °, and about 11.00 ° 2 Θ. In one exemplary embodiment, form F of compound 1 is characterized by its X-ray powder diffraction pattern having substantially all of the peaks at the following positions:

in certain embodiments, the present invention provides form G of compound 1. According to one embodiment, form G of compound 1 is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 6.36 °, about 9.56 °, about 9.94 °, about 10.41 °, about 10.77 °, about 12.71 °, about 12.89 °, about 17.56 °, about 18.12 °, about 19.09 °, about 19.35 °, about 19.74 °, about 20.83 °, about 23.49 °, and about 24.08 ° 2 θ. In some embodiments, form G of compound 1 is characterized by a powder X-ray diffraction pattern having peaks at about 6.36 °, about 12.71 °, and about 12.89 ° 2 Θ. In one exemplary embodiment, form G of compound 1 is characterized by its X-ray powder diffraction pattern having substantially all of the peaks at the following positions:

in certain embodiments, the present invention provides form H of compound 1. According to one embodiment, form H of compound 1 is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 10.37 °, about 12.81 °, about 19.31 °, about 19.75 °, and about 24.06 ° 2 θ. In some embodiments, form H of compound 1 is characterized by a powder X-ray diffraction pattern having peaks at about 12.81 °, about 19.31 °, and about 24.06 ° 2 Θ. In one exemplary embodiment, form H of compound 1 is characterized by its X-ray powder diffraction pattern having substantially all of the peaks at the following positions:

in certain embodiments, the present invention provides form I of compound 1. According to one embodiment, form I of compound 1 is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 6.73 °, about 8.44 °, about 13.45 °, about 15.27 °, about 17.53 °, about 20.54 °, about 23.95 °, and about 24.49 ° 2 θ. In some embodiments, form I of compound 1 is characterized by a powder X-ray diffraction pattern having peaks at about 6.73 °, about 8.44 °, and about 23.95 ° 2 Θ. In some embodiments, form I of compound 1 is characterized by a powder X-ray diffraction pattern having peaks at about 6.73 °, about 8.44 °, about 17.53 °, and about 23.95 ° 2 Θ. In some embodiments, form I of compound 1 is characterized by a powder X-ray diffraction pattern having peaks at about 6.73 °, about 8.44 °, about 15.27 °, about 17.53 °, and about 23.95 ° 2 Θ. In one exemplary embodiment, form I of compound 1 is characterized by its X-ray powder diffraction pattern having substantially all of the peaks at the following positions:

complex form of compound 1:

compound 1 may also be present in the complex. The term "complex" as used herein refers to a form comprising compound 1 non-covalently bound to a coformer. Such non-covalent binding includes, for example, ionic interactions, dipole-dipole interactions, pi-stacking interactions, hydrogen bonding interactions, and the like. It is to be understood that the term "complex", as used herein, includes salt forms derived from ionic interactions between compound 1 and an acid, as well as non-ionic bonding between compound 1 and a neutral species. Thus, in some embodiments, a "complex" is an inclusion complex, a salt form thereof, a co-crystal, a clathrate, or a hydrate and/or solvate, and the like. In some embodiments, the term "complex" is used to refer to a 1:1 (i.e., stoichiometric) ratio of compound 1 and a co-former. In some embodiments, the term "complex" does not necessarily denote any particular ratio of compound 1 to the coformer. In some embodiments, the complex is in the form of a salt, or a hydrate or solvate thereof. In some embodiments, the complex is in the form of a co-crystal, or a hydrate or solvate thereof. In some embodiments, the complex is an inclusion complex, or a hydrate or solvate thereof. In some embodiments, the complex is a clathrate, or a hydrate or solvate thereof. In some embodiments, the composite is an amorphous solid. In some embodiments, the complex is a crystalline solid. In some embodiments, the complex is in the form of a solution.

In some embodiments, the present invention provides a complex comprising compound 1 and a co-former. In some such embodiments, the coformer is selected from the group consisting of: t-aconitic acid, L-ascorbic acid, aspartic acid, benzoic acid, citric acid, gentisic acid, glutaric acid, 1-hydroxy-2-naphthoic acid, isethionic acid, ketoglutaric acid, L-lysine, maleic acid, malonic acid, methanesulfonic acid, naphthalene-1, 5-disulfonic acid, oxalic acid, phosphoric acid, saccharin, thiocyanic acid, p-toluenesulfonic acid and vanillin.

Accordingly, in some embodiments, the present invention provides a complex comprising compound 1 and a co-former X, wherein X is selected from the group consisting of: t-aconitic acid, L-ascorbic acid, aspartic acid, benzoic acid, citric acid, gentisic acid, glutaric acid, 1-hydroxy-2-naphthoic acid, isethionic acid, ketoglutaric acid, L-lysine, maleic acid, malonic acid, methanesulfonic acid, naphthalene-1, 5-disulfonic acid, oxalic acid, phosphoric acid, saccharin, thiocyanic acid, p-toluenesulfonic acid and vanillin.

In some embodiments, the complex comprising compound 1 and co-former X is referred to herein as compound 2. Thus, in some embodiments, compound 2 comprises compound 1 and a co-former X, wherein X is selected from the group consisting of: t-aconitic acid, L-ascorbic acid, aspartic acid, benzoic acid, citric acid, gentisic acid, glutaric acid, 1-hydroxy-2-naphthoic acid, isethionic acid, ketoglutaric acid, L-lysine, maleic acid, malonic acid, methanesulfonic acid, naphthalene-1, 5-disulfonic acid, oxalic acid, phosphoric acid, saccharin, thiocyanic acid, p-toluenesulfonic acid and vanillin.

In some embodiments, compound 2 is crystalline. In certain such embodiments, the crystalline form of compound 2 (i.e., the complex of compound 1 and co-former X) imparts or may impart characteristics such as improved water solubility, stability, and ease of formulation, as compared to amorphous compound 1 or amorphous compound 2.

According to one embodiment, the present invention provides compound 2 in amorphous form, crystalline form or a mixture thereof. In some embodiments, the present invention provides a mixture of compound 1 and compound 2. In some such embodiments, the mixture comprises form a of compound 1 and compound 2. In some embodiments, the present invention provides a mixture of compound 2 and a co-former. In some embodiments, the present invention provides a mixture comprising compound 1, compound 2, and a co-former. In some such embodiments, compound 1 is form a.

In other embodiments, the present invention provides compound 2 that is substantially free of impurities, such as starting materials, residual solvents, or any other impurities that may result from the preparation and/or isolation of compound 2. In certain embodiments, at least about 90% by weight of compound 2 is present. In certain embodiments, at least about 95% by weight of compound 2 is present. In other embodiments of the invention, at least about 99% by weight of compound 2 is present.

According to one embodiment, compound 2 is present in an amount of at least about 95, 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent, wherein the percentages are based on the total weight of the composition. According to another embodiment, compound 2 contains no more than about 5.0 area% HPLC total organic impurities, in certain embodiments no more than about 3.0 area% HPLC total organic impurities, and in certain embodiments no more than about 1.5 area% HPLC total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 2 contains no more than about 1.0 area% HPLC of any single impurity, no more than about 0.6 area% HPLC of any single impurity, and in certain embodiments no more than about 0.5 area% HPLC of any single impurity, relative to the total area of the HPLC chromatogram.

In some embodiments, the present invention provides compound 2, wherein X is t-aconitic acid ("t-aconitic acid complex"). In some embodiments, the t-aconitic acid complex is crystalline. In some such embodiments, the t-aconitic acid complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 3.91 °, about 7.81 °, about 10.98 °, about 23.58 °, about 23.90 °, about 24.54 °, and about 30.90 ° 2 θ. In some embodiments, the t-aconitic acid complex is characterized by a powder X-ray diffraction pattern having peaks at about 3.91 °, about 7.81 °, about 10.98 °, and about 30.90 ° 2 Θ.

In some embodiments, the present invention provides compound 2, wherein X is L-ascorbic acid ("L-ascorbic acid complex"). In some embodiments, the L-ascorbic acid complex is crystalline. In some such embodiments, the L-ascorbic acid complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 6.79 °, about 14.06 °, about 24.76 °, and about 25.68 ° 2 θ. In some embodiments, the L-ascorbic acid complex is characterized by a powder X-ray diffraction pattern having peaks at about 6.79 °, about 24.76 °, and about 25.68 ° 2 Θ.

In some embodiments, the present invention provides compound 2, wherein X is aspartic acid ("aspartate complex"). In some embodiments, the aspartate complex is crystalline. In some such embodiments, the aspartate complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 6.81 °, about 6.97 °, about 13.63 °, about 13.94 °, about 14.17 °, about 15.21 °, about 15.61 °, about 20.97 °, and about 24.03 ° 2 θ. In some embodiments, the aspartate complex is characterized by a powder X-ray diffraction pattern having peaks at about 6.81 °, about 6.97 °, about 20.97 °, and about 24.03 ° 2 Θ.

In some embodiments, the present invention provides compound 2, wherein X is benzoic acid ("benzoic acid complex"). In some embodiments, the benzoic acid complex is crystalline. In some such embodiments, the benzoic acid complex is characterized by a powder X-ray diffraction pattern having one or more peaks at positions selected from: about 9.94 °, about 10.55 °, about 14.91 °, about 19.90 °, and about 20.38 ° 2 θ. In some embodiments, the benzoic acid composite is characterized by a powder X-ray diffraction pattern having peaks at about 10.55 °, about 14.91 °, and about 19.90 ° 2 Θ.

In some embodiments, the present invention provides compound 2, wherein X is citric acid ("citrate complex"). In some embodiments, the citric acid complex is crystalline. In some such embodiments, the citric acid complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 11.07 °, about 12.97 °, about 14.52 °, about 15.58 °, about 21.30 °, about 22.10 °, about 23.79 °, and about 24.09 ° 2 θ. In some embodiments, the citric acid complex is characterized by a powder X-ray diffraction pattern having peaks at about 11.07 °, about 12.97 °, about 15.58 °, and about 21.30 ° 2 Θ. In an exemplary embodiment, the citric acid complex is characterized by substantially all of its X-ray powder diffraction pattern peaks at about 11.07 °, about 12.97 °, and about 15.58 ° 2 Θ.

In some embodiments, the present invention provides compound 2, wherein X is gentisic acid ("gentisic acid complex"). In some embodiments, the present invention provides form 1 of gentisic acid complex. In some embodiments, form 1 of the gentisic acid complex is crystalline. In some such embodiments, form 1 of the gentisic acid complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 6.65 °, about 13.10 °, about 13.30 °, about 13.49 °, about 14.01 °, about 14.96 °, about 20.03 °, about 24.79 °, and about 25.63 ° 2 θ. In some embodiments, form 1 of the gentisic acid complex is characterized by a powder X-ray diffraction pattern having peaks at about 6.65 °, about 20.03 °, about 24.79 °, and about 25.63 ° 2 Θ.

In some embodiments, the present invention provides form 2 of gentisic acid complex. In some embodiments, form 2 of the gentisic acid complex is crystalline. In some such embodiments, form 2 of gentisic acid complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 8.42 °, about 9.80 °, about 24.74 °, and about 27.60 ° 2 θ. In some embodiments, form 2 of gentisic acid complex is characterized by a powder X-ray diffraction pattern having peaks at about 8.42 °, about 9.80 °, about 24.74 °, and about 27.60 ° 2 Θ.

In some embodiments, the present invention provides compound 2, wherein X is glutaric acid ("glutaric acid complex"). In some embodiments, the glutaric acid complex is crystalline. In some such embodiments, the glutaric acid complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 4.59 °, about 7.15 °, about 11.97 °, about 16.78 °, about 17.49 °, about 37.25 °, and about 37.39 ° 2 θ. In some embodiments, the glutaric acid complex is characterized by a powder X-ray diffraction pattern having peaks at about 4.59 °, about 7.15 °, about 11.97 °, and about 16.78 ° 2 Θ.

In some embodiments, the present invention provides compound 2, wherein X is 1-hydroxy-2-naphthoic acid ("1-hydroxy-2-naphthoic acid complex"). In some embodiments, the present invention provides form 1 of a 1-hydroxy-2-naphthoic acid complex. In some embodiments, form 1 of the 1-hydroxy-2-naphthoic acid complex is crystalline. In some such embodiments, form 1 of the 1-hydroxy-2-naphthoic acid complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 7.40 °, about 9.53 °, about 11.18 °, about 17.24 °, about 22.46 °, about 23.37 °, and about 25.99 ° 2 θ. In some embodiments, form 1 of the 1-hydroxy-2-naphthoic acid complex is characterized by a powder X-ray diffraction pattern having peaks at about 7.40 °, about 9.53 °, about 11.18 °, and about 17.24 ° 2 Θ.

In some embodiments, the present invention provides form 2 of the 1-hydroxy-2-naphthoic acid complex. In some embodiments, form 2 of the 1-hydroxy-2-naphthoic acid complex is crystalline. In some such embodiments, form 2 of the 1-hydroxy-2-naphthoic acid complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 5.09 °, about 7.62 °, about 10.15 °, about 12.12 °, about 12.37 °, about 17.46 °, about 19.46 °, and about 24.04 ° 2 θ. In some embodiments, form 2 of the 1-hydroxy-2-naphthoic acid complex is characterized by a powder X-ray diffraction pattern having peaks at about 5.09 °, about 7.62 °, about 12.12 °, about 12.37 °, about 19.46 °, and about 24.04 ° 2 Θ.

In some embodiments, the present invention provides compound 2, wherein X is isethionic acid ("isethionic acid complex"). In some embodiments, the isethionic acid complex is crystalline. In some such embodiments, the isethionic acid complex is characterized by a powder X-ray diffraction pattern having one or more peaks at positions selected from: about 5.07 °, about 5.77 °, about 6.84 °, about 18.24 °, about 26.72 °, and about 27.35 ° 2 θ. In some embodiments, the isethionic acid complex is characterized by a powder X-ray diffraction pattern having peaks at about 5.07 °, about 5.77 °, about 6.84 °, about 26.72 °, and about 27.35 ° 2 Θ.

In some embodiments, the present invention provides compound 2, wherein X is ketoglutarate ("ketoglutarate complex"). In some embodiments, the ketoglutarate complex is crystalline. In some such embodiments, the ketoglutarate complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 8.31 °, about 9.25 °, about 11.23 °, about 20.08 °, about 25.50 °, about 32.44 °, about 33.12 °, about 33.74 °, and about 37.75 ° 2 θ. In some embodiments, the ketoglutarate complex is characterized by a powder X-ray diffraction pattern having peaks at about 8.31 °, about 9.25 °, about 11.23 °, and about 20.08 ° 2 Θ. In some embodiments, the ketoglutarate complex is characterized by a powder X-ray diffraction pattern having peaks at about 8.31 °, about 9.25 °, about 11.23 °, about 20.08 °, and about 25.50 ° 2 Θ.

In some embodiments, the present invention provides compound 2, wherein X is L-lysine ("L-lysine complex"). In some embodiments, the L-lysine complex is crystalline. In some such embodiments, the L-lysine complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 7.04 °, about 7.64 °, about 14.05 °, about 22.69 °, about 24.58 °, and about 25.80 ° 2 θ. In some embodiments, the L-lysine complex is characterized by a powder X-ray diffraction pattern having peaks at about 7.04 °, about 7.64 °, and about 22.69 ° 2 Θ.

In some embodiments, the present invention provides compound 2, wherein X is maleic acid ("maleic acid complex"). In some embodiments, the maleic acid complex is crystalline. In some such embodiments, the maleic acid complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 8.37 °, about 10.54 °, about 12.07 °, about 13.01 °, about 13.81 °, about 14.84 °, about 19.31 °, about 24.76 °, and about 25.27 ° 2 θ. In some embodiments, the maleic acid complex is characterized by a powder X-ray diffraction pattern having peaks at about 8.37 °, about 10.54 °, about 12.07 °, about 13.01 °, and about 19.31 ° 2 Θ.

In some embodiments, the present invention provides compound 2, wherein X is malonic acid ("malonic acid complex"). In some embodiments, the malonic acid complex is crystalline. In some such embodiments, the malonic acid complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 7.26 °, about 8.51 °, about 11.63 °, about 14.52 °, about 15.52 °, about 15.82 °, about 19.71 °, about 23.38 °, and about 27.98 ° 2 θ. In some embodiments, the malonic acid complex is characterized by a powder X-ray diffraction pattern having peaks at about 7.26 °, about 8.51 °, about 11.63 °, about 14.52 °, about 15.52 °, about 15.82 °, and about 19.71 ° 2 Θ.

In some embodiments, the present invention provides compound 2, wherein X is methanesulfonic acid ("methanesulfonic acid complex"). In some embodiments, the methanesulfonic acid complex is crystalline. In some such embodiments, the methanesulfonic acid complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 5.04 °, about 5.90 °, about 13.08 °, about 21.83 °, about 23.46 °, about 24.08 °, and about 26.02 ° 2 θ. In some embodiments, the methanesulfonic acid complex is characterized by a powder X-ray diffraction pattern having peaks, in terms of 2 Θ, at about 5.04 °, about 5.90 °, about 13.08 °, and about 21.83 °.

In some embodiments, the present invention provides compound 2, wherein X is naphthalene-1, 5-disulfonic acid ("naphthalene-1, 5-disulfonic acid complex"). In some embodiments, the naphthalene-1, 5-disulfonic acid complex is crystalline. In some such embodiments, the naphthalene-1, 5-disulfonic acid complex is characterized by a powder X-ray diffraction pattern having one or more peaks at positions selected from the group consisting of: about 12.02 °, about 20.61 °, about 20.98 °, about 21.25 °, about 22.49 °, and about 24.39 ° 2 θ. In some embodiments, the naphthalene-1, 5-disulfonic acid complex is characterized by a powder X-ray diffraction pattern having peaks at about 12.02 °, about 20.61 °, about 20.98 °, and about 21.25 ° 2 Θ.

In some embodiments, the present invention provides compound 2, wherein X is oxalic acid ("oxalic acid complex"). In some embodiments, the oxalic acid complex is crystalline. In some such embodiments, the oxalic acid complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 11.14 °, about 20.52 °, about 21.22 °, about 23.13 °, about 24.08 °, and about 24.67 ° 2 θ. In some embodiments, the oxalic acid composite is characterized by a powder X-ray diffraction pattern having peaks at about 11.14 °, about 20.52 °, about 24.08 °, and about 24.67 ° 2 Θ. In an exemplary embodiment, the oxalic acid complex is characterized by substantially all of the peaks in its X-ray powder diffraction pattern at about 11.14 °, about 24.08 °, and about 24.67 ° 2 Θ.

In some embodiments, the present invention provides compound 2, wherein X is phosphoric acid ("phosphate complex"). In some embodiments, the phosphate complex is crystalline. In some such embodiments, the phosphoric acid complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 6.79 °, about 7.08 °, about 7.39 °, about 9.93 °, about 11.95 °, about 14.18 °, and about 14.88 ° 2 θ. In some embodiments, the phosphoric acid complex is characterized by a powder X-ray diffraction pattern having peaks at about 6.79 °, about 7.08 °, about 7.39 °, about 9.93 °, and about 11.95 ° 2 Θ.

In some embodiments, the present invention provides compound 2, wherein X is saccharin ("saccharin complex"). In some embodiments, the saccharin complex is crystalline. In some such embodiments, the saccharin complex is characterized by a powder X-ray diffraction pattern having one or more peaks at positions selected from those of: about 6.82 °, about 10.24 °, about 20.53 °, and about 24.63 ° 2 θ. In some embodiments, the saccharin complex is characterized by a powder X-ray diffraction pattern having peaks at about 6.82 °, about 10.24 °, and about 20.53 ° 2 Θ.

In some embodiments, the present invention provides compound 2, wherein X is thiocyanic acid ("thiocyanic acid complex"). In some embodiments, the thiocyanate complex is crystalline. In some such embodiments, the thiocyanate complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from those of: about 6.86 °, about 6.95 °, about 14.17 °, about 25.80 ° 2 θ.

In some embodiments, the present invention provides compound 2, wherein X is p-toluenesulfonic acid ("p-toluenesulfonic acid complex"). In some embodiments, the toluenesulfonic acid complex is crystalline. In some such embodiments, the p-toluenesulfonic acid complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 6.49 °, about 9.65 °, about 10.00 °, about 13.22 °, about 19.99 °, about 23.55 °, about 23.79 °, and about 27.56 ° 2 θ. In some embodiments, the p-toluenesulfonic acid complex is characterized by having peaks in its powder X-ray diffraction pattern at about 6.49 °, about 9.65 °, about 10.00 °, and about 13.22 ° 2 Θ.

In some embodiments, the present invention provides compound 2, wherein X is vanillin ("vanillin complex"). In some embodiments, the vanillin complex is crystalline. In some such embodiments, the vanillin complex is characterized by having one or more peaks in its powder X-ray diffraction pattern at positions selected from: about 10.93 °, about 11.43 °, about 11.58 °, about 12.22 °, about 14.42 °, about 15.45 °, about 17.28 °, about 22.89 °, about 23.53 °, and about 23.77 ° 2 θ. In some embodiments, the vanillin complexes are characterized by a powder X-ray diffraction pattern having peaks at about 10.93 °, about 11.43 °, about 11.58 °, about 14.42 °, about 15.45 °, and about 17.28 ° 2 Θ. In an exemplary embodiment, the vanillin complex is characterized by substantially all peaks at about 11.43 °, about 11.58 °, about 14.42 °, about 15.45 °, and about 17.28 ° 2 Θ in its X-ray powder diffraction pattern.

General methods for providing compound 1 and compound 2:

compound 1 was prepared according to the methods described in detail in the' 463 application, which is incorporated herein by reference in its entirety. Various crystalline forms of compound 1 can be prepared by dissolving compound 1 in various suitable solvents and then returning compound 1 to the solid phase. The specific combination of solvent and conditions for returning compound 1 to the solid phase is discussed in more detail in the examples.

Suitable solvents may partially or completely dissolve compound 1. Examples of suitable solvents that can be used in the present invention are protic solvents, polar aprotic solvents or mixtures thereof. In certain embodiments, suitable solvents include ethers, esters, alcohols, ketones, or mixtures thereof. In certain embodiments, a suitable solvent is methanol, ethanol, Isopropanol (IPA), or acetone, wherein the solvent is anhydrous or used in combination with water, methyl tert-butyl ether (MTBE), or heptane. In other embodiments, suitable solvents include methyl acetate, isopropyl acetate, toluene, Tetrahydrofuran (THF), 1, 4-dioxane, Dimethylformamide (DMF), Dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), glyme, diglyme, methyl ethyl ketone, N-methyl-2-pyrrolidone, 2-methyltetrahydrofuran, methyl tert-butyl ether, tert-butyl alcohol, N-butyl alcohol, and acetonitrile.

According to one embodiment, the present invention provides a method of preparing a crystalline form of compound 1 comprising the steps of dissolving compound 1 in a suitable solvent, optionally heating to form a solution thereof, and isolating compound 1. In some embodiments, compound 1 is prepared by equilibration in a suitable solvent. In some such embodiments, compound 1 is dissolved in a suitable solvent and the solution is stirred at room temperature for a period of time, e.g., 1 day. In some embodiments, the sample is then gently heated (e.g., at 50 ℃) for a period of time, e.g., 1 day. Compound 1 can then be isolated by removing the supernatant (e.g., by filtration).

In some embodiments, compound 1 is prepared by evaporation of a suitable solvent. In some embodiments, compound 1 is dissolved in a suitable solvent and the solvent is allowed to evaporate. In some embodiments, the solvent is THF. In some embodiments, the solvent is THF/water. In some embodiments, the solvent is Dichloromethane (DCM). In some embodiments, the solvent is ethanol. In some embodiments, the solvent is ethanol/water.

In some embodiments, compound 1 is recrystallized in a solvent/anti-solvent system. In some embodiments, compound 1 is dissolved in a suitable solvent and the solution is then added to the anti-solvent. Anti-solvents that may be used for recrystallization of compound 1 include acetone, Acetonitrile (ACN), isopropanol, heptane, methyl acetate, toluene, and water. The mixture may be cooled and compound 1 isolated, for example, by filtration. In some embodiments, the solvent is DMSO and the anti-solvent is ACN. In some embodiments, the solvent is DMSO and the anti-solvent is IPA. In some embodiments, the solvent is DMSO and the anti-solvent is water.

Compound 1 is dissolved in a suitable solvent, optionally with heating, as generally described above. In certain embodiments, compound 1 is dissolved at about 50 to about 60 ℃. In other embodiments, compound 1 is dissolved at about 50 to about 55 ℃. In other embodiments, compound 1 is dissolved at the boiling temperature of the solvent. In other embodiments, compound 1 is soluble without heating (e.g., about 20-25 ℃ at ambient temperature).

In some embodiments, the present invention provides a method for preparing a crystalline form of compound 1, comprising dissolving compound 1 in a suitable solvent, optionally heating to form a solution thereof, and isolating compound 1. In some embodiments, a method for preparing a crystalline form of compound 1 comprises (a) dissolving compound 1 in a suitable solvent to form a mixture, (b) heating the mixture from step (a) to form a solution of compound 1, (c) allowing the solution to cool, and (d) isolating the crystalline form of compound 1.

In some embodiments, the present invention provides a process for preparing the anhydrate form of compound 1 comprising dissolving compound 1 in a suitable solvent in the presence of the anhydrate form of compound 1, optionally heating to form a solution thereof, and isolating compound 1.

In some embodiments, the present invention provides a process for preparing the anhydrate form of compound 1 comprising dissolving a hydrate or solvate of compound 1 in a suitable solvent in the presence of the anhydrate form of compound 1, optionally heating to form a solution thereof, and isolating compound 1.

In some embodiments, the present invention provides a process for preparing form a of compound 1, comprising dissolving a solvate of compound 1 in a suitable solvent in the presence of form a of compound 1, optionally heating to form a solution thereof, and isolating compound 1. In some embodiments, a method for preparing a crystalline form of compound 1 comprises (a) dissolving compound 1 in a suitable solvent, (b) heating the mixture from step (a) to form a solution of compound 1, (c) contacting the solution with form a of compound 1, (d) cooling the solution in the presence of form a of compound 1, and (e) isolating the crystalline form of compound 1.

In some embodiments, the present invention provides a process for preparing form a of compound 1, comprising dissolving form I of compound 1 in a suitable solvent in the presence of form a of compound 1, optionally heating to form a solution thereof, and isolating compound 1. In some embodiments, a method for preparing a crystalline form of compound 1 comprises (a) dissolving form I compound 1 in a suitable solvent, (b) heating the mixture from step (a) to form a solution of compound 1, (c) contacting the solution with form a of compound 1, (d) cooling the solution in the presence of form a of compound 1, and (e) isolating form a of compound 1.

In some embodiments, the present invention provides a method for preparing compound 2, comprising the steps of dissolving compound 1 in a suitable solvent, adding a coformer to the solution, optionally heating to form a solution thereof, and isolating compound 2.

In some embodiments, compound 2 is prepared by: compound 1 is dissolved in a suitable solvent, the coformer is added to the solution, and the solvent is evaporated. In some embodiments, the solvent is allowed to evaporate at room temperature.

In some embodiments, compound 2 is prepared by: compound 1 is slurried in a solution of the co-former in a suitable solvent and compound 2 is isolated. In some embodiments, compound 2 is prepared by: grinding compound 1 in a solution of a co-former in a suitable solvent, and isolating compound 2. In some embodiments, compound 2 is prepared by: dissolving compound 1 in a suitable solvent, adding the coformer, cooling the solution, and isolating compound 2.

In certain embodiments, compound 1 or compound 2 is precipitated from the mixture. In another embodiment, compound 1 or compound 2 is crystallized from a mixture. In other embodiments, compound 1 or compound 2 is crystallized from solution after seeding of the solution (i.e., addition of crystals of compound 1 or compound 2 to the solution).

Crystalline compound 1 or compound 2 can be precipitated from the reaction mixture or generated by: some or all of the solvent is removed by methods such as evaporation, distillation, filtration (e.g., nanofiltration, ultrafiltration), reverse osmosis, absorption, and reaction, by addition of an anti-solvent (e.g., water, MTBE, and/or heptane), by cooling (e.g., rapid cooling), or by various combinations of these methods.

Compound 1 or compound 2 is optionally isolated as generally described above. It is understood that compound 1 or compound 2 can be isolated by any suitable physical means known to those of ordinary skill in the art. In certain embodiments, the precipitated solid compound 1 or compound 2 is separated from the supernatant by filtration. In other embodiments, the precipitated solid compound 1 or compound 2 is separated from the supernatant by decanting the supernatant.

In certain embodiments, the precipitated solid compound 1 or compound 2 is isolated from the supernatant by filtration.

In certain embodiments, the isolated compound 1 or compound 2 is dried in air. In other embodiments, the isolated compound 1 or compound 2 is dried under reduced pressure, optionally at elevated temperature.

Use, formulation and administration

Pharmaceutically acceptable compositions

According to another embodiment, the present invention provides a composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, the amount of the compound in the compositions of the invention is such that it is effective to measurably inhibit MK2 or a mutant thereof in a biological sample or patient. In certain embodiments, the compositions of the present invention are formulated for administration to a patient in need of such compositions. In some embodiments, the compositions of the present invention are formulated for oral administration to a patient.

The compounds and compositions according to the methods of the present invention are administered in any amount and by any route of administration effective to treat or reduce the severity of the condition provided herein (i.e., an MK2 mediated disease or condition). The precise amount required will vary with each subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the present invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage.

The compositions of the invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intracisternally or via an implanted reservoir. In some embodiments, the composition is administered orally, intraperitoneally, or intravenously.

The sterile injectable form of the composition of the invention may be an aqueous or oily suspension. These suspensions may be formulated according to the techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as tweens (Tween), spans (Span) and other emulsifiers or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for formulation purposes.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporation of a bactericidal agent, in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of the compounds of the invention, it is generally desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. In addition, the rate of absorption of a compound depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered compound is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by embedding the compounds in liposomes or microemulsions which are compatible with body tissues.

In some embodiments, the provided pharmaceutically acceptable compositions are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without a food product. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with a food product.

The pharmaceutically acceptable compositions of the present invention may be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are desired for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

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

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose (lactose/milk sugar) and high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shell layers such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also have the following composition: said composition being such that they release the active ingredient, optionally in a delayed manner, only in or preferentially in certain parts of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycols and the like.

The active compound may also be present in microencapsulated form together with one or more of the excipients mentioned above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch. As in general practice, such dosage forms may also contain other substances in addition to inert diluents, for example tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also have a composition such that they release the active ingredient(s) only, or preferentially, in certain parts of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These suppositories can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

The pharmaceutically acceptable compositions of the present invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical administration, including diseases of the eye, skin or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical administration for the lower intestinal tract may be effected in the form of rectal suppository formulations (see above) or in suitable enema formulations. Topical transdermal patches may also be used.

For topical administration, the provided pharmaceutically acceptable compositions can be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the provided pharmaceutically acceptable compositions can be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ocular use, the provided pharmaceutically acceptable compositions can be formulated in the following forms with or without preservatives, such as benzalkonium chloride (benzalkonium chloride): a micronized suspension in isotonic pH adjusted sterile saline, or preferably a solution in isotonic pH adjusted sterile saline. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions may be formulated as ointments (e.g., petrolatum).

The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers as may be required. Ophthalmic formulations, ear drops and eye drops are also encompassed within the scope of the present invention. Furthermore, the present invention encompasses the use of transdermal patches that have the additional advantage of controllably delivering compounds to the body. Such dosage forms may be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Use of compounds and pharmaceutically acceptable compositions

The compounds and compositions described herein are generally useful for inhibiting the kinase activity of one or more enzymes. Examples of kinases that are inhibited by the compounds and compositions described herein and against which the methods described herein are suitable include MK2 or mutants thereof.

The activity of a compound used in the present invention as an inhibitor of MK2 kinase or a mutant thereof can be determined in vitro, in vivo, or in a cell line. In vitro assays include the following: measuring inhibition of phosphorylation activity and/or subsequent functional outcome, or inhibition of ATPase activity of activated MK2 kinase or a mutant thereof. An alternative in vitro assay quantifies the ability of a test compound to bind MK 2. Inhibitor binding can be measured by radiolabelling the test compound prior to binding, isolating the test compound/MK 2 complex, and determining the amount of bound radiolabel. Alternatively, inhibitor binding can be determined by performing a competition experiment in which a test compound is incubated with MK2 kinase bound to a known radioligand. The detailed conditions for determining compounds useful as inhibitors of MK2 or a mutant thereof in the present invention are described in detail in example 136-138 of the' 463 application.

According to one embodiment, the present invention relates to a method of inhibiting protein kinase activity in a biological sample comprising the step of contacting said biological sample with a compound of the present invention or a composition comprising said compound.

According to another embodiment, the present invention relates to a method of inhibiting MK2 kinase or mutant activity thereof in a biological sample comprising the step of contacting said biological sample with a compound of the present invention or a composition comprising said compound. In certain embodiments, the present invention relates to methods of irreversibly inhibiting MK2 kinase or mutant activity thereof in a biological sample comprising the step of contacting the biological sample with a compound of the invention or a composition comprising the compound.

According to another embodiment, the present invention relates to a method of inhibiting MK2 kinase or mutant activity thereof in a patient comprising the step of administering to said patient a compound of the present invention or a composition comprising said compound. According to certain embodiments, the present invention relates to a method of irreversibly inhibiting MK2 kinase or mutant activity thereof in a patient, comprising the step of administering to the patient a compound of the present invention or a composition comprising the compound. In other embodiments, the present invention provides a method for treating an MK 2-mediated disease or disorder in a patient in need thereof, comprising the step of administering to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

MK2 kinase

MAP kinase activating protein kinase 2 ("MK 2") is an enzyme encoded by the MAPKAPK2 gene in humans. The MAPKAPK2 gene encodes a member of the Ser/Thr protein kinase family, and two transcriptional variants have been found that encode two distinct isoforms. MK2 is regulated by direct phosphorylation of p38MAP kinase.

MK2 is a multi-domain protein consisting of an N-terminal proline-enriching domain, a catalytic domain, a self-inhibitory domain, and a C-terminal Nuclear Export Signal (NES) and Nuclear Localization Signal (NLS). Two isoforms of human MK2 have been characterized. One isoform consists of 400 amino acids and the other consists of 370 residues, which are considered splice variants lacking the C-terminal NLS.

MK2 is known to be involved in many cellular processes, including stress and inflammatory responses, nuclear export, regulation of gene expression, and cell proliferation. Indeed, MK2 regulates the biosynthesis of tumor necrosis factor α (TNF α) by a post-transcriptional mechanism, which is overproduced in inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. See Natesan et al, j.med.chem.2012, 55, 2035-.

The compounds of the present invention have been shown to inhibit the phosphorylation of heat shock protein 27(Hsp 27). See example 138 of the' 463 application. Inhibition of Hsp27 phosphorylation occurs by inhibiting the formation of the p38 kinase-MK 2-Hsp27 signaling complex. Phosphorylation of Hsp27 is the penultimate event in a complex signaling cascade that occurs in response to extracellular stimuli. See Zheng et al, The Journal of Biological Chemistry, Vol.281, No. 48, 37215-37226, 2006, 12/1/2006. Hsp27 is generally present in oligomeric forms and plays a role in the regulation of many cellular functions, such as inhibiting death receptor-mediated apoptosis, promoting proper refolding of denatured proteins by acting as a chaperone, and modulating the cytoskeleton. The presence of MK2 is a prerequisite for the formation of a p38 kinase-MK 2-Hsp27 signaling complex in a cell. See Zheng et al, The Journal of Biological Chemistry, Vol.281, No. 48, 37215-37226, 2006, 12/1/2006.

Evidence suggests that many signal transduction proteins form multimeric complexes. See Zheng et al, The journal Biological Chemistry, Vol.281, No. 48, 37215-37226, 1/12/2006. One such complex is Hsp27/Akt (a serine/threonine kinase) dimer, which forms in the cytoplasm of cells. Another complex is formed between MK2 and p 38. See Ben-Levy et al, Current Biology 1998, 8: 1049-; natesan et al, j.med.chem.2012, 55, 2035-; zheng et al, The Journal of biological chemistry, Vol.281, No. 48, No. 37215-37226, 2006, 12/1/2006.

Under unstimulated conditions, inactive p38 and unphosphorylated MK2 form this dimer in the nucleus. Upon activation, p38 phosphorylates MK2, causing a conformational change in the MK2 self-inhibitory domain, and exposing the active site for substrate binding. Once MK2 is phosphorylated, the p38-MK2 dimer translocates to the cytoplasm and forms a quaternary complex with Hsp27-Akt dimer here. See Zheng et al, The Journal of Biological Chemistry, Vol.281, No. 48, 37215-37226, 2006, 12/1/2006. Hsp27 is then phosphorylated by MK2, resulting in the degradation of the quaternary complex and the release of p-Hsp27 monomers and dimers. Without wishing to be bound by theory, since inhibition of MK2 prevents phosphorylation of Hsp27, it is believed that inhibition of MK2 prevents degradation of the p38-MK2-Akt-Hsp27 quaternary complex, thereby altering downstream effects. The amount of quaternary complex will increase as the degradation of quaternary complex is inhibited. Furthermore, the balance between cytoplasm and nucleus of p38 and MK2 will shift towards cytoplasm.

Interestingly, the MK2/p38 complex does not require catalytically active MK2 for transport out of the nucleus, since the active site mutant Asp207Ala is still transported into the cytoplasm. Phosphorylation of human MK2 by p38 at residues T222, S272, and T334 is thought to activate the enzyme by causing a conformational change in the self-inhibitory domain, thereby exposing the active site for substrate binding. Mutations in the two self-inhibitory domain residues W332A and K326E in murine MK2 confirmed an increase in basal activity, and deletion of the C-terminus of the self-inhibitory domain rendered the enzyme constitutively active, thereby providing additional evidence of the role of this domain in inhibiting MK2 activity.

Diseases or disorders associated with MK2 treated by the compounds of the invention include autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplasias, or cardiovascular or cerebrovascular disorders. Accordingly, in some embodiments, the present invention provides a method for treating an MK 2-mediated disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a provided compound or composition thereof. Such MK 2-mediated diseases or disorders include, but are not limited to, those described herein.

In some embodiments, the MK 2-mediated disease or disorder is an autoimmune disorder, a chronic and/or acute inflammatory disorder, and/or an autoinflammatory disorder. Exemplary autoimmune and/or inflammatory and/or autoinflammatory disorders include: inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease), multiple sclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis, juvenile arthritis, psoriatic arthritis, reactive arthritis, ankylosing spondylitis, cryptotropin-associated periodic syndrome, Muckle-Wells syndrome (Muckle-Wells syndrome), familial cold-induced autoinflammatory syndrome, neonatal onset multisystem inflammatory disease, TNF receptor-associated periodic syndrome, acute and chronic pancreatitis, atherosclerosis, gout, ankylosing spondylitis, fibrotic disorders (e.g., liver fibrosis or idiopathic pulmonary fibrosis), nephropathy, sarcoidosis, scleroderma, anaphylaxis, diabetes (e.g., type 1 diabetes or type 2 diabetes), diabetic retinopathy, Still's disease (Still's disease), Vasculitis, sarcoidosis, pulmonary inflammation, acute respiratory distress syndrome, wet and dry age-related macular degeneration, autoimmune hemolytic syndrome, autoimmune diseaseAnd inflammatory hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune testosterone, autoimmune thrombocytopenia, autoimmune diseases associated with silicone implantation, Sjogren's syndrome, familial mediterranean fever, systemic lupus erythematosus, vasculitis syndromes (e.g., temporal arteritis, Takayasu's arteritis and giant cell arteritis), Behcet's disease

disease) or Wegener's granulomatosis (Wegener's granulomatosis)), vitiligo, secondary blood manifestations of autoimmune disease (e.g. anemia), drug-induced autoimmunity, Hashimoto's thyroiditis, hypophysitis, idiopathic thrombocytopenic purpura, metal-induced autoimmunity, myasthenia gravis, pemphigus, autoimmune deafness (e.g. Meniere's disease), Goodpasture's syndrome, Graves ' disease, HW-related autoimmune syndrome, Guillain-Barre disease, Addison's disease, antiphospholipid syndrome, asthma, atopic dermatitis, chyle, Cushing's syndrome, idiopathic dermatomyositis, idiopathic thrombocytopenia, adrenocortical syndrome (Kawasaki's syndrome), hypophysitis, hypophysia, acanthosis, hypophysia, and hypophysia, Lambert-Eaton Syndrome (Lambert-Eaton Syndrome), pernicious anemia, pollinosis, polyarteritis nodosa, primary biliary cirrhosis, primary sclerosing cholangitis, Raynaud's disease, Reiter's Syndrome, recurrent polychondritis, Schmidt's Syndrome, thyrotoxicosis, sepsis, septic shock, endotoxic shock, exotoxin-induced toxic shock, exotoxin-negative sepsis, toxic shock Syndrome, glomerulonephritis, peritonitis, interstitial cystitis, hyperoxia-induced inflammation, Chronic Obstructive Pulmonary Disease (COPD), vasculitis, graft-versus-host reaction (e.g., graft-versus-host disease), allograft rejection (e.g., acute allograft rejection or chronic allograft rejection-versus-gram-negative sepsis), inflammatory bowel Syndrome (e.g., acute COPD), chronic inflammatory bowel Syndrome (COPD), and inflammatory bowel Syndrome (e.g., chronic inflammatory bowel Syndrome (ra-versus-host disease)Should), early graft rejection (e.g., acute allograft rejection), reperfusion injury, pain (e.g., acute pain, chronic pain, neuralgia or muscle fiber pain), chronic infection, meningitis, encephalitis, myocarditis, gingivitis, post-operative trauma, tissue damage, traumatic brain injury, enterocolitis, sinusitis, uveitis, ophthalmia, optic neuritis, gastric ulcer, esophagitis, peritonitis, periodontitis, dermatomyositis, gastritis, myositis, polymyalgia, pneumonia and bronchitis.

In some embodiments, the MK 2-mediated disease or disorder is a fibrotic disorder. Exemplary fibrotic conditions include systemic sclerosis/scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical scarring, spinal cord injury, CNS scarring, acute lung injury, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, chronic kidney disease (e.g., diabetic nephropathy), hypertension-induced kidney disease, digestive or gastrointestinal fibrosis, renal fibrosis, liver or biliary fibrosis, liver fibrosis (e.g., non-alcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), liver cirrhosis (e.g., primary biliary cirrhosis or liver cirrhosis caused by fatty liver disease (e.g., alcoholic and non-alcoholic steatodegeneration)), radiation-induced fibrosis (e.g., head and neck fibrosis, liver cirrhosis, liver fibrosis, liver, Gastrointestinal tract or lung), primary sclerosing cholangitis, restenosis, cardiac fibrosis (e.g. endocardial myocardial fibrosis or atrial fibrosis), ophthalmic scar, fibrosclerosis, fibrotic cancer, fibromatosis (fibroids), fibromas, fibroadenomas, fibrosarcoma, graft arteriopathy, keloids, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis and nephrogenic systemic fibrosis.

In some embodiments, the MK 2-mediated disease or disorder is a metabolic disorder. Exemplary metabolic disorders include obesity, steroid resistance, glucose intolerance, and metabolic syndrome.

In some embodiments, the MK 2-mediated disease or disorder is neoplasia. Exemplary neoplasias include cancer. In some embodiments, exemplary neoplasias include angiogenic disorders, multiple myeloma, leukemias (e.g., acute lymphocytic leukemia, acute and chronic myelogenous leukemias, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or promyelocytic leukemia), lymphomas (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma, mast cell tumors, hodgkin's disease or non-hodgkin's disease), myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, glioma, and schwannoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular cancer, Kaposi's sarcoma (karcosi's sarcoma), melanoma, and lymphomas, Teratomas, rhabdomyosarcomas, metastatic and skeletal disorders, as well as cancers of the bone, mouth/throat, esophagus, larynx, stomach, intestine, colon, rectum, lung (e.g., non-small cell lung cancer or small cell lung cancer), liver, pancreas, nerves, brain (e.g., glioma or glioblastoma multiforme), head and neck, throat, ovary, uterus, prostate, testes, bladder, kidney, breast, gall bladder, cervix, thyroid, prostate and skin.

In some embodiments, the MK 2-mediated disorder is a cardiovascular or cerebrovascular disorder. Exemplary cardiovascular disorders include atherosclerosis, restenosis of atherosclerotic coronary arteries, acute coronary syndrome, myocardial infarction, cardiac allograft vasculopathy, and stroke. Exemplary cerebrovascular diseases include central nervous system disorders with inflammatory or apoptotic components, alzheimer's disease, parkinson's disease, huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, neuronal ischemia, and peripheral neuropathy.

All features of each aspect of the invention are applicable to all other aspects mutatis mutandis.

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

Examples

As described in the examples below, in certain exemplary embodiments, the compounds are prepared according to the following general procedure. It is to be understood that while general methods describe the synthesis of certain compounds of the invention, the following general methods, as well as other methods known to those of ordinary skill in the art, can be applied to all compounds as described herein, as well as to the subclasses and species of each of these compounds.